JP2011517448A - Process for the preparation of benzo-fused dioxin derivatives - Google Patents

Abstract

  The present invention is directed to a process for the preparation of benzo-fused heteroaryl derivatives useful for the treatment of epilepsy and related diseases. The present invention is further directed to an intermediate preparation process in the synthesis of benzo-fused heteroaryl derivatives.

Description

  The present invention is directed to a process for the preparation of benzo-fused heteroaryl derivatives useful for the treatment of epilepsy and related diseases. The present invention is further directed to an intermediate preparation process in the synthesis of benzo-fused heteroaryl derivatives.

  Acupuncture describes symptoms in which a human has recurrent seizures due to a chronic underlying process. Because there are many types and causes of epilepsy, epilepsy refers to a clinical phenomenon rather than a single independent disease. Using the definition of epilepsy of two or more non-provocative seizures, the prevalence of epilepsy is estimated to be about 0.3-0.5 percent in various populations around the world, and the prevalence of epilepsy is 5 per 1000 people It is estimated to be 10 people.

  An essential step in the evaluation and management of stroke patients is to determine the type of stroke that occurred. The main feature that distinguishes different categories of seizures is whether seizure activity is partial (synonymous with focal) or systemic.

  Partial seizures are those in which seizure activity is limited to isolated areas of the cerebral cortex. If consciousness during a seizure is fully maintained, clinical symptoms are considered relatively simple, and the seizure is called a simple partial seizure. If consciousness is impaired, seizures are called complex partial seizures. An important additional subgroup includes those that begin as partial seizures and then diffusely spread throughout the cortex, known as partial seizures with secondary generalization.

  Generalized seizures involve the simultaneous diffusion to areas of the brain in a bilaterally symmetric manner. Absence seizures or minor seizures are characterized by a sudden and temporary loss of consciousness without loss of posture control. Atypical absence seizures typically have longer periods of loss of consciousness, less sudden onset and cessation, and more obvious motor signs that may include localized or lateralized characteristics Including that. The main type of generalized seizures, generalized tonic clonic seizures or major seizures, is characterized by sudden onset without warning. The early phase of the seizure is usually a marked increase in sympathetic tone leading to increased muscle tonic contraction, respiratory failure, heart rate, blood pressure, and pupil size. After 10-20 seconds, the tonic phase of the seizure typically develops into a chronic phase that results from the tonic muscle contraction superimposed on the muscle relaxation phase. The period of relaxation gradually increases until the end of the seizure period, which usually lasts less than 1 minute. The seizure period is characterized by unresponsiveness, muscle relaxation, and hypersalivation and may cause wheezing and partial airway obstruction. An tensionless seizure is characterized by a sudden loss of orthostatic muscle tone that lasts 1-2 seconds. Consciousness is temporarily impaired, but usually no post-seizure confusion occurs. Myoclonic attacks are characterized by sudden short muscle contractions involving part of the body or the whole body. (Harrisonsonline.com, March 29, 2001).

  US Patent Publication No. 2006/0041008 A1 (McComsey, D. et al., Dated February 23, 2006) and US Patent Publication No. 2005/0282887 A1 (McComsey, D. et al., Dated December 22, 2005) And compounds of formula (I) and their use in the treatment of and related diseases. US Patent Publication No. 2006/0041008 A1 (McComsey, D. et al. And US Patent Publication No. 2005/0282887 A1 (McComsey, D. et al.) Further comprise reacting a suitable substituted amine with sulfamide. A process for the preparation of compounds of formula (I) is also disclosed.

McComsey, D.M. In this process disclosed by J. et al., R ¹ and R ² are each hydrogen in the compound of formula (I), and sulfamoyl chloride (Cl—SO ₂ —NH ₂ ) is used as a reagent. It is described as being unsuitable for scale or commercial scale preparation. However, there remains a need for processes suitable for the preparation of large scale materials and / or commercial preparations of compounds of formula (I).

  The present invention is directed to a process for the preparation of compounds of formula (I),

式中、

Where

からなる群から選択され、
ｂは０〜４の整数であり、ｃは０〜２の整数であり、
各Ｒ⁵はハロゲン、低級アルキル、及びニトロからなる群から独立して選択され、
Ｒ⁴は水素及び低級アルキルからなる群から選択され、
Ｒ¹及びＲ²は、水素及び低級アルキル、
又は製薬上許容できるそれらの塩からなる群からそれぞれ独立して選択されるものであり、

Selected from the group consisting of
b is an integer of 0 to 4, c is an integer of 0 to 2,
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl, and nitro;
R ⁴ is selected from the group consisting of hydrogen and lower alkyl;
R ¹ and R ² are hydrogen and lower alkyl,
Or each independently selected from the group consisting of pharmaceutically acceptable salts thereof,

