JP2000063277A - Crf receptor antagonist - Google Patents
Crf receptor antagonistInfo
- Publication number
- JP2000063277A JP2000063277A JP10228329A JP22832998A JP2000063277A JP 2000063277 A JP2000063277 A JP 2000063277A JP 10228329 A JP10228329 A JP 10228329A JP 22832998 A JP22832998 A JP 22832998A JP 2000063277 A JP2000063277 A JP 2000063277A
- Authority
- JP
- Japan
- Prior art keywords
- group
- carbon atoms
- substituted
- alkyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000002769 corticotropin releasing factor antagonist Substances 0.000 title claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 125000005843 halogen group Chemical group 0.000 claims abstract description 17
- 239000004480 active ingredient Substances 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 9
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 6
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 6
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- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
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- YAMQOOCGNXAQGW-UHFFFAOYSA-M magnesium;methylbenzene;bromide Chemical compound [Mg+2].[Br-].CC1=CC=CC=[C-]1 YAMQOOCGNXAQGW-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- FSUMZUVANZAHBW-UHFFFAOYSA-N n,n-dimethoxyaniline Chemical compound CON(OC)C1=CC=CC=C1 FSUMZUVANZAHBW-UHFFFAOYSA-N 0.000 description 1
- FZGZXFYZQCOJCH-UHFFFAOYSA-N n-ethyl-2-methylsulfanyl-4-propan-2-ylaniline Chemical compound CCNC1=CC=C(C(C)C)C=C1SC FZGZXFYZQCOJCH-UHFFFAOYSA-N 0.000 description 1
- LLPNQJXSRDEPCF-UHFFFAOYSA-N n-ethyl-4-methyl-6-[5-(2-methylphenyl)-3,6-dihydro-2h-pyridin-1-yl]-n-(2-methylsulfanyl-4-propan-2-ylphenyl)pyrimidin-2-amine;hydrochloride Chemical compound Cl.C=1C=C(C(C)C)C=C(SC)C=1N(CC)C(N=1)=NC(C)=CC=1N(C1)CCC=C1C1=CC=CC=C1C LLPNQJXSRDEPCF-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- USISRUCGEISZIB-UHFFFAOYSA-N piperidin-3-one Chemical compound O=C1CCCNC1 USISRUCGEISZIB-UHFFFAOYSA-N 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- SAALQYKUFCIMHR-UHFFFAOYSA-N propan-2-ol;2-propan-2-yloxypropane Chemical compound CC(C)O.CC(C)OC(C)C SAALQYKUFCIMHR-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RIFXIGDBUBXKEI-UHFFFAOYSA-N tert-butyl 3-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(=O)C1 RIFXIGDBUBXKEI-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、4−テトラヒドロ
ピリジルピリミジン誘導体又はその医薬上許容される塩
を有効成分とするCRF受容体拮抗薬に関する。TECHNICAL FIELD The present invention relates to a CRF receptor antagonist containing a 4-tetrahydropyridylpyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
【0002】[0002]
【従来の技術】CRF(副腎皮質刺激ホルモン放出因
子)は41個のアミノ酸から成るホルモンであり(Scien
ce, 213, 1394-1397,1981; J. Neurosci., 7, 88-100,
1987)、ストレスに対する生体反応の中核的役割を果た
していることが示唆されている(Cell. Mol. Neurobio
l., 14, 579-588,1994; Endocrinol., 132, 723-728, 1
994; Neuroendocrinol., 61, 445-452, 1995)。CRF
は視床下部−下垂体−副腎系を介して末梢の免疫系、交
感神経系に作用する経路と中枢神経系において神経伝達
物質として機能する2つの経路がある(in Corticotrop
in Releasing Factor:Basic and Clinical Studies of
a Neuropeptide, pp 29-52, 1990 )。下垂体除去ラッ
ト及び正常ラットにCRFを脳室内投与すると両ラット
で不安様症状(Pharmacol. Rev., 43, 425-473, 1991;
Brain Res. Rev., 15, 71-100, 1990 )が惹起される。
すなわち、CRFは視床下部−下垂体−副腎系に対する
関与と中枢神経系において神経伝達物質として機能する
経路が考えられる。CRF (corticotropin releasing factor) is a hormone consisting of 41 amino acids (Scien
ce, 213, 1394-1397,1981; J. Neurosci., 7, 88-100,
1987), it has been suggested that it plays a central role in the biological response to stress (Cell. Mol. Neurobio
l., 14, 579-588, 1994; Endocrinol., 132, 723-728, 1
994; Neuroendocrinol., 61, 445-452, 1995). CRF
Has a pathway that acts on the peripheral immune system and the sympathetic nervous system via the hypothalamus-pituitary-adrenal system and two pathways that function as neurotransmitters in the central nervous system (in Corticotropin).
in Releasing Factor: Basic and Clinical Studies of
a Neuropeptide, pp 29-52, 1990). When CRF was intraventricularly administered to pituitary-depleted rats and normal rats, anxiety-like symptoms were observed in both rats (Pharmacol. Rev., 43, 425-473, 1991;
Brain Res. Rev., 15, 71-100, 1990).
That is, CRF may be involved in the hypothalamus-pituitary-adrenal system and a pathway that functions as a neurotransmitter in the central nervous system.
【0003】CRFが関与する疾患は1991年 Owens
及び Nemeroff の総説(Pharmacol.Rev., 43, 425-474,
1991)にまとめられている。すなわち、うつ症、不安
症、アルツハイマー病、パーキンソン病、ハンチントン
舞踏病、摂食障害、高血圧、消化器疾患、薬物依存症、
炎症、免疫関連疾患などにCRFが関与している。最近
はてんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷にもC
RFが関与していることが報告されている(Brain Re
s., 545, 339-342, 1991; Ann. Neurol., 31, 488-494,
1992; Dev. Brain Res., 91, 245-251, 1996; Brain R
es., 744, 166-170,1997 )。Diseases associated with CRF are Owens, 1991.
And Nemeroff's review (Pharmacol. Rev., 43, 425-474,
1991). That is, depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, digestive disorders, drug addiction,
CRF is involved in inflammation, immune-related diseases and the like. Recently, C has been used for epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, and head injury.
It has been reported that RF is involved (Brain Re
s., 545, 339-342, 1991; Ann. Neurol., 31, 488-494,
1992; Dev. Brain Res., 91, 245-251, 1996; Brain R
es., 744, 166-170, 1997).
【0004】このようにCRF受容体拮抗薬は、うつ
症、不安症、アルツハイマー病、パーキンソン病、ハン
チントン舞踏病、摂食障害、高血圧、消化器疾患、薬物
依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外
傷、炎症、免疫関連疾患などCRFが関与しているとさ
れる疾患の治療剤又は予防剤としての有用性が期待され
る。As described above, CRF receptor antagonists include depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, digestive disorders, drug addiction, epilepsy, cerebral infarction, cerebral dysfunction. It is expected to be useful as a therapeutic or prophylactic agent for diseases associated with CRF such as blood, cerebral edema, head injury, inflammation and immune related diseases.
【0005】[0005]
【発明が解決しようとする課題】本発明の目的は、親和
性及び特異性がともに優れたCRF受容体拮抗薬を提供
することにある。The object of the present invention is to provide a CRF receptor antagonist having excellent affinity and specificity.
【0006】[0006]
【課題を解決するための手段】本発明者らは、4−テト
ラヒドロピリジルピリミジン誘導体について鋭意検討し
た結果、CRF受容体に高い親和性を示す4−テトラヒ
ドロピリジルピリミジン誘導体を見出し、本発明を完成
した。以下、本発明を説明する。本発明は、以下の発明
を包含する。
(1)式[I]Means for Solving the Problems As a result of intensive studies on 4-tetrahydropyridylpyrimidine derivatives, the present inventors have found 4-tetrahydropyridylpyrimidine derivatives having high affinity for CRF receptors, and completed the present invention. . The present invention will be described below. The present invention includes the following inventions. (1) Formula [I]
【0007】[0007]
【化2】 [Chemical 2]
【0008】(式中、Arはハロゲン原子、炭素数1〜
5のアルキル基、炭素数1〜5のアルコキシ基及びトリ
フルオロメチル基から選択された1〜3個で置換された
フェニル基、フェニル基、チエニル基又はフリル基を示
し、R1 は水素原子、炭素数1〜5のアルキル基、アミ
ノ基又は1若しくは2個の炭素数1〜5のアルキル基で
置換されたアミノ基を示し、R2 は炭素数1〜5のアル
キル基、炭素数4〜7のシクロアルキルアルキル基、炭
素数2〜5のアルケニル基又は炭素数2〜5のアルキニ
ル基を示し、X1 、X2 及びX3 は同一又は異なって水
素原子、ハロゲン原子、炭素数1〜5のアルキル基、炭
素数1〜5のアルコキシ基、炭素数1〜5のアルキルチ
オ基、アミノ基又は1若しくは2個の炭素数1〜5のア
ルキル基で置換されたアミノ基を示す。)で表される4
−テトラヒドロピリジルピリミジン誘導体又はその医薬
上許容される塩を有効成分とするCRF受容体拮抗薬。(In the formula, Ar represents a halogen atom and has 1 to 1 carbon atoms.
5 represents an alkyl group having 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, and a phenyl group substituted by 1 to 3 selected from a trifluoromethyl group, a phenyl group, a thienyl group or a furyl group, and R 1 represents a hydrogen atom, A C1-C5 alkyl group, an amino group, or an amino group substituted by 1 or 2 C1-C5 alkyl groups is shown, R < 2 > is a C1-C5 alkyl group, C4-C4. 7 is a cycloalkylalkyl group, an alkenyl group having 2 to 5 carbon atoms or an alkynyl group having 2 to 5 carbon atoms, wherein X 1 , X 2 and X 3 are the same or different and each is a hydrogen atom, a halogen atom, or a carbon number of 1 to 1. 5 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, an amino group, or an amino group substituted with 1 or 2 alkyl groups having 1 to 2 carbon atoms. ) Represented by 4
-A CRF receptor antagonist comprising a tetrahydropyridylpyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
【0009】(2)有効成分が、前記式[I]におい
て、Arがテトラヒドロピリジン環の4位に置換し、A
rがハロゲン原子、炭素数1〜5のアルキル基、炭素数
1〜5のアルコキシ基及びトリフルオロメチル基から選
択された1〜3個で置換されたフェニル基、フェニル
基、チエニル基又はフリル基であり、R1 がメチル基で
あり、R2 がエチル基、シクロプロピルメチル基、アリ
ル基又はプロパルギル基であり、X1 が水素原子であ
り、X2 がベンゼン環の2位に置換したハロゲン原子又
はメチルチオ基であり、X3 がベンゼン環の4位に置換
したイソプロピル基又はジメチルアミノ基である4−テ
トラヒドロピリジルピリミジン誘導体又はその医薬上許
容される塩である前記(1)に記載のCRF受容体拮抗
薬。(2) The active ingredient is represented by the formula [I] wherein Ar is substituted at the 4-position of the tetrahydropyridine ring, and A
r is a halogen atom, an alkyl group having 1 to 5 carbon atoms, a phenyl group substituted with 1 to 3 selected from an alkoxy group having 1 to 5 carbon atoms and a trifluoromethyl group, a phenyl group, a thienyl group or a furyl group. R 1 is a methyl group, R 2 is an ethyl group, a cyclopropylmethyl group, an allyl group or a propargyl group, X 1 is a hydrogen atom, and X 2 is a halogen substituted at the 2-position of the benzene ring. The CRF according to (1) above, which is a 4-tetrahydropyridylpyrimidine derivative in which X 3 is an isopropyl group substituted at the 4-position of the benzene ring or a dimethylamino group, or a pharmaceutically acceptable salt thereof, which is an atom or a methylthio group. Receptor antagonist.
