JP6736660B2 - 疼痛のための治療化合物及びその合成 - Google Patents
疼痛のための治療化合物及びその合成 Download PDFInfo
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- JP6736660B2 JP6736660B2 JP2018511605A JP2018511605A JP6736660B2 JP 6736660 B2 JP6736660 B2 JP 6736660B2 JP 2018511605 A JP2018511605 A JP 2018511605A JP 2018511605 A JP2018511605 A JP 2018511605A JP 6736660 B2 JP6736660 B2 JP 6736660B2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/12—Oxygen atoms acylated by aromatic or heteroaromatic carboxylic acids, e.g. cocaine
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Description
本特許出願は、2016年9月4日出願の米国仮出願第62/214,727号、及び2015年9月4日出願の米国仮出願第62/214,734号の利益を主張し、各々が参照によりその全体が本明細書に組み込まれる。
本発明は、動物、哺乳動物、及びヒトにおける病態及び障害を治療するために使用することができる、新しい薬学的に活性な化学化合物を提供する。
「アルキル」という用語とは、例えば、鎖内に1〜12個の炭素原子を有する炭化水素鎖内の、分岐又は非分岐炭化水素鎖を指す。いくつかの実施形態において、アルキル基は、C1〜C6アルキル基である。いくつかの実施形態において、アルキル基は、C1〜C4アルキル基である。アルキル基の例としては、メチル(Me)エチル(Et)、n−プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル(tBu)、ペンチル、イソペンチル、tert−ペンチル、ヘキシル、イソヘキシル、及び当該技術分野における従来技術及び本明細書に提供される教示に照らして、前述の例のうちのいずれか1つに等価であるとみなされる基が挙げられる。
本発明は、式1の構造の化合物
本発明の化合物は、薬学的薬剤として有用であり、本明細書で定義される、治療有効量の本発明の化合物、及び薬学的に許容される担体又は希釈剤を含む薬学的組成物に組み込まれ得る。
式1の化合物は、スキーム1〜18において後述される工程によって、式19の化合物(スコポラミン[51−34−3])((2S)−(1R,2R,4S,5S)−9−メチル−3−オキサ−9−アザトリシクロ[3.3.1.02,4]ノナン−7−イル−3−ヒドロキシ−2−フェニルプロパノエート臭化水素酸三水和物)から合成した。
表7は、異なる投与経路を使用する繰り返し連日投与後の、神経因性疼痛のマウスモデルにおける式1の活性を要約する。
以下に、本願の当初の特許請求の範囲に記載された発明を付記する。
[1] 式1の化合物、
又はその立体異性体、薬学的に許容される塩、若しくは混合物。
[2] 式1が、
又はその立体異性体、薬学的に許容される塩、若しくは混合物である、[1]に記載の化合物。
[3] [2]に記載の化合物と、薬学的に許容される担体又は希釈剤と、を含む、薬学的組成物。
[4] 病態、疾患、又は障害に罹患している対象(ヒト若しくは動物)を治療するための方法であって、前記対象に、有効量の[2]に記載の化合物を投与することを含む、方法。
[5] 前記化合物が投与されて、前記対象に局所送達をもたらす、[4]に記載の方法。
[6] 前記化合物が投与されて、前記対象に全身送達をもたらす、[4]に記載の方法。
[7] 前記病態又は障害が、神経因性疼痛又は慢性疼痛である、[4]に記載の方法。
[8] 式1の化合物を製造する方法であって、
式2の化合物
を、還元剤の存在下で6−メトキシ−2−ナフタレンカルボキシアルデヒドと反応させることを含む、方法。
[9] 前記6−メトキシ−2−ナフタレンカルボキシアルデヒドが、前記還元剤の前に添加された、[8]に記載の方法。
[10] 前記還元剤が、トリアセトキシ水素化ホウ素ナトリウムである、[8]に記載の方法。
[11] 前記式1の化合物が、キラル的に分離される、[8]に記載の方法。
[12] 式3の化合物
を、酸と反応させることによって、前記式2の化合物を製造することを更に含む、[8]に記載の方法。
[13] 前記酸が、トリフルオロ酢酸である、[12]に記載の方法。
[14] 式4の化合物
を、ジメチルアミノピリジン(DMAP)と反応させることによって、前記式3の化合物を製造することを更に含む、[12]に記載の方法。
[15] 式5の化合物
を、tert−ブチルジフェニルクロロシランと反応させることによって、前記式4の化合物を製造することを更に含む、[14]に記載の方法。
[16] 前記反応が、ピリジンを更に含む、[15]に記載の方法。
[17] 式6.bの化合物
を、3,3,3−トリフルオロプロパン酸と反応させることによって、前記式5の化合物を製造することを更に含む、[15]に記載の方法。
[18] 前記反応が、N−N−ジイソプロピルエチルアミンを更に含む、[17]に記載の方法。