  Protecting the compound of formula (X) to obtain a compound corresponding to formula (XI),

からなる群から選択され、式中Ｐｇ¹はアルコール保護基である、保護する工程と、

A protecting step, wherein Pg ¹ is an alcohol protecting group, selected from the group consisting of:

  Reacting a compound of formula (XI) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XII);

  To obtain a compound corresponding to formula (XIII), the compound of formula (XII) is reacted with an organic or inorganic base in an organic solvent, in an organic solvent mixture, or in a mixture of one or more organic solvents and water. A process of

  Reacting a compound of formula (XIII) with an epoxy-methylene source in the presence of an inorganic base in an organic solvent at a temperature above about room temperature to obtain a compound corresponding to formula (XIV);

  Deprotecting the compound of formula (XIV) to obtain a compound corresponding to formula (XV);

  Reacting the compound of formula (XV) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V);

  Reacting a compound of formula (V) to obtain a compound corresponding to formula (I).

  The present invention is further directed to a process for preparing a compound of formula (V),

式中、

Where

からなる群から選択され、
ｂは０〜４の整数であり、ｃは０〜２の整数であり、
各Ｒ⁵はハロゲン、低級アルキル、及びニトロからなる群から独立して選択され、

Selected from the group consisting of
b is an integer of 0 to 4, c is an integer of 0 to 2,
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl, and nitro;

Protecting a compound of formula (X) to obtain a compound corresponding to formula (XI), wherein Pg ¹ is an alcohol protecting group;

  Reacting a compound of formula (XI) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XII);

  To obtain a compound corresponding to formula (XIII), the compound of formula (XII) is reacted with an organic or inorganic base in an organic solvent, in a mixture of organic solvents, or in a mixture of one or more organic solvents and water. A process of

  Reacting a compound of formula (XIII) with an epoxy-methylene source in the presence of an inorganic base in an organic solvent at a temperature above about room temperature to obtain a compound corresponding to formula (XIV);

  Deprotecting the compound of formula (XIV) to obtain a compound corresponding to formula (XV);

  Reacting the compound of formula (XV) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V).

  In one embodiment, the present invention provides a compound of formula (IS)

又は製薬上許容できるその塩（式（Ｉ−Ｓ）の化合物は、Ｎ−［［（２Ｓ）−６−クロロ−２，３−ジヒドロ−１，４−ベンゾダイオキシン−２−イル］メチル］−スルファミドとしても既知である）の調製プロセスを目的とし、

Or a pharmaceutically acceptable salt thereof (the compound of formula (IS) is N-[[(2S) -6-chloro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl]- For the preparation process) (also known as sulfamide)

Protecting the compound of formula (XS) to obtain a compound corresponding to formula (XI-S), wherein Pg ¹ is an alcohol protecting group;

  Reacting a compound of formula (XI-S) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XII-S);

  In order to obtain a compound corresponding to formula (XIII-S), the compound of formula (XII-S) can be organic or organic or in a mixture of organic solvents or in a mixture of one or more organic solvents and water. Reacting with an inorganic base;

  To obtain the compound corresponding to formula (XIV-S), the compound of formula (XIII-S) is reacted with the (R) -epoxy-methylene source in the presence of an inorganic base in an organic solvent at a temperature above about room temperature. A process of

  Deprotecting the compound of formula (XIV-S) to obtain a compound corresponding to formula (XV-S);

  Reacting the compound of formula (XV-S) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V-S);

  Reacting the compound of formula (VS) to obtain a compound corresponding to formula (IS).

  In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (VS)

  This compound is also known as (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl)-(S) -methanol,

Protecting the compound of formula (XS) to obtain a compound corresponding to formula (XI-S), wherein Pg ¹ is an alcohol protecting group;

  Reacting a compound of formula (XI-S) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XII-S);

  In order to obtain a compound corresponding to formula (XIII-S), the compound of formula (XII-S) can be organic or organic or in a mixture of organic solvents or in a mixture of one or more organic solvents and water. Reacting with an inorganic base;

  To obtain the compound corresponding to formula (XIV-S), the compound of formula (XIII-S) is reacted with the (R) -epoxy-methylene source in the presence of an inorganic base in an organic solvent at a temperature above about room temperature. A process of

  Deprotecting the compound of formula (XIV-S) to obtain a compound corresponding to formula (XV-S);

  Reacting the compound of formula (XV-S) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V-S).