【0010】(3)有効成分が、前記式[I]におい
て、Arがテトラヒドロピリジン環の5位に置換し、A
rがハロゲン原子、炭素数1〜5のアルキル基、炭素数
1〜5のアルコキシ基及びトリフルオロメチル基から選
択された1〜3個で置換されたフェニル基、フェニル
基、チエニル基又はフリル基であり、R1 がメチル基で
あり、R2 がエチル基、シクロプロピルメチル基、アリ
ル基又はプロパルギル基であり、X1 が水素原子であ
り、X2 がベンゼン環の2位に置換したハロゲン原子又
はメチルチオ基であり、X3 がベンゼン環の4位に置換
したイソプロピル基又はジメチルアミノ基である4−テ
トラヒドロピリジルピリミジン誘導体又はその医薬上許
容される塩である前記(1)に記載のCRF受容体拮抗
薬。(3) The active ingredient is represented by the formula [I] wherein Ar is substituted at the 5-position of the tetrahydropyridine ring, and A
r is a halogen atom, an alkyl group having 1 to 5 carbon atoms, a phenyl group substituted with 1 to 3 selected from an alkoxy group having 1 to 5 carbon atoms and a trifluoromethyl group, a phenyl group, a thienyl group or a furyl group. R 1 is a methyl group, R 2 is an ethyl group, a cyclopropylmethyl group, an allyl group or a propargyl group, X 1 is a hydrogen atom, and X 2 is a halogen substituted at the 2-position of the benzene ring. The CRF according to (1) above, which is a 4-tetrahydropyridylpyrimidine derivative in which X 3 is an isopropyl group substituted at the 4-position of the benzene ring or a dimethylamino group, or a pharmaceutically acceptable salt thereof, which is an atom or a methylthio group. Receptor antagonist.
【0011】本発明において、Arの置換位置はテトラ
ヒドロピリジン環の4位又は5位である。ハロゲン原
子、炭素数1〜5のアルキル基、炭素数1〜5のアルコ
キシ基及びトリフルオロメチル基から選択された1〜3
個で置換されたフェニル基とは、例えば2−フルオロフ
ェニル基、3−フルオロフェニル基、4−フルオロフェ
ニル基、2−クロロフェニル基、3−クロロフェニル
基、4−クロロフェニル基、2−ブロモフェニル基、3
−ブロモフェニル基、4−ブロモフェニル基、2−メチ
ルフェニル基、3−メチルフェニル基、4−メチルフェ
ニル基、2−メトキシフェニル基、3−メトキシフェニ
ル基、4−メトキシフェニル基、3, 4−ジフルオロフ
ェニル基、3, 5−ジフルオロフェニル基、2, 4−ジ
フルオロフェニル基、3, 4−ジクロロフェニル基、
3, 5−ジクロロフェニル基、3−トリフルオロメチル
フェニル基などである。In the present invention, the substitution position of Ar is the 4-position or 5-position of the tetrahydropyridine ring. 1-3 selected from a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, and a trifluoromethyl group
The phenyl group substituted with a piece includes, for example, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2-bromophenyl group, Three
-Bromophenyl group, 4-bromophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3, 4 -Difluorophenyl group, 3,5-difluorophenyl group, 2,4-difluorophenyl group, 3,4-dichlorophenyl group,
Examples thereof include a 3,5-dichlorophenyl group and a 3-trifluoromethylphenyl group.
【0012】炭素数1〜5のアルキル基とは直鎖状又は
分岐鎖状のアルキル基を示し、例えばメチル基、エチル
基、プロピル基、イソプロピル基、ブチル基、イソブチ
ル基、ペンチル基、イソペンチル基などである。炭素数
4〜7のシクロアルキルアルキル基とはシクロプロピル
メチル基、シクロプロピルエチル基、シクロプロピルプ
ロピル基などである。1若しくは2個の炭素数1〜5の
アルキル基で置換されたアミノ基とは、例えばメチルア
ミノ基、ジメチルアミノ基、エチルアミノ基、ジエチル
アミノ基、プロピルアミノ基、ジプロピルアミノ基、イ
ソプロピルアミノ基などである。炭素数2〜5のアルケ
ニル基とは直鎖状又は分岐鎖状のアルケニル基を示し、
例えばアリル基、2−ブテニル基などである。炭素数2
〜5のアルキニル基とは直鎖状又は分岐鎖状のアルキニ
ル基を示し、例えばプロパルギル基、2−ブチニル基な
どである。ハロゲン原子とは、フッ素原子、塩素原子、
臭素原子又はヨウ素原子である。炭素数1〜5のアルコ
キシ基とは直鎖状又は分岐鎖状のアルコキシ基を示し、
例えばメトキシ基、エトキシ基、プロポキシ基、イソプ
ロポキシ基、ブトキシ基、イソブトキシ基、ペンチルオ
キシ基、イソペンチルオキシ基などである。炭素数1〜
5のアルキルチオ基とは直鎖状又は分岐鎖状のアルキル
チオ基を示し、例えばメチルチオ基、エチルチオ基、プ
ロピルチオ基、イソプロピルチオ基、ブチルチオ基、イ
ソブチルチオ基、ペンチルチオ基、イソペンチルチオ基
などである。The alkyl group having 1 to 5 carbon atoms means a linear or branched alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, isopentyl group. And so on. The cycloalkylalkyl group having 4 to 7 carbon atoms includes cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpropyl group and the like. The amino group substituted with 1 or 2 alkyl groups having 1 to 5 carbon atoms includes, for example, methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group, isopropylamino group. And so on. The alkenyl group having 2 to 5 carbon atoms represents a linear or branched alkenyl group,
For example, an allyl group, a 2-butenyl group and the like. Carbon number 2
The alkynyl group of 5 represents a linear or branched alkynyl group, and examples thereof include a propargyl group and a 2-butynyl group. Halogen atom means fluorine atom, chlorine atom,
It is a bromine atom or an iodine atom. The alkoxy group having 1 to 5 carbon atoms represents a linear or branched alkoxy group,
For example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, pentyloxy group, isopentyloxy group and the like. Carbon number 1
The alkylthio group of 5 represents a linear or branched alkylthio group, and examples thereof include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a pentylthio group and an isopentylthio group. .
【0013】また、本発明における医薬上許容される塩
とは、例えば硫酸、塩酸、リン酸などの鉱酸との塩、酢
酸、シュウ酸、乳酸、酒石酸、フマール酸、マレイン
酸、クエン酸、ベンゼンスルホン酸、メタンスルホン酸
などの有機酸との塩などである。The pharmaceutically acceptable salts in the present invention include salts with mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, Examples thereof include salts with organic acids such as benzenesulfonic acid and methanesulfonic acid.
【0014】式[I]において好ましい置換基として
は、R1 はメチル基、R2 はエチル基、シクロプロピル
メチル基、アリル基又はプロパルギル基、X1 は水素原
子、X2 はベンゼン環の2位に置換したハロゲン原子又
はメチルチオ基、X3 はベンゼン環の4位に置換したイ
ソプロピル基又はジメチルアミノ基を挙げることができ
る。更に、Arがテトラヒドロピリジン環の4位に置換
した場合はArが1つのハロゲン原子で置換されたフェ
ニル基が好ましく、Arがテトラヒドロピリジン環の5
位に置換した場合はArが炭素数1〜5のアルキル基で
2位が置換されたフェニル基が好ましい。[0014] Formula A preferable substituent in [I], R 1 is methyl, R 2 is an ethyl group, a cyclopropylmethyl group, an allyl group or a propargyl group, X 1 is a hydrogen atom, X 2 is 2 benzene rings A halogen atom or a methylthio group substituted at the position, and X 3 is an isopropyl group or a dimethylamino group substituted at the 4-position of the benzene ring. Further, when Ar is substituted at the 4-position of the tetrahydropyridine ring, Ar is preferably a phenyl group substituted with one halogen atom, and Ar is 5 of the tetrahydropyridine ring.
When it is substituted at the position, Ar is preferably a phenyl group in which the 2-position is substituted with an alkyl group having 1 to 5 carbon atoms.
【0015】[0015]
【発明の実施の形態】式[I]の化合物は、以下の製造
法によって製造することができる[以下の反応式中、A
r、R1 、R2 、X1 、X2 及びX3 は前記と同様であ
り、R3 は水素原子又はR2 を示し、R4 及びR5 は同
一又は異なって炭素数1〜5のアルキル基を示すか、又
は一緒になって隣接する酸素原子と共に1, 2−エチレ
ンジオキシ基若しくは1, 3−プロピレンジオキシ基を
示し、R4 O及びR5 Oの結合位置は共に3位又は4位
の同一炭素であることを示し、X4 は塩素原子、臭素原
子又はヨウ素原子を示し、X5 は水素原子、塩素原子、
臭素原子又はヨウ素原子を示し、Yはアシル基(アセチ
ル基、ベンゾイル基など)、アルコキシカルボニル基
(エトキシカルボニル基、tert−ブトキシカルボニル基
など)、炭素数1〜5のアルキル基又はベンジル基を示
す。]
<製造法1>BEST MODE FOR CARRYING OUT THE INVENTION The compound of the formula [I] can be produced by the following production method [in the following reaction scheme, A
r, R 1 , R 2 , X 1 , X 2 and X 3 are the same as defined above, R 3 represents a hydrogen atom or R 2 , and R 4 and R 5 are the same or different and have 1 to 5 carbon atoms. It represents an alkyl group or, together with it, represents a 1,2-ethylenedioxy group or a 1,3-propylenedioxy group together with an adjacent oxygen atom, and the bonding positions of R 4 O and R 5 O are both the 3-position. Or the same carbon atom at the 4-position, X 4 represents a chlorine atom, a bromine atom or an iodine atom, X 5 represents a hydrogen atom, a chlorine atom,
Represents a bromine atom or an iodine atom, Y represents an acyl group (acetyl group, benzoyl group, etc.), an alkoxycarbonyl group (ethoxycarbonyl group, tert-butoxycarbonyl group, etc.), an alkyl group having 1 to 5 carbon atoms, or a benzyl group. . <Production Method 1>
【0016】[0016]
【化3】 [Chemical 3]
【0017】工程A:1, 2, 3, 6−テトラヒドロピ
リジン化合物(1)を2, 4−ジクロロピリミジン化合
物(2)と塩基の存在下、不活性溶媒中反応させ、式
(3)の化合物を得る。ここで塩基とは、例えばトリエ
チルアミン、ジイソプロピルエチルアミン、ピリジン等
のアミン類、炭酸ナトリウム、炭酸カリウム、炭酸水素
ナトリウム、炭酸水素カリウム、水酸化ナトリウム、水
素化ナトリウム等の無機塩基、ナトリウムメトキシド、
ナトリウムエトキシド、カリウム tert −ブトキシド等
のアルコラート類、ナトリウムアミド、リチウムジイソ
プロピルアミド等の金属アミド類等である。不活性溶媒
とは、例えばメタノール、エタノール、イソプロピルア
ルコール、エチレングリコール等のアルコール類、ジエ
チルエーテル、テトラヒドロフラン、ジオキサン、1,
2−ジメトキシエタン等のエーテル類、ベンゼン、トル
エン等の炭化水素類、N, N−ジメチルホルムアミド等
のアミド類、アセトニトリル、水、又はこれらの混合溶
媒等である。Step A: 1,2,3,6-Tetrahydropyridine compound (1) is reacted with 2,4-dichloropyrimidine compound (2) in the presence of a base in an inert solvent to give a compound of formula (3) To get Here, the base is, for example, amines such as triethylamine, diisopropylethylamine, pyridine, etc., sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, inorganic bases such as sodium hydride, sodium methoxide,
Examples thereof include alcoholates such as sodium ethoxide and potassium tert-butoxide, and metal amides such as sodium amide and lithium diisopropylamide. Examples of the inert solvent include alcohols such as methanol, ethanol, isopropyl alcohol, and ethylene glycol, diethyl ether, tetrahydrofuran, dioxane, 1,
Examples thereof include ethers such as 2-dimethoxyethane, hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide, acetonitrile, water, and mixed solvents thereof.