[19] 前記反応が、(1−[Bis(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム3−オキシドヘキサフルオロホスフェート)トリアセトキシ水素化ホウ素ナトリウムを更に含む、[18]に記載の方法。
[20] 式7の化合物
をキラル的に分離することによって、前記式6.bの化合物を製造することを更に含む、[17]に記載の方法。
[21] 式8の化合物
を、触媒の存在下で水素と反応させることによって、前記式7の化合物を製造することを更に含む、[20]に記載の方法。
[22] 前記触媒が、パラジウムを含む、[21]に記載の方法。
[23] 前記触媒が、炭素上のパラジウムである、[22]に記載の方法。
[24] 式9の化合物
を、Boc 2 Oと反応させることによって、前記式8の化合物を製造することを更に含む、[21]に記載の方法。
[25] 前記反応が、トリエチルアミン(Et 3 N)を更に含む、[24]に記載の方法。
[26] 式10の化合物
を、ヨードトリメチルシランと反応させることによって、前記式9の化合物を製造することを更に含む、[24]に記載の方法。
[27] 前記反応が、60℃より高い温度で起こる、[26]に記載の方法。
[28] 式11の化合物
を、tert−ブチルジフェニルクロロシランと反応させることによって、前記式9の化合物を製造することを更に含む、[26]に記載の方法。
[29] 前記反応が、イミダゾールを更に含む、[28]に記載の方法。
[30] 式12の化合物
を、ベンズアルデヒドと反応させることによって、前記式11の化合物を製造することを更に含む、[28]に記載の方法。
[31] 前記反応が、トリアセトキシ水素化ホウ素ナトリウムを更に含む、[30]に記載の方法。
[32] 式12.aの化合物
を、溶媒中で環化することによって、前記式11の化合物を製造することを更に含む、[30]に記載の方法。
[33] 前記溶媒が、エタノールである、[32]に記載の方法。
[34] 式13の化合物
を、触媒の存在下で水素と反応させることによって、前記式12.aの化合物を製造することを更に含む、[30]に記載の方法。
[35] 前記触媒が、ラネーニッケルである、[34]に記載の方法。
[36] 式14の化合物
を、シアン化カリウムと反応させることによって、前記式13の化合物を製造することを更に含む、[34]に記載の方法。
[37] 前記反応が、18−クラウン−6を更に含む、[36]に記載の方法。
[38] 式15の化合物
を、塩化メシルと反応させることによって、前記式14の化合物を製造することを更に含む、[36]に記載の方法。
[39] 前記反応が、トリエチルアミン(Et 3 N)を更に含む、[38]に記載の方法。
[40] 式16の化合物
を、還元剤と反応させることによって、前記式15の化合物を製造することを更に含む、[38]に記載の方法。
[41] 前記還元剤が、水素化ホウ素ナトリウムである、[40]に記載の方法。
[42] 式17の化合物
を、クロロギ酸エチルと反応させることによって、前記式16の化合物を製造することを更に含む、[40]に記載の方法。
[43] 前記反応が、塩基を更に含む、[42]に記載の方法。
[44] 前記塩基が、炭酸カリウムである、[43]に記載の方法。
[45] 式18の化合物
を、活性化剤の存在下で安息香酸と反応させることによって、前記式17の化合物を製造することを更に含む、[42]に記載の方法。
[46] 前記活性化剤が、トリフェニルホスフィンとジエチルアゾジカルボキシレート(DEAD)、又はトリフェニルホスフィンとジイソプロピルアゾジカルボキシレート(DIAD)である、[45]に記載の方法。
[47] 式19の化合物
を、還元剤と反応させることによって、前記式18の化合物を製造することを更に含む、[48]に記載の方法。
[48] 前記還元剤が、水素化ホウ素ナトリウムである、[47]に記載の方法。
[49] 前記反応が、イソプロピルアルコール中のHClを更に含む、[47]に記載の方法。
Claims (18)
- 式1の化合物、
- 式1が、
- 請求項2に記載の化合物と、薬学的に許容される担体又は希釈剤とを含む、薬学的組成物。
- 疼痛を治療するためのものである、請求項3に記載の薬学的組成物。
- 局所送達をもたらすためのものである、請求項4に記載の薬学的組成物。
- 全身送達をもたらすためのものである、請求項4に記載の薬学的組成物。
- 前記疼痛が、神経因性疼痛又は慢性疼痛である、請求項4〜6のいずれか1項に記載の薬学的組成物。
- 式1の化合物を製造する方法であって、
- 前記式1の化合物が、キラル的に分離される、請求項8に記載の方法。
- 式3の化合物
- 式4の化合物
- 式5の化合物
- 式6.bの化合物
- 式7の化合物
- スコポラミンと還元剤とを反応させることを含む、式1の化合物
- 前記方法が更に、式2の化合物
- 前記方法が更に、式7の化合物
- 前記方法が更に、式12.aの化合物
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JP6736661B2 (ja) * | 2015-09-04 | 2020-08-05 | ヤンセン ファーマシューティカ エヌ.ベー. | 治療化合物及び合成 |
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