  The present invention is further directed to a process for preparing compounds of formula (I),

式中、

Where

からなる群から選択され、
ｂは０〜４の整数であり、ｃは０〜２の整数であり、
各Ｒ⁵はハロゲン、低級アルキル、及びニトロからなる群から独立して選択され、
Ｒ⁴は水素及び低級アルキルからなる群から選択され、
Ｒ¹及びＲ²は、水素及び低級アルキル、
又は製薬上許容できるそれらの塩からなる群からそれぞれ独立して選択されるものであり、

Selected from the group consisting of
b is an integer of 0 to 4, c is an integer of 0 to 2,
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl, and nitro;
R ⁴ is selected from the group consisting of hydrogen and lower alkyl;
R ¹ and R ² are hydrogen and lower alkyl,
Or each independently selected from the group consisting of pharmaceutically acceptable salts thereof,

  In order to obtain a compound corresponding to formula (XVII), a compound of formula (XVI) (wherein

からなる群から選択され、Ｑは−Ｃ（Ｏ）−（Ｃ_1〜4アルキル）からなる群から選択される）、無機塩基の存在下でエポキシ−メチレン源と反応させる工程と、

And Q is selected from the group consisting of —C (O) — (C _1-4 alkyl)), reacting with an epoxy-methylene source in the presence of an inorganic base;

  Reacting a compound of formula (XVII) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XVIII);

  Reacting a compound of formula (XVIII) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V);

  Reacting a compound of formula (V) to obtain a compound corresponding to formula (I).

  The present invention is further directed to a process for preparing a compound of formula (V),

式中、

Where

からなる群から選択され、
ｂは０〜４の整数であり、ｃは０〜２の整数であり、
各Ｒ⁵はハロゲン、低級アルキル、及びニトロからなる群から独立して選択され、

Selected from the group consisting of
b is an integer of 0 to 4, c is an integer of 0 to 2,
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl, and nitro;

In order to obtain a compound corresponding to formula (XVII), a compound of formula (XVI) (wherein Q consists of —C (O) — (C _1-4 alkyl) in an organic solvent at temperatures above about room temperature) Reacting with an epoxy-methylene source in the presence of an inorganic base;

  Reacting a compound of formula (XVII) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XVIII);

  Reacting the compound of formula (XVIII) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V).

  In one embodiment, the object of the present invention is the formula

又は製薬上許容できるその塩（式（Ｉ−Ｓ）の化合物は、Ｎ−［［（２Ｓ）−６−クロロ−２，３−ジヒドロ−１，４−ベンゾダイオキシン−２−イル］メチル］−スルファミドとしても既知である）の化合物の調製プロセスを目的とし、

Or a pharmaceutically acceptable salt thereof (the compound of formula (IS) is N-[[(2S) -6-chloro-2,3-dihydro-1,4-benzodioxin-2-yl] methyl]- For the preparation process of compounds of (also known as sulfamide)

To obtain a compound corresponding to formula (XVII-S), a compound of formula (XVI-S) in an organic solvent at a temperature above about room temperature, wherein Q is -C (O)-(C _1-4 Reacting with (R) -epoxy-methylene source in the presence of an inorganic base;

  Reacting a compound of formula (XVII-S) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XVIII-S);

  Reacting a compound of formula (XVIII-S) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V-S);

  Reacting the compound of formula (VS) to obtain a compound corresponding to formula (IS).

  In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (VS)

  This compound is also known as (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl)-(S) -methanol,

To obtain a compound corresponding to formula (XVII-S), a compound of formula (XVI-S) in an organic solvent at a temperature above about room temperature, wherein Q is -C (O)-(C _1-4 Reacting with (R) -epoxy-methylene source in the presence of an inorganic base;

  Reacting a compound of formula (XVII-S) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XVIII-S);

  Reacting the compound of formula (XVIII-S) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V-S).

  The present invention is further directed to a crystalline form of the compound of formula (IS).

  In one embodiment, the object of the present invention is directed to the crystalline form (I-SA) according to the following definition. In another embodiment, the present invention is directed to a crystalline form (I-SB) according to the following definitions.

  The present invention is further directed to products manufactured according to any of the methods described herein.

  Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any crystalline form described herein or a product prepared by any process described herein. An illustration of the invention is made by mixing any crystalline form described herein or a product prepared by any process described herein with a pharmaceutically acceptable carrier. It is a pharmaceutical composition. An exemplary process of the present invention comprises mixing any crystalline form described herein or a product prepared by any process described herein and a pharmaceutically acceptable carrier. Is a process for producing a pharmaceutical composition.

  A representative example of the present invention is a method for the treatment of epilepsy or related diseases comprising administering to a patient in need thereof a therapeutically effective amount of any compound or pharmaceutical composition described above.

FIG. 6 illustrates a representative XRD spectrum of a representative sample in crystalline form (I-SA) (labeled b and c) and crystalline form (I-SB) (labeled a).