【0018】工程B:式(3)の化合物はアニリン化合
物(4)と塩基の存在下又は非存在下、不活性溶媒中反
応させ、化合物(5)を得る。ここで塩基とは、例えば
トリエチルアミン、ジイソプロピルエチルアミン、ピリ
ジン等のアミン類、炭酸ナトリウム、炭酸カリウム、炭
酸水素ナトリウム、炭酸水素カリウム、水酸化ナトリウ
ム、水素化ナトリウム等の無機塩基、ナトリウムメトキ
シド、ナトリウムエトキシド、カリウム tert −ブトキ
シド等のアルコラート類、ナトリウムアミド、リチウム
ジイソプロピルアミド等の金属アミド類等である。不活
性溶媒とは、例えばメタノール、エタノール、イソプロ
ピルアルコール、エチレングリコール等のアルコール
類、ジエチルエーテル、テトラヒドロフラン、ジオキサ
ン、1, 2−ジメトキシエタン等のエーテル類、ベンゼ
ン、トルエン、キシレン等の炭化水素類、例えばN, N
−ジメチルホルムアミド等のアミド類、ジメチルスルホ
キシド等である。
<製造法2>Step B: The compound of formula (3) is reacted with the aniline compound (4) in the presence or absence of a base in an inert solvent to obtain a compound (5). Here, the base includes, for example, amines such as triethylamine, diisopropylethylamine and pyridine, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide and sodium hydride, sodium methoxide and sodium ethoxy. And alcoholic acids such as potassium tert-butoxide, metal amides such as sodium amide and lithium diisopropylamide. Examples of the inert solvent include alcohols such as methanol, ethanol, isopropyl alcohol, and ethylene glycol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, and xylene. For example N, N
-Amides such as dimethylformamide, dimethylsulfoxide and the like. <Production method 2>
【0019】[0019]
【化4】 [Chemical 4]
【0020】工程C:化合物(5)のR3 が水素原子で
ある化合物(6)はハライド(7)と塩基の存在下、不
活性溶媒中反応させることによって本発明の有効成分で
ある化合物(8)へ導かれる。ここで塩基とは、例えば
トリエチルアミン、ジイソプロピルエチルアミン、ピリ
ジン等のアミン類、例えば炭酸ナトリウム、炭酸カリウ
ム、炭酸水素ナトリウム、炭酸水素カリウム、水酸化ナ
トリウム、水素化ナトリウム等の無機塩基、例えばナト
リウムメトキシド、ナトリウムエトキシド、カリウム t
ert −ブトキシド等のアルコラート類、例えばナトリウ
ムアミド、リチウムジイソプロピルアミド等の金属アミ
ド類等である。不活性溶媒とは、例えばメタノール、エ
タノール、イソプロピルアルコール、エチレングリコー
ル等のアルコール類、例えばジエチルエーテル、テトラ
ヒドロフラン、ジオキサン、1,2−ジメトキシエタン
等のエーテル類、例えばベンゼン、トルエン、キシレン
等の炭化水素類、例えばN, N−ジメチルホルムアミド
等のアミド類、ジメチルスルホキシド、アセトニトリ
ル、水、又はこれらの混合溶媒等である。
<製造法3>Step C: Compound (6) in which R 3 of compound (5) is a hydrogen atom is reacted with halide (7) in the presence of a base in an inert solvent to give a compound ( You are led to 8). Here, the base is, for example, amines such as triethylamine, diisopropylethylamine, pyridine and the like, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, sodium hydride and the like, for example sodium methoxide, Sodium ethoxide, potassium t
Examples thereof include alcoholates such as ert-butoxide, and metal amides such as sodium amide and lithium diisopropylamide. Examples of the inert solvent include alcohols such as methanol, ethanol, isopropyl alcohol and ethylene glycol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene and xylene. Examples thereof include amides such as N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, water, and mixed solvents thereof. <Production method 3>
【0021】[0021]
【化5】 [Chemical 5]
【0022】式(9)で示される化合物を出発原料とし
ても本発明の有効成分である化合物(8)を得ることが
できる。すなわち、式(9)で示される化合物と2, 4
−ジクロロピリミジン化合物(2)を原料とし、前記工
程A、B、及びR3 が水素原子であるときは続いて工程
Cによってケタール化合物(10)を得ることができ
る。The compound (8), which is the active ingredient of the present invention, can be obtained by using the compound represented by the formula (9) as a starting material. That is, the compound represented by the formula (9) and 2,4
The ketal compound (10) can be obtained by using the dichloropyrimidine compound (2) as a raw material and then the steps A, B, and R 3 when each is a hydrogen atom, and then the step C.
【0023】工程D:次いで、ケタール化合物(10)
は不活性溶媒中、酸で処理することによってケトン化合
物(11)を与える。ここで不活性溶媒とは、例えばメ
タノール、エタノール、イソプロピルアルコール、エチ
レングリコール等のアルコール類、例えばジエチルエー
テル、テトラヒドロフラン、ジオキサン、1, 2−ジメ
トキシエタン等のエーテル類、例えばベンゼン、トルエ
ン、キシレン等の炭化水素類、アセトン、メチルエチル
ケトン等のケトン類、例えばN, N−ジメチルホルムア
ミド等のアミド類、水、又はこれらの混合溶媒である。
酸とは、例えば塩酸、臭化水素酸、硫酸等の無機酸、例
えばp−トルエンスルホン酸、メタンスルホン酸、トリ
フルオロ酢酸等の有機酸類である。Step D: Next, ketal compound (10)
Is treated with an acid in an inert solvent to give the ketone compound (11). Here, the inert solvent includes alcohols such as methanol, ethanol, isopropyl alcohol, and ethylene glycol, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, such as benzene, toluene, and xylene. Hydrocarbons, ketones such as acetone and methyl ethyl ketone, amides such as N, N-dimethylformamide, water, or a mixed solvent thereof.
The acid is, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as p-toluenesulfonic acid, methanesulfonic acid or trifluoroacetic acid.
【0024】工程E:ケトン化合物(11)と、式(1
2)の化合物及び金属試薬から得られる金属化合物とを
不活性溶媒中反応させて、アルコール化合物(13)を
得る。ここで金属試薬とは、例えばマグネシウム、リチ
ウム等の金属、及び、例えばn−ブチルリチウム、tert
−ブチルリチウム、フェニルリチウム、リチウムジイソ
プロピルアミド、リチウムビス(トリメチルシリル)ア
ミド等の有機リチウム化合物等である。不活性溶媒と
は、例えばジエチルエーテル、テトラヒドロフラン、ジ
オキサン、1, 2−ジメトキシエタン等のエーテル類、
例えばヘキサン、ベンゼン、トルエン、キシレン等の炭
化水素類等である。Step E: The ketone compound (11) and the compound of formula (1)
The alcohol compound (13) is obtained by reacting the compound of 2) and the metal compound obtained from the metal reagent in an inert solvent. Here, the metal reagents include, for example, metals such as magnesium and lithium, and n-butyllithium, tert.
-Organolithium compounds such as butyllithium, phenyllithium, lithium diisopropylamide, and lithium bis (trimethylsilyl) amide. Examples of the inert solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane,
For example, hydrocarbons such as hexane, benzene, toluene, xylene and the like.
【0025】工程F:次いで、アルコール化合物(1
3)を酸性条件下脱水するか、又はアルコール化合物
(13)を活性体に変換後、塩基性条件下反応させるこ
とによって、目的化合物(8)を得ることができる。こ
こで酸性条件下の脱水とは、不活性溶媒として、例えば
メタノール、エタノール、イソプロピルアルコール、エ
チレングリコール等のアルコール類、例えばジエチルエ
ーテル、テトラヒドロフラン、ジオキサン、1, 2−ジ
メトキシエタン等のエーテル類、例えばアセトン、メチ
ルエチルケトン等のケトン類、水、又はこれらの混合溶
媒を用い、酸として、例えば塩酸、臭化水素酸、硫酸等
の無機酸、例えば塩化水素、臭化水素等のハロゲン化水
素類、例えばp−トルエンスルホン酸、メタンスルホン
酸、トリフルオロ酢酸、蟻酸等の有機酸類を用いる反応
を意味する。活性体とは、アルコール体(13)の水酸
基のスルホニル体又はアシル体、又はアルコール体(1
3)の水酸基のハロゲン原子での置換体を意味する。こ
れらの活性体は、不活性溶媒として、例えばジエチルエ
ーテル、テトラヒドロフラン、ジオキサン、1, 2−ジ
メトキシエタン等のエーテル類、例えばベンゼン、トル
エン、キシレン等の炭化水素類、例えばクロロホルム、
ジクロロメタン等のハロゲン化物、例えばN, N−ジメ
チルホルムアミド等のアミド類等を用い、塩基として、
例えばトリエチルアミン、ジイソプロピルエチルアミ
ン、ピリジン、4−ジメチルアミノピリジン等のアミン
類、例えば炭酸ナトリウム、炭酸カリウム、炭酸水素ナ
トリウム、炭酸水素カリウム、水酸化ナトリウム、水素
化ナトリウム等の無機塩基、例えばナトリウムアミド、
リチウムジイソプロピルアミド等の金属アミド類等を用
い、例えばメタンスルホニルクロライド、p−トルエン
スルホニルクロライド等のスルホニルクロライド類、例
えばアセチルクロライド等の有機カルボニルクロライ
ド、例えば無水酢酸、無水トリフルオロ酢酸等の有機カ
ルボン酸無水物、例えば塩化スルホニル、塩化ホスホリ
ル等のハロゲン化剤等をアルコール体(13)と反応さ
せて得られる。塩基性条件下反応するとは、前記アルコ
ール化合物(13)の活性体を、不活性溶媒として、例
えばジエチルエーテル、テトラヒドロフラン、ジオキサ
ン、1, 2−ジメトキシエタン等のエーテル類、例えば
ベンゼン、トルエン、キシレン等の炭化水素類、例えば
クロロホルム、ジクロロメタン等のハロゲン化物、例え
ばN, N−ジメチルホルムアミド等のアミド類等を用
い、例えばトリエチルアミン、ジイソプロピルエチルア
ミン、ピリジン、1, 8−ジアザビシクロ[5. 4.
0]−7−ウンデセン等のアミン類、例えば炭酸ナトリ
ウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カ
リウム、水酸化ナトリウム、水素化ナトリウム等の無機
塩基、例えばナトリウムアミド、リチウムジイソプロピ
ルアミド等の金属アミド類、例えばカリウム tert −ブ
トキシド等のアルコラート類等の塩基と作用させること
を意味する。なお、製造法1で用いた式(1)の化合物
は公知であるか、又は式(14)のケトン化合物より以
下に示す方法によって製造することができる。Step F: Next, the alcohol compound (1
The target compound (8) can be obtained by dehydrating 3) under acidic conditions or converting the alcohol compound (13) into an active form and then reacting under basic conditions. Here, dehydration under acidic conditions means, as an inert solvent, alcohols such as methanol, ethanol, isopropyl alcohol, and ethylene glycol, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, for example, Acetone, ketones such as methyl ethyl ketone, water, or a mixed solvent thereof is used as an acid, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid, for example, hydrogen halides such as hydrogen chloride or hydrogen bromide, for example, It means a reaction using organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid and formic acid. The activator means a sulfonyl group or an acyl group of a hydroxyl group of the alcohol body (13), or an alcohol body (1
It means a substitution product of the hydroxyl group of 3) with a halogen atom. These activators are, for example, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene and xylene, such as chloroform, as an inert solvent.
Using a halide such as dichloromethane, for example, an amide such as N, N-dimethylformamide, as a base,
For example, amines such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, sodium hydride and the like, for example sodium amide,
Using metal amides such as lithium diisopropylamide, sulfonyl chlorides such as methanesulfonyl chloride and p-toluenesulfonyl chloride, organic carbonyl chlorides such as acetyl chloride, organic carboxylic acids such as acetic anhydride and trifluoroacetic anhydride It can be obtained by reacting an anhydride, for example, a halogenating agent such as sulfonyl chloride or phosphoryl chloride with the alcohol derivative (13). The reaction under basic conditions means that the active form of the alcohol compound (13) is used as an inert solvent such as diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, such as benzene, toluene, xylene. Hydrocarbons such as chloroform and dichloromethane, and amides such as N, N-dimethylformamide, for example, triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.
0] -7-undecene and other amines, for example, inorganic carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, sodium hydride, and metal amides such as sodium amide and lithium diisopropylamide. , For example, with a base such as an alcoholate such as potassium tert-butoxide. The compound of formula (1) used in production method 1 is known or can be produced from the ketone compound of formula (14) by the following method.
【0026】[0026]
【化6】 [Chemical 6]
【0027】ケトン化合物(14)の保護基Yがアルコ
キシカルボニル基、アシル基、スルホニル基の場合は、
前記工程E及びFと同様の条件によって式(16)の化
合物に導かれる。即ち、式(12)の化合物と金属試薬
から得られる金属化合物とケトン化合物(14)とを反
応させて得られるアルコール化合物(15)に、酸とし
て例えば塩酸、臭化水素酸、硫酸などの無機酸、トリフ
ルオロ酢酸、蟻酸、メタンスルホン酸などの有機酸、塩
化水素のジオキサン溶液又は酢酸エチル溶液などを用い
た場合は、脱水反応と脱保護を同時に行なうかあるいは
段階的に行なうことによってYが水素原子である式(1
6)の化合物[すなわち、式(1)の化合物]に変換さ
れる。この時最初に脱水反応のみ進行した場合、Yの脱
保護を、例えば水酸化ナトリウム、水酸化カリウム、水
酸化バリウムなどの無機塩基等で行なっても同様にYが
水素原子である式(16)の化合物に変換される。ま
た、式(15)のアルコールを工程Fの場合と同様に活
性体とした後に、塩基性条件下反応させた場合、保護基
は前記酸又は塩基によって除かれる。When the protecting group Y of the ketone compound (14) is an alkoxycarbonyl group, an acyl group or a sulfonyl group,
The compound of formula (16) is derived under the same conditions as in steps E and F above. That is, an alcohol compound (15) obtained by reacting a compound of formula (12) with a metal compound obtained from a metal reagent and a ketone compound (14) is added to an inorganic compound such as hydrochloric acid, hydrobromic acid or sulfuric acid as an acid. When an acid, an organic acid such as trifluoroacetic acid, formic acid, methanesulfonic acid, etc., or a dioxane solution of hydrogen chloride or an ethyl acetate solution is used, the dehydration reaction and the deprotection are carried out simultaneously or in a stepwise manner so that Y Formula (1 which is hydrogen atom
It is converted to the compound of 6) [ie, the compound of formula (1)]. At this time, when only the dehydration reaction first proceeds, even if deprotection of Y is carried out with an inorganic base such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc., the formula (16) in which Y is a hydrogen atom is similarly obtained. Is converted to the compound. Further, when the alcohol of the formula (15) is made into an active form as in the case of step F and then reacted under basic conditions, the protecting group is removed by the acid or base.
【0028】工程G:ケトン化合物(14)の保護基Y
が炭素数1〜5のアルキル基又はベンジル基の場合は、
工程E及びFを経た後、この保護基は例えばクロロ蟻酸
エチル等のハロ蟻酸アルキルと、例えば炭酸ナトリウ
ム、炭酸カリウム等の無機塩基又は例えばトリエチルア
ミン、N, N−ジイソプロピルエチルアミンなどの有機
塩基の存在下又は非存在下反応し、アルコキシカルボニ
ル基に変換後、前記と同様に塩基又は酸の条件下で脱保
護し、式(1)で示される化合物に誘導することができ
る。Step G: Protecting group Y of ketone compound (14)
Is an alkyl group having 1 to 5 carbon atoms or a benzyl group,
After steps E and F, this protecting group is in the presence of an alkyl haloformate such as ethyl chloroformate and an inorganic base such as sodium carbonate, potassium carbonate or an organic base such as triethylamine, N, N-diisopropylethylamine. Alternatively, after reacting in the absence of the compound to convert it to an alkoxycarbonyl group, it can be deprotected under the conditions of a base or an acid in the same manner as described above to obtain a compound represented by the formula (1).
【0029】本発明のCRF受容体拮抗薬は、優れたC
RF受容体拮抗作用を有しており、CRFが関与してい
るとされるうつ症、不安症、アルツハイマー病、パーキ
ンソン病、ハンチントン舞踏病、摂食障害、高血圧、消
化器疾患、薬物依存症、てんかん、脳梗塞、脳虚血、脳
浮腫、頭部外傷、炎症、免疫関連疾患の治療剤又は予防
剤として有用である。The CRF receptor antagonist of the present invention has excellent C
Depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, gastrointestinal disorders, drug addiction, which have RF receptor antagonism and are considered to be involved in CRF. It is useful as a therapeutic or prophylactic agent for epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, and immune-related diseases.
【0030】本発明のCRF受容体拮抗薬の投与方法と
しては非経口投与または経口投与が挙げられる。その投
与剤形は、非経口の場合は注射剤であり、経口投与の場
合には錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤、
乳剤、懸濁剤から選ばれるいずれか一つの剤形である。
これらの投与剤形は、患者の症状、年齢及び治療の目的
に応じて適宜選択することができる。各種剤形の製剤の
製造においては、常用の賦形剤(例えば、結晶セルロー
ス、デンプン、乳糖、マンニトールなど)、結合剤(例
えば、ヒドロキシプロピルセルロース、ポリビニルピロ
リドンなど)、崩壊剤(例えば、カルボキシメチルセル
ロースカルシウムなど)、滑沢剤(例えば、ステアリン
酸マグネシウム、タルクなど)などを用いることがで
き、通常の製造法によって調製することができる。Examples of the administration method of the CRF receptor antagonist of the present invention include parenteral administration and oral administration. The dosage form is an injection for parenteral administration, and tablets, pills, capsules, granules, powders, liquids for oral administration.
One of the dosage forms selected from emulsions and suspensions.
These dosage forms can be appropriately selected according to the patient's symptoms, age and treatment purpose. In the production of various dosage forms, conventional excipients (eg, crystalline cellulose, starch, lactose, mannitol, etc.), binders (eg, hydroxypropyl cellulose, polyvinylpyrrolidone, etc.), disintegrants (eg, carboxymethyl cellulose) Calcium etc.), lubricants (eg magnesium stearate, talc etc.) and the like can be used, and they can be prepared by a usual production method.
【0031】本発明のCRF受容体拮抗薬は、有効成分
である化合物[I]として成人の患者に対して0. 1〜
500mg/日を1日1回又は数回に分けて経口又は非
経口で投与することができる。この投与量は疾患の種
類、患者の年齢、体重、症状により適宜増減することが
できる。The CRF receptor antagonist of the present invention is used as an active ingredient, Compound [I], in an amount of 0.1 to 1 for adult patients.
500 mg / day can be administered orally or parenterally once or several times a day. This dose can be appropriately increased or decreased depending on the type of disease, the age, weight and symptoms of the patient.
【0032】[0032]
【実施例】以下、製造例、試験例及び製剤例を示し本発
明を具体的に説明する。
製造例1
2−[N−(2−ブロモ−4−イソプロピルフェニル)
−N−エチルアミノ]−4−(4−フェニル−1, 2,
3, 6−テトラヒドロピリジン−1−イル)−6−メチ
ルピリミジン塩酸塩の合成EXAMPLES The present invention will be described in detail below with reference to production examples, test examples and formulation examples. Production Example 1 2- [N- (2-bromo-4-isopropylphenyl)
-N-ethylamino] -4- (4-phenyl-1,2,2
Synthesis of 3,6-tetrahydropyridin-1-yl) -6-methylpyrimidine hydrochloride
【0033】(1)2, 4−ジクロロ−6−メチルピリ
ミジン415mgをエタノール4mlに溶解し氷水にて
冷却した。この溶液に4−フェニル−1, 2, 3, 6−
テトラヒドロピリジン塩酸塩503mgとジイソプロピ
ルエチルアミン664mgを加え、氷冷下一夜撹拌し
た。反応溶液を飽和炭酸水素ナトリウム水溶液に注ぎ、
酢酸エチル抽出した。抽出液は飽和食塩水にて洗浄し、
無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、濾
液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグ
ラフィー(展開溶媒;ヘキサン:酢酸エチル=10:1
〜3:1)にて精製し、結晶として4−(4−フェニル
−1, 2, 3, 6−テトラヒドロピリジン−1−イル)
−2−クロロ−6−メチルピリミジン491mgを得
た。(1) 415 mg of 2,4-dichloro-6-methylpyrimidine was dissolved in 4 ml of ethanol and cooled with ice water. 4-phenyl-1,2,3,6-
Tetrahydropyridine hydrochloride 503 mg and diisopropylethylamine 664 mg were added, and the mixture was stirred overnight under ice cooling. Pour the reaction solution into saturated aqueous sodium hydrogen carbonate solution,
Extracted with ethyl acetate. The extract is washed with saturated saline,
It was dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 10: 1).
~ 3: 1) and crystallized as 4- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)
491 mg of 2-chloro-6-methylpyrimidine were obtained.
【0034】(2)4−(4−フェニル−1, 2, 3,
6−テトラヒドロピリジン−1−イル)−2−クロロ−
6−メチルピリミジン466mg、2−ブロモ−4−イ
ソプロピルアニリン塩酸塩408mg及びジイソプロピ
ルエチルアミン232mgをエチレングリコール5ml
中で1時間加熱還流した。反応溶液を飽和炭酸水素ナト
リウム水溶液に注ぎ、酢酸エチル抽出した。抽出液は
水、飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾
燥した。乾燥剤を濾別後、濾液を減圧下濃縮し、残渣を
シリカゲルカラムクロマトグラフィー(展開溶媒;ヘキ
サン:酢酸エチル=6:1)にて精製し、アモルファス
として2−[N−(2−ブロモ−4−イソプロピルフェ
ニル)アミノ]−4−(4−フェニル−1, 2, 3, 6
−テトラヒドロピリジン−1−イル)−6−メチルピリ
ミジン458mgを得た。(2) 4- (4-phenyl-1, 2, 3,
6-tetrahydropyridin-1-yl) -2-chloro-
6-Methylpyrimidine 466 mg, 2-bromo-4-isopropylaniline hydrochloride 408 mg and diisopropylethylamine 232 mg were added to ethylene glycol 5 ml.
Heated at reflux for 1 hour. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 6: 1) to give 2- [N- (2-bromo- 4-Isopropylphenyl) amino] -4- (4-phenyl-1,2,3,6)
-Tetrahydropyridin-1-yl) -6-methylpyrimidine 458 mg was obtained.