  The present invention is directed to a process for the preparation of a compound of formula (I)

式中Ｒ¹、Ｒ²、Ｒ⁴及び

In which R ¹ , R ² , R ⁴ and

は、本明細書で定義されたとおりである。本発明の化合物は、癲癇及び関連疾患の治療に有用である。

Is as defined herein. The compounds of the present invention are useful for the treatment of epilepsy and related diseases.

  The present invention is further directed to a process for preparing a compound of formula (V) and can be represented herein by any of the following formulas.

  Compounds of formula (V) are useful as intermediates in the synthesis of compounds of formula (I).

  In one embodiment, the present invention provides a formula

又は製薬上許容できるこれらの塩の化合物の調製プロセスを目的とする。別の実施形態において、本発明は、式（Ｖ−Ｓ）の化合物の調製プロセスを目的とする。

Alternatively, it is directed to a process for the preparation of pharmaceutically acceptable compounds of these salts. In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (VS).

  In one embodiment, the present invention provides a formula

及び製薬上許容できるこれらの塩の合成プロセスを目的とし、式中ｂ及びＲ⁵は本明細書に定義したとおりである。好ましくは、ｂは０〜２の整数であり、より好ましくは、ｂは０〜１の整数である。好ましくは、Ｒ⁵はハロゲンであり、より好ましくは、Ｒ⁵はクロロである。

And for the synthesis process of these pharmaceutically acceptable salts, wherein b and R ⁵ are as defined herein. Preferably, b is an integer from 0 to 2, more preferably b is an integer from 0 to 1. Preferably R ⁵ is halogen, more preferably R ⁵ is chloro.

In one embodiment of the invention, R ¹ is selected from the group consisting of hydrogen and methyl. In another embodiment of the invention, R ² is selected from the group consisting of hydrogen and methyl. In yet another embodiment of the invention, R ¹ and R ² are each hydrogen, or R ¹ and R ² are each methyl.

In one embodiment of the invention, R ⁴ is selected from the group consisting of hydrogen and methyl, preferably R ⁴ is hydrogen.

  In one embodiment of the present invention, b is an integer of 0-2. In another embodiment of the invention, c is an integer from 0-2. In another embodiment of the invention b is an integer from 0 to 1. In another embodiment of the invention, c is an integer from 0-1. In yet another embodiment of the present invention, the sum of b and c is an integer from 0 to 2, preferably an integer from 0 to 1. In yet another embodiment of the present invention, b is an integer from 0 to 2 and c is 0.

In one embodiment of the invention, R ⁵ is selected from the group consisting of hydrogen and lower alkyl. In another embodiment of the invention, R ⁵ is selected from chloro, fluoro, bromo, and methyl.

  In one embodiment of the invention,

からなる群から選択される環状構造である。本発明の別の実施形態において、

A cyclic structure selected from the group consisting of In another embodiment of the invention,

からなる群から選択される。

Selected from the group consisting of

  In one embodiment of the invention,

は、２−（６−クロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（５−クロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（７−ニトロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（６，７−ジクロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、及び２−（２，３−ジヒドロ−ナフト［２，３−ｂ］［１，４］ジオキシニル）からなる群から選択される環状構造である。本発明の別の実施形態において、

Are 2- (6-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (5-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7 -Nitro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6,7-dichloro-2,3-dihydro-benzo [1,4] dioxinyl), and 2- (2,3- A cyclic structure selected from the group consisting of dihydro-naphtho [2,3-b] [1,4] dioxinyl). In another embodiment of the invention,

は、２−（５−クロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（７−ニトロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（６，７−ジクロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、及び２−（２，３−ジヒドロ−ナフト［２，３−ｂ］［１，４］ジオキシニル）からなる群から選択される環状構造である。

Are 2- (5-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-nitro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6 , 7-dichloro-2,3-dihydro-benzo [1,4] dioxinyl), and 2- (2,3-dihydro-naphtho [2,3-b] [1,4] dioxinyl) A ring structure.