【0035】(3)2−[N−(2−ブロモ−4−イソ
プロピルフェニル)アミノ]−4−(4−フェニル−
1, 2, 3, 6−テトラヒドロピリジン−1−イル)−
6−メチルピリミジン453mgをN, N−ジメチルホ
ルムアミド5mlに溶解し、60%水素化ナトリウム/
オイル51mgを加え、室温で1時間撹拌した。この混
合物にヨウ化エチル214mgを加え、一夜室温にて撹
拌した。反応溶液を水に注ぎ、酢酸エチル抽出した。抽
出液は水、飽和食塩水にて洗浄し、無水硫酸ナトリウム
にて乾燥した。乾燥剤を濾別後、濾液を減圧下濃縮し、
残渣をシリカゲルカラムクロマトグラフィー(展開溶
媒;ヘキサン:酢酸エチル=8:1)にて精製した。得
られたフリーアミン体はメタノール中4規定塩化水素/
酢酸エチル処理により塩酸塩とし、エーテルより結晶化
し、2−[N−(2−ブロモ−4−イソプロピルフェニ
ル)−N−エチルアミノ]−4−(4−フェニル−1,
2, 3, 6−テトラヒドロピリジン−1−イル)−6−
メチルピリミジン塩酸塩325mgを得た。本化合物及
び同様にして得た化合物の構造と物性データを表1に記
した。(3) 2- [N- (2-bromo-4-isopropylphenyl) amino] -4- (4-phenyl-)
1,2,3,6-tetrahydropyridin-1-yl)-
453 mg of 6-methylpyrimidine was dissolved in 5 ml of N, N-dimethylformamide, and 60% sodium hydride /
Oil 51 mg was added, and the mixture was stirred at room temperature for 1 hour. 214 mg of ethyl iodide was added to this mixture, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 8: 1). The obtained free amine compound is 4N hydrogen chloride in methanol /
Hydrochloric acid salt was treated with ethyl acetate and crystallized from ether to give 2- [N- (2-bromo-4-isopropylphenyl) -N-ethylamino] -4- (4-phenyl-1,
2,3,6-Tetrahydropyridin-1-yl) -6-
325 mg of methylpyrimidine hydrochloride were obtained. Table 1 shows the structure and physical property data of this compound and the compound obtained in the same manner.
【0036】製造例2
2−[N−(2, 4−ジメトキシフェニル)−N−エチ
ルアミノ]−4−[4−(3, 4−ジクロロフェニル)
−1, 2, 3, 6−テトラヒドロピリジン−1−イル]
−6−メチルピリミジンの合成
製造例1と同様にして、2, 4−ジクロロ−6−メチル
ピリミジンと4−(3, 4−ジクロロフェニル)−1,
2, 3, 6−テトラヒドロピリジンより得られた4−
[4−(3, 4−ジクロロフェニル)−1, 2, 3, 6
−テトラヒドロピリジン−1−イル]−2−クロロ−6
−メチルピリミジン500mg、N−エチル−2, 4−
ジメトキシアニリン281mgをエチレングリコール2
ml中1.5時間170℃に加熱した。反応溶液を飽和
炭酸水素ナトリウム水溶液に注ぎ、酢酸エチル抽出し
た。抽出液は水、飽和食塩水にて洗浄し、無水硫酸ナト
リウムにて乾燥した。乾燥剤を濾別後、濾液を減圧下濃
縮し、残渣をシリカゲルカラムクロマトグラフィー(展
開溶媒;ヘキサン:酢酸エチル=4:1)にて精製後、
ジエチルエーテルより再結晶し2−[N−(2, 4−ジ
メトキシフェニル)−N−エチルアミノ]−4−[4−
(3, 4−ジクロロフェニル)−1, 2, 3, 6−テト
ラヒドロピリジン−1−イル]−6−メチルピリミジン
360mgを得た。本化合物及び同様にして得た化合物
の構造と物性データを表1に記した。Production Example 2 2- [N- (2,4-dimethoxyphenyl) -N-ethylamino] -4- [4- (3,4-dichlorophenyl)
-1,2,3,6-Tetrahydropyridin-1-yl]
Synthesis of -6-methylpyrimidine In the same manner as in Production Example 1, 2,4-dichloro-6-methylpyrimidine and 4- (3,4-dichlorophenyl) -1,
4-obtained from 2,3,6-tetrahydropyridine
[4- (3,4-dichlorophenyl) -1,2,3,6
-Tetrahydropyridin-1-yl] -2-chloro-6
-Methylpyrimidine 500 mg, N-ethyl-2,4-
281 mg of dimethoxyaniline and ethylene glycol 2
Heat to 170 ° C. in ml for 1.5 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 4: 1).
Recrystallized from diethyl ether to give 2- [N- (2,4-dimethoxyphenyl) -N-ethylamino] -4- [4-
360 mg of (3,4-dichlorophenyl) -1,2,3,6-tetrahydropyridin-1-yl] -6-methylpyrimidine was obtained. Table 1 shows the structure and physical property data of this compound and the compound obtained in the same manner.
【0037】製造例3
2−[N−(2−ブロモ−4−イソプロピルフェニル)
−N−エチルアミノ]−4−[4−(3−クロロフェニ
ル)−1, 2, 3, 6−テトラヒドロピリジン−1−イ
ル]−6−メチルピリミジン塩酸塩の合成
(1)製造例1と同様にして2, 4−ジクロロ−6−メ
チルピリミジンと4−(1, 3−ジオキソラン−2−イ
ル)ピペリジンより得られた2−[N−(2−ブロモ−
4−イソプロピルフェニル)−N−エチルアミノ]−4
−[4−(1,3−ジオキソラン−2−イル)ピペリジ
ン−1−イル]−6−メチルピリミジン14. 25gを
テトラヒドロフラン75mlに溶解し、4規定塩酸75
mlを加え、室温で6時間撹拌した。反応溶液を約80
mlまで減圧下濃縮し、これを飽和炭酸水素ナトリウム
水溶液に注ぎ、酢酸エチル抽出した。抽出液は飽和食塩
水にて洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥
剤を濾別後、濾液を減圧下濃縮し、残渣をシリカゲルカ
ラムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エ
チル=7:1〜6:1)にて精製し、油状の2−[N−
(2−ブロモ−4−イソプロピルフェニル)−N−エチ
ルアミノ]−6−メチル−4−(4−オキソピペリジン
−1−イル)ピリミジン12. 93gを得た。Production Example 3 2- [N- (2-bromo-4-isopropylphenyl)
Synthesis of -N-ethylamino] -4- [4- (3-chlorophenyl) -1,2,3,6-tetrahydropyridin-1-yl] -6-methylpyrimidine hydrochloride (1) Same as Production Example 1 To give 2- [N- (2-bromo-) obtained from 2,4-dichloro-6-methylpyrimidine and 4- (1,3-dioxolan-2-yl) piperidine.
4-Isopropylphenyl) -N-ethylamino] -4
14.25 g of-[4- (1,3-dioxolan-2-yl) piperidin-1-yl] -6-methylpyrimidine was dissolved in 75 ml of tetrahydrofuran and 4N hydrochloric acid 75
ml was added, and the mixture was stirred at room temperature for 6 hours. About 80 reaction solution
The mixture was concentrated under reduced pressure to ml, poured into saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 7: 1 to 6: 1) to give oily 2- [N-
There were obtained 12.93 g of (2-bromo-4-isopropylphenyl) -N-ethylamino] -6-methyl-4- (4-oxopiperidin-1-yl) pyrimidine.
【0038】(2)3−ブロモクロロベンゼン427m
g、マグネシウム27mgと微量のヨウ素をテトラヒド
ロフラン5ml中1時間加熱還流した。この反応液を氷
冷下冷却後、2−[N−(2−ブロモ−4−イソプロピ
ルフェニル)−N−エチルアミノ]−6−メチル−4−
(4−オキソピペリジン−1−イル)ピリミジン321
mgのテトラヒドロフラン3mlの溶液中に滴下し、氷
冷下1時間続いて室温で1時間撹拌した。再び反応液を
氷冷下冷却し、飽和塩化アンモニウム水溶液を滴下し、
室温で10分間撹拌後、酢酸エチルにて抽出した。抽出
液は飽和塩化アンモニウム水溶液、飽和炭酸水素ナトリ
ウム水溶液、飽和食塩水にて順次洗浄し、無水硫酸ナト
リウムにて乾燥した。乾燥剤を濾別後、濾液を減圧下濃
縮し、残渣をシリカゲルカラムクロマトグラフィー(展
開溶媒;ヘキサン:酢酸エチル=4:1)にて精製し、
2−[N−(2−ブロモ−4−イソプロピルフェニル)
−N−エチルアミノ]−4−[4−(3−クロロフェニ
ル)−4−ヒドロキシピペリジン−1−イル]−6−メ
チルピリミジン238mgを得た。(2) 3-bromochlorobenzene 427 m
g, 27 mg of magnesium and a trace amount of iodine were heated to reflux in 5 ml of tetrahydrofuran for 1 hour. The reaction mixture was cooled under ice-cooling and then 2- [N- (2-bromo-4-isopropylphenyl) -N-ethylamino] -6-methyl-4-.
(4-oxopiperidin-1-yl) pyrimidine 321
The solution was added dropwise to a solution of 3 mg of tetrahydrofuran in 3 ml, and the mixture was stirred under ice cooling for 1 hour and then stirred at room temperature for 1 hour. The reaction solution was cooled again under ice cooling, and a saturated ammonium chloride aqueous solution was added dropwise.
After stirring at room temperature for 10 minutes, the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 4: 1),
2- [N- (2-bromo-4-isopropylphenyl)
238 mg of -N-ethylamino] -4- [4- (3-chlorophenyl) -4-hydroxypiperidin-1-yl] -6-methylpyrimidine were obtained.
【0039】(3)2−[N−(2−ブロモ−4−イソ
プロピルフェニル)−N−エチルアミノ]−4−[4−
(3−クロロフェニル)−4−ヒドロキシピペリジン−
1−イル]−6−メチルピリミジン170mgにトリフ
ルオロ酢酸1. 25mlを加え、室温で2日間撹拌し
た。反応溶液を減圧下濃縮し、残渣に飽和炭酸水素ナト
リウム水溶液を加え、酢酸エチル抽出した。抽出液を飽
和炭酸水素ナトリウム水溶液、飽和食塩水にて順次洗浄
し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別
後、濾液を減圧下濃縮し、残渣をシリカゲルカラムクロ
マトグラフィー(展開溶媒;ヘキサン:酢酸エチル=
7:1)にて精製した。得られたフリーアミン体はメタ
ノール中4規定塩化水素/酢酸エチル処理により塩酸塩
とし、イソプロパノール−ジイソプロピルエーテルより
再結晶し、2−[N−(2−ブロモ−4−イソプロピル
フェニル)−N−エチルアミノ]−4−[4−(3−ク
ロロフェニル)−1, 2, 3, 6−テトラヒドロピリジ
ン−1−イル]−6−メチルピリミジン塩酸塩131m
gを得た。本化合物及び同様にして得た化合物の構造と
物性データを表1に記した。(3) 2- [N- (2-bromo-4-isopropylphenyl) -N-ethylamino] -4- [4-
(3-chlorophenyl) -4-hydroxypiperidine-
Trifluoroacetic acid (1.25 ml) was added to 1-yl] -6-methylpyrimidine (170 mg), and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate =
7: 1). The obtained free amine compound was treated with 4N hydrogen chloride / ethyl acetate in methanol to give a hydrochloride, and recrystallized from isopropanol-diisopropyl ether to give 2- [N- (2-bromo-4-isopropylphenyl) -N-ethyl. Amino] -4- [4- (3-chlorophenyl) -1,2,3,6-tetrahydropyridin-1-yl] -6-methylpyrimidine hydrochloride 131m
g was obtained. Table 1 shows the structure and physical property data of this compound and the compound obtained in the same manner.
【0040】製造例4
2−[N−(2−ブロモ−4−イソプロピルフェニル)
−N−エチルアミノ]−4−[4−(フラン−2−イ
ル)−1, 2, 3, 6−テトラヒドロピリジン−1−イ
ル]−6−メチルピリミジンの合成
(1)フラン136mgのテトラヒドロフラン1mlの
溶液に1. 63Mのn−ブチルリチウムのn−ヘキサン
溶液0. 9mlを、−15℃に冷却下10分間で滴下
し、5℃で20分間撹拌した。この反応液に2−[N−
(2−ブロモ−4−イソプロピルフェニル)−N−エチ
ルアミノ]−6−メチル−4−(4−オキソピペリジン
−1−イル)ピリミジン432mgのテトラヒドロフラ
ン2mlの溶液を−15℃に冷却下10分間で滴下し、
−15℃〜0℃で30分間撹拌した。更に室温で1時間
撹拌後、飽和塩化アンモニウム水溶液を氷冷下滴下し、
酢酸エチル抽出した。抽出液は飽和塩化アンモニウム水
溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水にて
順次洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤
を濾別後、濾液を減圧下濃縮し、残渣をシリカゲルカラ
ムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エチ
ル=3:1)にて精製し、2−[N−(2−ブロモ−4
−イソプロピルフェニル)−N−エチルアミノ]−4−
[4−(フラン−2−イル)−4−ヒドロキシピペリジ
ン−1−イル]−6−メチルピリミジン279mgを得
た。Production Example 4 2- [N- (2-bromo-4-isopropylphenyl)
Synthesis of -N-ethylamino] -4- [4- (furan-2-yl) -1,2,3,6-tetrahydropyridin-1-yl] -6-methylpyrimidine (1) Furan 136 mg tetrahydrofuran 1 ml 0.9 ml of a 1.63 M n-hexane solution of n-butyllithium was added dropwise to the above solution at −15 ° C. under cooling for 10 minutes, and the mixture was stirred at 5 ° C. for 20 minutes. 2- [N-
A solution of 432 mg of (2-bromo-4-isopropylphenyl) -N-ethylamino] -6-methyl-4- (4-oxopiperidin-1-yl) pyrimidine in 2 ml of tetrahydrofuran was cooled to -15 ° C in 10 minutes. Dripping,
The mixture was stirred at -15 ° C to 0 ° C for 30 minutes. After further stirring at room temperature for 1 hour, a saturated aqueous solution of ammonium chloride was added dropwise under ice cooling,
Extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 3: 1) to give 2- [N- (2-bromo-4
-Isopropylphenyl) -N-ethylamino] -4-
279 mg of [4- (furan-2-yl) -4-hydroxypiperidin-1-yl] -6-methylpyrimidine were obtained.
【0041】(2)2−[N−(2−ブロモ−4−イソ
プロピルフェニル)−N−エチルアミノ]−4−[4−
(フラン−2−イル)−4−ヒドロキシピペリジン−1
−イル]−6−メチルピリミジン104mg、トリエチ
ルアミン85mg及び4−ジメチルアミノピリジン13
mgのジクロロメタン1mlの溶液に、メタンスルホニ
ルクロライド48mgのジクロロメタン0. 5mlの溶
液を氷冷下滴下し、15分間撹拌後、更に室温で2時間
撹拌した。反応溶液を飽和炭酸水素ナトリウム水溶液に
注ぎ、酢酸エチル抽出した。抽出液は飽和炭酸水素ナト
リウム水溶液、飽和食塩水にて順次洗浄し、無水硫酸ナ
トリウムにて乾燥した。乾燥剤を濾別後、濾液を減圧下
濃縮し、残渣をシリカゲルカラムクロマトグラフィー
(展開溶媒;ヘキサン:酢酸エチル=9:1)にて精製
し、2−[N−(2−ブロモ−4−イソプロピルフェニ
ル)−N−エチルアミノ]−4−[4−(フラン−2−
イル)−1, 2, 3, 6−テトラヒドロピリジン−1−
イル]−6−メチルピリミジン70mgを得た。本化合
物及び同様にして得た化合物の構造と物性データを表1
に記した。(2) 2- [N- (2-bromo-4-isopropylphenyl) -N-ethylamino] -4- [4-
(Fran-2-yl) -4-hydroxypiperidine-1
-Yl] -6-methylpyrimidine 104 mg, triethylamine 85 mg and 4-dimethylaminopyridine 13
A solution of 48 mg of methanesulfonyl chloride in 0.5 ml of dichloromethane was added dropwise to a solution of mg of dichloromethane in 1 ml under ice-cooling, and the mixture was stirred for 15 minutes and further stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 9: 1) to give 2- [N- (2-bromo-4- Isopropylphenyl) -N-ethylamino] -4- [4- (furan-2-
Yl) -1,2,3,6-tetrahydropyridine-1-
70 mg of [yl] -6-methylpyrimidine was obtained. Table 1 shows the structure and physical property data of this compound and the compound obtained in the same manner.
I wrote it in.
【0042】製造例5
2−[N−(2−ブロモ−4−イソプロピルフェニル)
−N−エチルアミノ]−4−[4−(チオフェン−2−
イル)−1, 2, 3, 6−テトラヒドロピリジン−1−
イル]−6−メチルピリミジンの合成
(1)チオフェン168mg及び2−[N−(2−ブロ
モ−4−イソプロピルフェニル)−N−エチルアミノ]
−6−メチル−4−(4−オキソピペリジン−1−イ
ル)ピリミジン432mgを用い製造例4の(1)と同
様の操作にて2−[N−(2−ブロモ−4−イソプロピ
ルフェニル)−N−エチルアミノ]−4−[4−(チオ
フェン−2−イル)−4−ヒドロキシピペリジン−1−
イル]−6−メチルピリミジン228mgを得た。Production Example 5 2- [N- (2-bromo-4-isopropylphenyl)
-N-ethylamino] -4- [4- (thiophen-2-
Yl) -1,2,3,6-tetrahydropyridine-1-
Synthesis of yl] -6-methylpyrimidine (1) 168 mg of thiophene and 2- [N- (2-bromo-4-isopropylphenyl) -N-ethylamino]
2- [N- (2-bromo-4-isopropylphenyl)-was prepared in the same manner as in Production Example 4 (1) using 432 mg of -6-methyl-4- (4-oxopiperidin-1-yl) pyrimidine. N-Ethylamino] -4- [4- (thiophen-2-yl) -4-hydroxypiperidine-1-
228 mg of [yl] -6-methylpyrimidine was obtained.
【0043】(2)2−[N−(2−ブロモ−4−イソ
プロピルフェニル)−N−エチルアミノ]−4−[4−
(チオフェン−2−イル)−4−ヒドロキシピペリジン
−1−イル]−6−メチルピリミジン166mgを99
%ギ酸0. 5ml中室温で2時間撹拌した。反応溶液を
飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸エチル抽出
した。抽出液は飽和炭酸水素ナトリウム水溶液、飽和食
塩水にて順次洗浄し、無水硫酸ナトリウムにて乾燥し
た。乾燥剤を濾別後、濾液を減圧下濃縮し、残渣をシリ
カゲルカラムクロマトグラフィー(展開溶媒;ヘキサ
ン:酢酸エチル=5:1)にて精製し、2−[N−(2
−ブロモ−4−イソプロピルフェニル)−N−エチルア
ミノ]−4−[4−(チオフェン−2−イル)−1,
2, 3, 6−テトラヒドロピリジン−1−イル]−6−
メチルピリミジン132mgを得た。本化合物及び同様
にして得た化合物の構造と物性データを表1に記した。(2) 2- [N- (2-bromo-4-isopropylphenyl) -N-ethylamino] -4- [4-
99% of 166 mg of (thiophen-2-yl) -4-hydroxypiperidin-1-yl] -6-methylpyrimidine
The mixture was stirred for 2 hours at room temperature in 0.5 ml of formic acid. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 5: 1) to give 2- [N- (2
-Bromo-4-isopropylphenyl) -N-ethylamino] -4- [4- (thiophen-2-yl) -1,
2,3,6-Tetrahydropyridin-1-yl] -6-
132 mg of methylpyrimidine were obtained. Table 1 shows the structure and physical property data of this compound and the compound obtained in the same manner.
【0044】[0044]
【表1】 [Table 1]
【0045】 [0045]
【0046】 [0046]
【0047】 [0047]
【0048】 [0048]
【0049】 [0049]
【0050】製造例6
2−[N−(2−ブロモ−4−イソプロピルフェニル)
−N−エチルアミノ]−4−(5−フェニル−1, 2,
3, 6−テトラヒドロピリジン−1−イル)−6−メチ
ルピリミジン塩酸塩の合成
(1)N−tert−ブトキシカルボニル−3−オキソピペ
リジン5. 00gのテトラヒドロフラン10mlの溶液
を、ブロモベンゼン4. 73gとマグネシウム0. 79
gからテトラヒドロフラン50ml中で調製したグリニ
ャール試薬の溶液に氷冷下滴下した。室温で1時間攪拌
後、氷冷した反応混合物に飽和塩化アンモニウム水溶液
100mlを滴下した。この反応混合物を酢酸エチル抽
出し、飽和炭酸水素ナトリウム水溶液、次いで飽和食塩
水にて洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥
剤を濾別後、濾液を減圧下濃縮し、残渣をシリカゲルカ
ラムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エ
チル=3:1)にて精製し、N−tert−ブトキシカルボ
ニル−3−ヒドロキシ−3−フェニルピペリジン4. 2
1gを得た。Production Example 6 2- [N- (2-bromo-4-isopropylphenyl)
-N-ethylamino] -4- (5-phenyl-1,2,
Synthesis of 3,6-tetrahydropyridin-1-yl) -6-methylpyrimidine hydrochloride (1) A solution of 5.00 g of N-tert-butoxycarbonyl-3-oxopiperidine in 10 ml of tetrahydrofuran was added with 4.73 g of bromobenzene. Magnesium 0.79
g to a solution of Grignard reagent prepared in 50 ml of tetrahydrofuran under ice cooling. After stirring at room temperature for 1 hour, 100 ml of saturated ammonium chloride aqueous solution was added dropwise to the ice-cooled reaction mixture. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, then saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 3: 1), and N-tert-butoxycarbonyl-3-hydroxy-3. -Phenylpiperidine 4.2
1 g was obtained.
【0051】(2)N−tert−ブトキシカルボニル−3
−ヒドロキシ−3−フェニルピペリジン3. 63gにト
リフルオロ酢酸49. 2mlを加え、室温で一夜攪拌
後、更に5時間加熱還流した。反応液を減圧下濃縮し、
残渣をジクロロメタン10mlに溶解後、4規定塩化水
素/ジオキサン6mlを加え、再び減圧下濃縮した。(2) N-tert-butoxycarbonyl-3
43.6 ml of trifluoroacetic acid was added to 3.63 g of -hydroxy-3-phenylpiperidine, and the mixture was stirred overnight at room temperature and then heated under reflux for 5 hours. The reaction solution is concentrated under reduced pressure,
The residue was dissolved in dichloromethane (10 ml), 4N hydrogen chloride / dioxane (6 ml) was added, and the mixture was concentrated again under reduced pressure.