  In one embodiment of the invention,

は、２−（２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（６−クロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（６−フルオロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（５−フルオロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（７−クロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（７−ニトロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（７−メチル−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（５−クロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（６−ブロモ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（６，７−ジクロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（８−クロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、及び２−（２，３−ジヒドロ−ナフト［２，３−ｂ］［１，４］ジオキシニル）からなる群から選択される。

Are 2- (2,3-dihydro-benzo [1,4] dioxinyl), 2- (6-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6-fluoro-2 , 3-Dihydro-benzo [1,4] dioxinyl), 2- (5-fluoro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-nitro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-methyl-2,3-dihydro-benzo [1,4] dioxinyl ), 2- (5-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6-bromo-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6 , 7-Dichloro-2,3-dihydro-benzo [1,4] Oxynyl), 2- (8-chloro-2,3-dihydro-benzo [1,4] dioxinyl), and 2- (2,3-dihydro-naphtho [2,3-b] [1,4] dioxinyl) Selected from the group consisting of

  In another embodiment of the invention,

は、２−（２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（６−クロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（７−クロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（７−メチル−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（６−ブロモ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、及び２−（６，７−ジクロロ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）からなる群から選択される。本発明の別の実施形態において、

Are 2- (2,3-dihydro-benzo [1,4] dioxinyl), 2- (6-chloro-2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-chloro-2 , 3-Dihydro-benzo [1,4] dioxinyl), 2- (7-methyl-2,3-dihydro-benzo [1,4] dioxinyl), 2- (6-bromo-2,3-dihydro-benzo [1,4] dioxinyl), and 2- (6,7-dichloro-2,3-dihydro-benzo [1,4] dioxinyl). In another embodiment of the invention,

は、２−（２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、２−（７−メチル−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）、及び２−（６−ブロモ−２，３−ジヒドロ−ベンゾ［１，４］ジオキシニル）からなる群から選択される。

Are 2- (2,3-dihydro-benzo [1,4] dioxinyl), 2- (7-methyl-2,3-dihydro-benzo [1,4] dioxinyl), and 2- (6-bromo- 2,3-dihydro-benzo [1,4] dioxinyl).

  In one embodiment of the invention, the stereogenic center of the compound of formula (I) is in the S configuration. In another embodiment of the invention the stereogenic center of the compound of formula (I) is in the R configuration.

  In one embodiment of the invention, the compound of formula (I) is present as an enantiomerically enriched mixture, and the enantiomeric enrichment (% ee) is greater than about 75%, preferably greater than about 85%. More preferably greater than about 90%, more preferably greater than about 95%, more preferably greater than about 98%, and most preferably greater than 99%.

  Representative compounds of the present invention are as listed in Tables 1 and 2 below. In Tables 1 and 2 below, the column headed “Stereoscopic” indicates the configuration at the carbon atom of the heterocyclic ring attached to the bond marked with an asterisk. In the table, the compounds not specified are those prepared as a mixture of steric configurations. Where “R” or “S” is designated, the configuration is based on the enantiomerically enriched starting material.

Additional embodiments of the present invention are those wherein substituents selected for one or more of the variables specified herein (eg, R ¹ , R ² , R ⁴ , b, and R ⁵ ) are present. Including any independently selected as any individual substituent or any subset of substituents selected from the full list specified in the specification.

  As used herein, unless otherwise indicated, the term “halogen” means chlorine, bromine, fluorine, and iodine.

  As used herein, unless stated otherwise, the term “alkyl” includes straight and branched chains either when used alone or as part of a substituent. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and the like. Unless otherwise specified, “lower” when used with alkyl means a carbon chain configuration of from 1 to 4 carbon atoms.

  As used herein, unless otherwise specified, “alkoxy” shall refer to an oxygen ether group of the above linear or branched alkyl group. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.

As used herein, the notation “ ^* ” indicates the presence of a stereocenter.

  As used herein, unless otherwise specified, the term “enantiomerically enriched” when used as a description of a compound having one stereocenter, results in one steric configuration of the compound opposing the compound. It means that it exists in a larger amount than the three-dimensional configuration. Preferably, when a compound is referred to as enantiomerically enriched, the desired enantiomer of the compound is at least about 75% ee, more preferably at least 85% ee, more preferably at least 90% ee, more preferably at least It is present in an enantiomeric excess of 95% ee, more preferably at least 98% ee, most preferably at least 99% ee.

  Abbreviations used in the specification, particularly in the schemes and examples, are as follows:

  As used herein, unless otherwise noted, the term “vaginosis and related injuries” refers to the subject (preferably a human adult, child, or infant) experiencing one or more seizures and / or tremors. Means any failure. Suitable examples include sputum (including but not limited to sputum (locally related sputum, generalized sputum, sputum that causes both generalization and local seizures)), seizures as a combination of diseases or conditions (brain disorders, Phenylketonuria, juvenile Gaucher disease, Lundborg progressive clonic convulsions, stroke, head injury, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, seizures associated with sleep blockage, etc.) Examples include, but are not limited to, sexual tremor and restless foot syndrome. Preferably, the disorder is selected from epilepsy (regardless of type, underlying cause or origin), essential tremor, or restless leg syndrome, more preferably the disorder is epilepsy (type, underlying cause or Regardless of origin) or essential tremor.

  As used herein, the term “patient” refers to an animal, preferably a mammal, most preferably a human, that has been or has been the subject of treatment, observation, or experimentation.

  As used herein, the term “therapeutically effective amount” includes alleviation of symptoms of the disease or disorder being treated, as sought by a researcher, veterinarian, physician, or other clinician. The amount of active compound or pharmaceutical agent that elicits a biological or pharmaceutical response within a tissue system, animal, or human.

  As used herein, the term “composition” includes products that contain a particular component in a particular amount, as well as any product that is obtained directly or indirectly from a combination of a particular amount of a particular component. Intended to be.

  Unless otherwise noted, one skilled in the art will recognize that the reaction steps described herein and in the claims are more suitable under known conditions (eg, suitable solvents and solvents) to provide the desired product. It will be understood that it is carried out under temperature, pressure) with / or reactants. The term “suitable conditions” is carried out under known conditions (eg, with suitable solvents and / or reactants, at temperature, pressure) by known methods for the reaction step to provide the desired product. Means that

  One skilled in the art also refers to one reagent or reagent class / type / (eg, base, solvent, etc.) in multiple steps of the process in the specification and claims described in this disclosure. In some cases, it will be understood that the individual reagents are independently selected for each reaction step and may be the same or different from one another. For example, if two steps of the process list an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same as or different from the organic or inorganic base of the second step. .

  To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. Whether or not the term “about” is explicitly used, all amounts stated herein are meant to refer to their actual values, and approximate such values by experiment and / or measurement conditions. Is also meant to refer to an approximation of such a value as reasonably inferred based on ordinary skill in the art.

  As used herein, unless otherwise noted, the term “aprotic solvent” shall mean any solvent that does not produce protons. Suitable examples include, but are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene and the like.

  As used herein, unless otherwise indicated, the term “leaving group” shall mean a charged or uncharged atom or group that leaves during a substitution or displacement reaction. Suitable examples include, but are not limited to Br, Cl, I, mesylate, tosylate and the like.

As used herein, unless otherwise indicated, the term “nitrogen protecting group” can be attached to a nitrogen atom to protect it from participating in the reaction and is easily removed after the reaction. It shall mean a possible group. Suitable nitrogen protecting groups, carbamates - formula -C (O) OR [wherein, R is, for example, methyl, ethyl, t- butyl, benzyl, _{phenylethyl, CH 2 = CH-CH 2} - and the like] A group of amide-formula-C (O) -R ′ [wherein R ′ is, for example, methyl, phenyl, trifluoromethyl, etc.], an N-sulfonyl derivative—formula —SO ₂ —R ″ [wherein , R ″ is, for example, a group of tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamitylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, etc.] For example, but not limited to. Other suitable nitrogen protecting groups are T.I. W. Greene & P. G. M.M. Wuts' “Protective Groups in Organic Synthesis” (John Wiley & Sons, 1991).

  As used herein, unless otherwise noted, the term “alcohol protecting group” refers to the hydroxy group (OH) bonded to oxygen to protect the hydroxy group and prevent the hydroxy group from participating in the reaction. Means a group which can be removed easily after the reaction. Suitable alcohol protecting groups include t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, ethoxyethyl, THP, SEM, benzyl, 4-nitrobenzyl, 4-methoxybenzyl, allyl, and the like. It is not limited. Other suitable alcohol protecting groups are T.I. W. Greene & P. G. M.M. Wuts' “Protective Groups in Organic Synthesis” (John Wiley & Sons, 1991).

  If the compounds according to the invention have at least one chiral center, they can consequently exist as enantiomers. If the compounds have more than one chiral center, they can also exist as diastereomers. All such isomers and mixtures thereof are included within the scope of the present invention. Preferably, when the compound is present as an enantiomer, the enantiomer has an enantiomeric excess of about 75% or more, more preferably an enantiomeric excess of about 85% or more, even more preferably about 90%. % Enantiomeric excess, even more preferably about 95% or higher enantiomeric excess, even more preferably about 98% or higher enantiomeric excess, most preferably about 99% or higher. Present in enantiomeric excess. Similarly, when the compound is present as a diastereomer, the diastereomer has a diastereomeric excess of about 75% or more, more preferably a diastereomeric excess of about 85% or more, more preferably about 90%. With the above diastereomeric excess, even more preferably with a diastereomeric excess of about 95% or more, even more preferably with a diastereomeric excess of about 98% or more, most preferably with a diastereomeric excess of about 99% or more. Present in stereomeric excess.

  Furthermore, some crystalline forms of the compounds of the invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention can form solvates with water (ie, hydrates) or solvates with common organic solvents, such solvates also It is intended to be included within the scope of the present invention.