【0052】この残渣をエタノール35mlに溶解し、
ジイソプロピルエチルアミン5. 16gと2, 4−ジク
ロロ−6−メチルピリミジン2. 60mgを加え、氷冷
下一夜撹拌した。反応溶液を飽和炭酸水素ナトリウム水
溶液に注ぎ、酢酸エチル抽出した。抽出液は飽和食塩水
にて洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤
を濾別後、濾液を減圧下濃縮し、残渣をシリカゲルカラ
ムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エチ
ル=3:1)にて精製し、結晶として4−( 5−フェニ
ル−1, 2, 3, 6−テトラヒドロピリジン−1−イ
ル) −2−クロロ−6−メチルピリミジン2. 17mg
を得た。This residue was dissolved in 35 ml of ethanol,
Diisopropylethylamine (5.16 g) and 2,4-dichloro-6-methylpyrimidine (2.60 mg) were added, and the mixture was stirred overnight under ice cooling. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 3: 1) to give 4- (5-phenyl-1,2) as crystals. , 3,6-Tetrahydropyridin-1-yl) -2-chloro-6-methylpyrimidine 2.17 mg
Got
【0053】(3)4−( 5−フェニル−1, 2, 3,
6−テトラヒドロピリジン−1−イル) −2−クロロ−
6−メチルピリミジン1. 10g、2−ブロモ−4−イ
ソプロピルアニリン塩酸塩0. 97g及びジイソプロピ
ルエチルアミン0. 50gをエチレングリコール5ml
中1時間加熱還流した。反応溶液を飽和炭酸水素ナトリ
ウム水溶液に注ぎ、酢酸エチル抽出した。抽出液は水、
飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥し
た。乾燥剤を濾別後、濾液を減圧下濃縮し、残渣をシリ
カゲルカラムクロマトグラフィー(展開溶媒;ヘキサ
ン:酢酸エチル=3:1)にて精製し、アモルファスと
して2−[ N−( 2−ブロモ−4−イソプロピルフェニ
ル) アミノ] −4−( 5−フェニル−1, 2, 3, 6−
テトラヒドロピリジン−1−イル) −6−メチルピリミ
ジン1. 32gを得た。(3) 4- (5-phenyl-1,2,3,3
6-Tetrahydropyridin-1-yl) -2-chloro-
6-Methylpyrimidine 1.10 g, 2-bromo-4-isopropylaniline hydrochloride 0.97 g and diisopropylethylamine 0.50 g were added to ethylene glycol 5 ml.
Heated to reflux for 1 hour. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract is water,
The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 3: 1) to give 2- [N- (2-bromo- 4-Isopropylphenyl) amino] -4- (5-phenyl-1,2,3,6-
1.32 g of tetrahydropyridin-1-yl) -6-methylpyrimidine were obtained.
【0054】(4)2−[ N−( 2−ブロモ−4−イソ
プロピルフェニル) アミノ] −4−( 5−フェニル−
1, 2, 3, 6−テトラヒドロピリジン−1−イル) −
6−メチルピリミジン1. 21gをN, N−ジメチルホ
ルムアミド12mlに溶解し、60%水素化ナトリウム
/オイル136mgを加え、室温で1時間撹拌した。こ
の混合物にヨウ化エチル570mgを加え、一夜室温に
て撹拌した。反応溶液を水に注ぎ、酢酸エチル抽出し
た。抽出液は水、飽和食塩水にて洗浄し、無水硫酸ナト
リウムにて乾燥した。乾燥剤を濾別後、濾液を減圧下濃
縮し、残渣をシリカゲルカラムクロマトグラフィー(展
開溶媒;ヘキサン:アセトン=9:1)にて精製した。
得られたフリーアミン体はメタノール中4規定塩化水素
/酢酸エチル処理により塩酸塩とし、エーテルより結晶
化し、2−[ N−( 2−ブロモ−4−イソプロピルフェ
ニル) −N−エチルアミノ] −4−( 5−フェニル−
1, 2,3, 6−テトラヒドロピリジン−1−イル) −
6−メチルピリミジン塩酸塩1.02gを得た。本化合
物及び同様にして得た化合物の構造と物性データを表2
に記した。(4) 2- [N- (2-bromo-4-isopropylphenyl) amino] -4- (5-phenyl-
1,2,3,6-tetrahydropyridin-1-yl)-
1.21 g of 6-methylpyrimidine was dissolved in 12 ml of N, N-dimethylformamide, 136 mg of 60% sodium hydride / oil was added, and the mixture was stirred at room temperature for 1 hour. 570 mg of ethyl iodide was added to this mixture, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: acetone = 9: 1).
The obtained free amine compound was treated with 4N hydrogen chloride / ethyl acetate in methanol to give a hydrochloride, and crystallized from ether to give 2- [N- (2-bromo-4-isopropylphenyl) -N-ethylamino] -4. -(5-phenyl-
1,2,3,6-tetrahydropyridin-1-yl)-
1.02 g of 6-methylpyrimidine hydrochloride was obtained. Table 2 shows the structure and physical property data of this compound and the compound obtained in the same manner.
I wrote it in.
【0055】製造例7
2−[ N−( 4−イソプロピル−2−メチルチオフェニ
ル) −N−エチルアミノ] −4−[ 5−( 2−メチルフ
ェニル) −1, 2, 3, 6−テトラヒドロピリジン−1
−イル] −6−メチルピリミジン塩酸塩の合成
製造例6と同様にしてN−tert−ブトキシカルボニル−
3−オキソピペリジン、2−メチルフェニルマグネシウ
ムブロマイド、2, 4−ジクロロ−6−メチルピリミジ
ンより得られた4−[ 5−( 2−メチルフェニル) −
1, 2, 3, 6−テトラヒドロピリジン−1−イル] −
2−クロロ−6−メチルピリミジン905mg、N−エ
チル−4−イソプロピル−2−メチルチオアニリン63
2mgをエチレングリコール10ml中1. 5時間17
0℃に加熱した。反応溶液を飽和炭酸水素ナトリウム水
溶液に注ぎ、クロロホルム抽出した。抽出液は飽和食塩
水にて洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥
剤を濾別後、濾液を減圧下濃縮し、残渣をシリカゲルカ
ラムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エ
チル=10:1〜4:1)にて精製した。得られたフリ
ーアミン体はジクロロメタン中4規定塩化水素/酢酸エ
チル処理により塩酸塩とし、酢酸エチル:エーテルより
再結晶し、2−[ N−( 4−イソプロピル−2−メチル
チオフェニル)−N−エチルアミノ] −4−[ 5−( 2
−メチルフェニル) −1, 2, 3, 6−テトラヒドロピ
リジン−1−イル] −6−メチルピリミジン塩酸塩1.
05gを得た。本化合物及び同様にして得た化合物の構
造と物性データを表2に記した。Production Example 7 2- [N- (4-isopropyl-2-methylthiophenyl) -N-ethylamino] -4- [5- (2-methylphenyl) -1,2,3,6-tetrahydropyridine -1
-Yl] -6-Methylpyrimidine Hydrochloride N-tert-butoxycarbonyl-
4- [5- (2-methylphenyl) -obtained from 3-oxopiperidine, 2-methylphenylmagnesium bromide and 2,4-dichloro-6-methylpyrimidine
1,2,3,6-tetrahydropyridin-1-yl]-
2-Chloro-6-methylpyrimidine 905 mg, N-ethyl-4-isopropyl-2-methylthioaniline 63
2 mg in ethylene glycol 10 ml for 1.5 hours 17
Heated to 0 ° C. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 10: 1 to 4: 1). The obtained free amine compound was treated with 4N hydrogen chloride / ethyl acetate in dichloromethane to give a hydrochloride, and recrystallized from ethyl acetate: ether to give 2- [N- (4-isopropyl-2-methylthiophenyl) -N-ethyl. Amino] -4- [5- (2
-Methylphenyl) -1,2,3,6-tetrahydropyridin-1-yl] -6-methylpyrimidine hydrochloride 1.
05 g was obtained. Table 2 shows the structure and physical property data of this compound and the compound obtained in the same manner.
【0056】[0056]
【表2】 [Table 2]
【0057】 [0057]
【0058】試験例1
[CRF受容体結合実験]受容体標品としてラット前頭
皮質膜を用いた。125I標識リガンドとして125I−CR
Fを用いた。125I標識リガンドを用いた結合反応は、T
he Journal ofNeuroscience,7, 88( 1987年) に
記載された以下の方法で行った。Test Example 1 [CRF Receptor Binding Experiment] Rat frontal cortex membrane was used as a receptor preparation. 125 I-CR as a 125 I-labeled ligand
F was used. The binding reaction using 125 I-labeled ligand
It was carried out by the following method described in he Journal of Neuroscience, 7, 88 (1987).
【0059】受容体膜標品の調製:ラット前頭皮質を1
0mM MgCl2 及び2mM EDTAを含む50m
Mトリス塩酸緩衝液(pH7. 0)でホモジナイズし、
48, 000×gで遠心分離し、沈渣をトリス塩酸緩衝
液で1度洗浄した。沈渣を10mM MgCl2 、2m
M EDTA、0. 1%ウシ血清アルブミン及び100
カリクレインユニット/mlアプロチニンを含む50m
Mトリス塩酸緩衝液(pH7. 0)に懸濁し、膜標品と
した。Preparation of receptor membrane preparation: 1 rat frontal cortex
50m containing 0mM MgCl 2 and 2mM EDTA
Homogenize with M Tris-HCl buffer (pH 7.0),
After centrifugation at 48,000 xg, the precipitate was washed once with Tris-HCl buffer. Sediment 10mMgCl 2 , 2m
M EDTA, 0.1% bovine serum albumin and 100
50m containing kallikrein unit / ml aprotinin
The membrane was suspended in M Tris-hydrochloric acid buffer (pH 7.0) to prepare a membrane sample.
【0060】CRF受容体結合実験:膜標品(0. 3m
gタンパク質/ml)、125I−CRF(0. 2nM)
及び被験薬を、25℃で2時間反応させた。反応終了
後、0. 3%ポリエチレンイミンで処理したガラスフィ
ルター(GF/C)に吸引濾過し、ガラスフィルターを
0. 01%TritonX−100を含むリン酸緩衝化
生理食塩水で3度洗浄した。洗浄後、濾紙の放射能をガ
ンマーカウンターにて測定した。CRF receptor binding experiment: membrane preparation (0.3 m
g protein / ml), 125 I-CRF (0.2 nM)
And the test drug was reacted at 25 ° C. for 2 hours. After completion of the reaction, suction filtration was performed on a glass filter (GF / C) treated with 0.3% polyethyleneimine, and the glass filter was washed 3 times with phosphate buffered saline containing 0.01% Triton X-100. After washing, the radioactivity of the filter paper was measured with a gamma counter.
【0061】1μM CRF存在下で反応を行った時の
結合量を、125I−CRFの非特異結合とし、総結合と
非特異結合との差を特異結合とした。一定濃度(0. 2
nM)の125I−CRFと濃度を変えた被験薬を上記の
条件で反応させることで抑制曲線を得、この抑制曲線か
ら125I- CRF結合を50%抑制する被験薬の濃度
(IC50)を求め、結果を表3に示した。The amount of binding when the reaction was performed in the presence of 1 μM CRF was defined as the nonspecific binding of 125 I-CRF, and the difference between the total binding and the nonspecific binding was defined as the specific binding. Constant concentration (0.2
(nM) 125 I-CRF and a test drug with varying concentrations were reacted under the above conditions to obtain an inhibition curve, and from this inhibition curve, the concentration of the test drug that inhibits 125 I-CRF binding by 50% (IC 50 ). Was calculated and the results are shown in Table 3.