  One skilled in the art will recognize that the reaction steps of the present invention can be performed in a variety of solvents or solvent systems, and that the reaction steps can also be performed in a suitable solvent or mixture of solvent systems.

  If the process for producing the compounds according to the invention results in a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or the individual enantiomers may be prepared either by enantioselective synthesis or degradation. The compound is salted with optically active acids such as, for example, standard techniques such as (−)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid. After forming a diastereomeric pair by formation, fractional crystallization and free base regeneration can be performed to decompose them into their constituent enantiomers. Compounds can also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of chiral auxiliary groups. Alternatively, the compound may be resolved using a chiral HPLC column.

  During any process of preparation of the compounds of the invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule involved. This is described in “Protective Groups in Organic Chemistry”, J. Org. F. W. McOmie, Plenum Press, 1973, and T.W. W. Greene & P. G. M.M. This can be achieved by conventional protecting groups such as those described in Wuts' “Protective Groups in Organic Synthesis” (John Wiley & Sons, 1991). The protecting group may be removed at a convenient subsequent stage using methods known in the art.

  When used as a medicament, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts." However, other salts may be useful in preparing the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of these compounds include acid addition salts, which can be used, for example, to dissolve a solution of the compound in a pharmaceutically acceptable base such as NaOH, KOH, NaH, chloline hydroxide. It can be formed by mixing with a solution of (preferably a strong base).

  The present invention is directed to a process for the preparation of compounds of formula (V) detailed in Scheme 1 below.

  Therefore,

からなる群から選択される、好適に置換された式（Ｘ）の化合物、既知の化合物、又は既知の方法によって調製される化合物は、好適な保護剤（すなわち、例えば加水分解及び酸化のような後の反応条件下で安定な保護剤）、例えば、ベンジルブロミド、アリルブロミド、２−（トリメチルシリル）エトキシメチルクロライド（ＳＥＭ−Ｃｌ）、ｔ−ブチル−ジフェニルシリルクロライド、メトキシ又はニトロで置換されたベンジルブロミド（例えば、４−ニトロ−ベンジルブロミド、４−メトキシベンジルブロミドなど）、１−（Ｃ_1〜4アルコキシ）メチルハロゲン化物又は１−（Ｃ_1〜4アルコキシ）エチルハロゲン化物（このハロゲン化物はＣｌ、Ｂｒ、又はＩ（例えば、ＭＯＭ−Ｃｌ、エトキシエチルクロライドなど）である）などと、Ｋ₂ＣＯ₃、Ｎａ₂ＣＯ₃、Ｃｓ₂ＣＯ₃、テトラメチルグアニジン、ＴＥＡなどであり好ましくはＫ₂ＣＯ₃である有機又は無機塩基の存在下で（この塩基は好ましくは約１モル当量以上で、より好ましくは過剰量で存在する）、ほぼ室温より高い、好ましくは約４０℃〜約１００℃の範囲の温度で、より好ましくは、約６０℃〜約８０℃の範囲の温度で、最も好ましくは約６０℃の温度で、ＤＭＦ、ＴＨＦ、Ｎ−メチルピロリジノンなどのような有機溶媒中で、反応され保護されて、Ｐｇ¹が対応するアルコール保護基である式（ＸＩ）の化合物に対応する化合物をもたらす。例えば、保護剤がベンジルブロミドである場合、Ｐｇ¹は保護剤がアリルブロミドであるベンジルであり、Ｐｇ¹は保護剤がＭＯＭ−Ｃｌであるアリルであり、Ｐｇ¹はメトキシメチルエーテル（ＭＯＭ）である。当業者であれば、例えばＴ．Ｗ．Ｇｒｅｅｎｅ ＆ Ｐ．Ｇ．Ｍ．Ｗｕｔｓの「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」（Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ、１９９１年）（その全文は参照により本明細書に組み込まれる）に記載されているようなその他の保護基及びこれらの保護基を組み込むための方法が当該技術分野において既知であることを理解するであろう。