【0062】[0062]
【表3】 [Table 3]
【0063】試験例2
[ストレス誘発不安症モデルに対する作用]雄性ICR
マウス(20−30g、日本チャールスリバー)を用い
た。動物を水温25℃のプール(直径13cm、高さ2
0cm)に10分間泳がせ水浸ストレスを与えた。水浸
ストレス10分後にCrawley及びGoodwin
(ファーマコロジー・バイオケミストリー・アンド・ビ
ヘービア、13巻167−170頁、1980)の方法
に従い明暗選択試験を行った。不安の程度は明室での滞
在時間を指標とした。化合物は0.3%Tween80
に懸濁し、水浸ストレスの30分前に経口投与した。1
群10から14匹の動物を用いた。このマウス水浸拘束
ストレス誘発不安症状に対する効果を表4に記す。Test Example 2 [Action on stress-induced anxiety model] Male ICR
Mice (20-30 g, Charles River Japan) were used. Pool the animals at a water temperature of 25 ° C (diameter 13 cm, height 2
0 cm) was allowed to swim for 10 minutes to apply water immersion stress. Crowley and Goodwin 10 minutes after water immersion stress
The light-dark selection test was performed according to the method of (Pharmacology Biochemistry and Behavior, Vol. 13, pp. 167-170, 1980). The degree of anxiety was based on the staying time in the bright room. Compound is 0.3% Tween80
And was orally administered 30 minutes before the water immersion stress. 1
Groups 10 to 14 animals were used. Table 4 shows the effect of this mouse on water immersion restraint stress-induced anxiety symptoms.
【0064】[0064]
【表4】 [Table 4]
【0065】製剤例1
化合物1−02を10g、乳糖45g、結晶セルロース
26g、カルボキシメチルセルロースカルシウム10g
及びヒドロキシプロピルセルロース5gをよく混合し、
常法により精製水で造粒し、乾燥後整粒した。これにス
テアリン酸マグネシウム4gを加えて混合後、常法によ
り1錠10mgの錠剤とした。Formulation Example 1 10 g of compound 1-02, 45 g of lactose, 26 g of crystalline cellulose, 10 g of calcium carboxymethyl cellulose
And 5 g of hydroxypropyl cellulose are mixed well,
The product was granulated with purified water by a conventional method, dried and then sized. To this, 4 g of magnesium stearate was added and mixed, and then a tablet of 10 mg was prepared by a conventional method.
【0066】製剤例2
化合物1−06を10g、マンニトール590g及びト
ウモロコシデンプン380gをよく混合し、これに10
%ヒドロキシプロピルセルロース水溶液200gを加
え、造粒、30号ふるいにかけて、1%含有の散剤とし
た。Formulation Example 2 10 g of compound 1-06, 590 g of mannitol and 380 g of corn starch were mixed well and mixed with 10 g of this.
% Hydroxypropylcellulose aqueous solution (200 g) was added, and the mixture was granulated and sieved through No. 30 sieve to give a powder containing 1%.
【0067】製剤例3
化合物1−06を1g、精製卵黄レシチン18g及びオ
レイン酸2.4gを100gの精製大豆油に加え、溶解
後、グリセリン22.1gを混合した注射用水800m
lを添加し、乳化機により乳化した。これに注射用水を
添加し、1000mlとした後、1mlのアンプルに分
注、封入、滅菌して注射剤とした。Formulation Example 3 1 g of Compound 1-06, 18 g of purified egg yolk lecithin and 2.4 g of oleic acid were added to 100 g of purified soybean oil, dissolved and then mixed with 22.1 g of glycerin 800 m water for injection.
1 was added and emulsified by an emulsifying machine. Water for injection was added to this to make 1000 ml, which was then dispensed, sealed and sterilized in a 1 ml ampoule to give an injection.
【0068】[0068]
【発明の効果】本発明のCRF受容体拮抗薬は、優れた
CRF受容体拮抗作用を有しており、CRFが関与して
いるとされるうつ症、不安症、アルツハイマー病、パー
キンソン病、ハンチントン舞踏病、摂食障害、高血圧、
消化器疾患、薬物依存症、てんかん、脳梗塞、脳虚血、
脳浮腫、頭部外傷、炎症、免疫関連疾患の治療剤又は予
防剤として有用である。INDUSTRIAL APPLICABILITY The CRF receptor antagonist of the present invention has an excellent CRF receptor antagonism, and depression, anxiety, Alzheimer's disease, Parkinson's disease, and Huntington, which are believed to involve CRF. Chorea, eating disorders, hypertension,
Digestive disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia,
It is useful as a therapeutic or preventive agent for cerebral edema, head injury, inflammation, and immune-related diseases.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 FI テーマコート゛(参考) A61K 31/505 AAM A61K 31/505 AAM ABA ABA ABE ABE ABN ABN ABU ABU ACT ACT ADR ADR C07D 401/04 239 C07D 401/04 239 405/14 211 405/14 211 409/14 211 409/14 211 (72)発明者 奥山 茂 東京都豊島区高田3丁目24番1号 大正製 薬株式会社内 (72)発明者 茶木 茂之 東京都豊島区高田3丁目24番1号 大正製 薬株式会社内 (72)発明者 冨沢 一雪 東京都豊島区高田3丁目24番1号 大正製 薬株式会社内 Fターム(参考) 4C063 AA01 BB02 CC29 DD11 EE01 4C086 AA01 AA02 BC16 BC42 GA07 MA01 MA04 NA14 ZA02 ZA05 ZA06 ZA12 ZA16 ZA36 ZA42 ZA66 ZB01 ZB11 ZC02 ZC39 ZC42 ─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 7 Identification code FI theme code (reference) A61K 31/505 AAM A61K 31/505 AAM ABA ABA ABE ABE ABN ABN ABU ABU ACT ACT ADR ADR C07D 401/04 2 C07D 401/04 239 405/14 211 405/14 211 409/14 211 211 409/14 211 (72) Inventor Shigeru Okuyama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Seiyaku Co., Ltd. (72) Inventor Shigeyuki Chaki 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Ikki Tomizawa 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. F-term (reference) 4C063 AA01 BB02 CC29 DD11 EE01 4C086 AA01 AA02 BC16 BC42 GA07 MA01 MA04 NA14 ZA02 ZA05 ZA06 ZA12 ZA16 ZA36 ZA42 Z A66 ZB01 ZB11 ZC02 ZC39 ZC42
Claims (5)
基、炭素数1〜5のアルコキシ基及びトリフルオロメチ
ル基から選択された1〜3個で置換されたフェニル基、
フェニル基、チエニル基又はフリル基を示し、R1 は水
素原子、炭素数1〜5のアルキル基、アミノ基又は1若
しくは2個の炭素数1〜5のアルキル基で置換されたア
ミノ基を示し、R2 は炭素数1〜5のアルキル基、炭素
数4〜7のシクロアルキルアルキル基、炭素数2〜5の
アルケニル基又は炭素数2〜5のアルキニル基を示し、
X1 、X2 及びX3 は同一又は異なって水素原子、ハロ
ゲン原子、炭素数1〜5のアルキル基、炭素数1〜5の
アルコキシ基、炭素数1〜5のアルキルチオ基、アミノ
基又は1若しくは2個の炭素数1〜5のアルキル基で置
換されたアミノ基を示す。)で表される4−テトラヒド
ロピリジルピリミジン誘導体又はその医薬上許容される
塩を有効成分とするCRF受容体拮抗薬。1. The formula [I]: (In the formula, Ar is a phenyl group substituted with 1 to 3 selected from a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, and a trifluoromethyl group,
Represents a phenyl group, a thienyl group, or a furyl group, R 1 represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an amino group, or an amino group substituted with 1 or 2 alkyl groups having 1 to 5 carbon atoms. , R 2 represents an alkyl group having 1 to 5 carbon atoms, a cycloalkylalkyl group having 4 to 7 carbon atoms, an alkenyl group having 2 to 5 carbon atoms or an alkynyl group having 2 to 5 carbon atoms,
X 1 , X 2 and X 3 are the same or different and each is a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, an amino group or 1 Alternatively, it represents an amino group substituted with two alkyl groups having 1 to 5 carbon atoms. ) A CRF receptor antagonist comprising a 4-tetrahydropyridylpyrimidine derivative represented by the formula (4) or a pharmaceutically acceptable salt thereof as an active ingredient.
rがテトラヒドロピリジン環の4位に置換し、Arがハ
ロゲン原子、炭素数1〜5のアルキル基、炭素数1〜5
のアルコキシ基及びトリフルオロメチル基から選択され
た1〜3個で置換されたフェニル基、フェニル基、チエ
ニル基又はフリル基であり、R1 がメチル基であり、R
2 がエチル基、シクロプロピルメチル基、アリル基又は
プロパルギル基であり、X1 が水素原子であり、X2 が
ベンゼン環の2位に置換したハロゲン原子又はメチルチ
オ基であり、X3 がベンゼン環の4位に置換したイソプ
ロピル基又はジメチルアミノ基である4−テトラヒドロ
ピリジルピリミジン誘導体又はその医薬上許容される塩
である請求項1記載のCRF受容体拮抗薬。2. The active ingredient is A in the formula [I].
r is substituted at the 4-position of the tetrahydropyridine ring, Ar is a halogen atom, an alkyl group having 1 to 5 carbon atoms, and 1 to 5 carbon atoms.
Is a phenyl group substituted with 1 to 3 selected from the alkoxy group and the trifluoromethyl group, a phenyl group, a thienyl group or a furyl group, R 1 is a methyl group, and R is
2 is an ethyl group, a cyclopropylmethyl group, an allyl group or a propargyl group, X 1 is a hydrogen atom, X 2 is a halogen atom substituted at the 2-position of the benzene ring or a methylthio group, and X 3 is a benzene ring. 4. The CRF receptor antagonist according to claim 1, which is a 4-tetrahydropyridylpyrimidine derivative having an isopropyl group or a dimethylamino group substituted at the 4-position thereof or a pharmaceutically acceptable salt thereof.
rがテトラヒドロピリジン環の5位に置換し、Arがハ
ロゲン原子、炭素数1〜5のアルキル基、炭素数1〜5
のアルコキシ基及びトリフルオロメチル基から選択され
た1〜3個で置換されたフェニル基、フェニル基、チエ
ニル基又はフリル基であり、R1 がメチル基であり、R
2 がエチル基、シクロプロピルメチル基、アリル基又は
プロパルギル基であり、X1 が水素原子であり、X2 が
ベンゼン環の2位に置換したハロゲン原子又はメチルチ
オ基であり、X3 がベンゼン環の4位に置換したイソプ
ロピル基又はジメチルアミノ基である4−テトラヒドロ
ピリジルピリミジン誘導体又はその医薬上許容される塩
である請求項1記載のCRF受容体拮抗薬。3. The active ingredient is A in the formula [I].
r is substituted at the 5-position of the tetrahydropyridine ring, Ar is a halogen atom, an alkyl group having 1 to 5 carbon atoms, and 1 to 5 carbon atoms.
Is a phenyl group substituted with 1 to 3 selected from the alkoxy group and the trifluoromethyl group, a phenyl group, a thienyl group or a furyl group, R 1 is a methyl group, and R is
2 is an ethyl group, a cyclopropylmethyl group, an allyl group or a propargyl group, X 1 is a hydrogen atom, X 2 is a halogen atom substituted at the 2-position of the benzene ring or a methylthio group, and X 3 is a benzene ring. 4. The CRF receptor antagonist according to claim 1, which is a 4-tetrahydropyridylpyrimidine derivative having an isopropyl group or a dimethylamino group substituted at the 4-position thereof or a pharmaceutically acceptable salt thereof.
ル基である請求項2記載のCRF受容体拮抗薬。4. The CRF receptor antagonist according to claim 2, wherein Ar is a phenyl group substituted with a halogen atom.
されたフェニル基である請求項3記載のCRF受容体拮
抗薬。5. The CRF receptor antagonist according to claim 3, wherein Ar is a phenyl group substituted with an alkyl group having 1 to 5 carbon atoms.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002019975A1 (en) * | 2000-09-05 | 2002-03-14 | Taisho Pharmaceutical Co., Ltd. | Hair growth stimulants |
-
1998
- 1998-08-12 JP JP10228329A patent/JP2000063277A/en not_active Withdrawn
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