Suitably substituted compounds of formula (X), known compounds, or compounds prepared by known methods selected from the group consisting of are suitable protecting agents (ie, such as, for example, hydrolysis and oxidation). Protective agents that are stable under subsequent reaction conditions) such as benzyl bromide, allyl bromide, 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), t-butyl-diphenylsilyl chloride, benzyl substituted with methoxy or nitro Bromide (eg, 4-nitro-benzyl bromide, 4-methoxybenzyl bromide, etc.), 1- (C _1-4 alkoxy) methyl halide or 1- (C _1-4 alkoxy) ethyl halide (this halide is Cl , Br, or I (for example, MOM-Cl, ethoxyethyl chloride, etc.) _{K 2 CO 3, Na 2 CO} 3, Cs 2 CO 3, tetramethylguanidine, TEA, and the like preferably in the presence of an organic or inorganic base is K ₂ CO ₃ (this base is preferably about 1 molar equivalent or more And more preferably present in excess) at temperatures above about room temperature, preferably in the range of about 40 ° C. to about 100 ° C., more preferably in the range of about 60 ° C. to about 80 ° C. Preferably, at a temperature of about 60 ° C., reacted and protected in an organic solvent such as DMF, THF, N-methylpyrrolidinone, etc., corresponding to a compound of formula (XI), wherein Pg ¹ is the corresponding alcohol protecting group Resulting in a compound. For example, when the protective agent is benzyl bromide, Pg ¹ is benzyl whose protective agent is allyl bromide, Pg ¹ is allyl whose protective agent is MOM-Cl, and Pg ¹ is methoxymethyl ether (MOM). is there. A person skilled in the art, for example, T.W. W. Greene & P. G. M.M. To incorporate other protecting groups and those protecting groups as described in Wuts' Protective Groups in Organic Synthesis (John Wiley & Sons, 1991, which is incorporated herein by reference in its entirety). It will be understood that these methods are known in the art.

  The compound of formula (XI) is m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate, etc., preferably a suitably selected oxidizing agent such as m-CPBA (the oxidizing agent is at least about 1 mole) Equivalent, preferably about 1-2 molar equivalents) and DCE, DCM, chloroform, acetonitrile, NMP, etc., preferably reacted in an organic solvent such as DCM, preferably at about room temperature. To give compounds corresponding to formula (XII).

The compound of formula (XII) is NaOCH ₃ , Kt-butoxide, sodium carbonate, potassium bicarbonate, etc., preferably an organic or inorganic base such as NaOCH ₃ (this base is preferably about 1 to about 5 In an amount in the range of molar equivalents, more preferably in an amount in the range of about 2 to about 3 molar equivalents) and in an inorganic solvent or mixture thereof such as methanol, ethanol, propanol, a mixture of THF and alcohol, etc. Or in a mixture of one or more organic solvents and water, preferably in alcohol, more preferably in methanol, preferably at a temperature in the range from about room temperature to about reflux temperature, more preferably at about room temperature. Reacted to give the compound corresponding to formula (XIII).

  The compound of formula (XIII) is glycidyl-m-nosylate, glycidyl-tosylate, epichlorohydrin, epibromohydrin, etc., preferably glycidyl-m-nosylate or glycidyl-tosylate, preferably enantiomerically enriched. An epoxy-methylene source, more preferably an epoxy-methylene source such as (R) -glycidyl-m-nosylate or (R) -glycidyl-tosylate (ie

）（エポキシ−メチレン源は好ましくは約１〜約５モル当量の範囲の量、より好ましくは約１〜約２モル当量の範囲の量、より好ましくは約１．１〜約１．５モル当量の範囲の量で存在する）と、Ｋ₂ＣＯ₃、Ｎａ₂ＣＯ₃、Ｃｓ₂ＣＯ₃、ＮａＨ、ＫＨなどであり好ましくはＫ₂ＣＯ₃のような無機塩基（この無機塩基は、好ましくは約１モル当量以上の量で、より好ましくは過剰量で存在する）の存在下で、ほぼ室温より高い温度で、好ましくはほぼ室温〜約１００℃の範囲の温度で、より好ましくは約４０℃〜約６０℃の範囲の温度で、最も好ましくは４０℃の温度で、ＤＭＦ、ＴＨＦ、Ｎ−メチルピロリジノンなどであり、好ましくはＤＭＦのような有機溶媒中で反応されて、式（ＸＩＶ）に対応する化合物をもたらす。

) (Epoxy-methylene source is preferably in an amount ranging from about 1 to about 5 molar equivalents, more preferably in an amount ranging from about 1 to about 2 molar equivalents, more preferably from about 1.1 to about 1.5 molar equivalents. And an inorganic base such as K ₂ CO ₃ , preferably K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH, etc. In the presence of about 1 molar equivalent or more, more preferably in excess) at a temperature above about room temperature, preferably at a temperature in the range of about room temperature to about 100 ° C., more preferably about 40 ° C. Reacting in an organic solvent such as DMF, at a temperature in the range of ~ 60 ° C, most preferably at a temperature of 40 ° C, preferably in an organic solvent such as DMF to give formula (XIV) This gives the corresponding compound.

The compound of formula (XIV) is deprotected according to known methods to give the compound corresponding to formula (XV). For example, in the compound of formula (XIV), Pg ¹ is benzyl, allyl, etc., and the compound of formula (XIV) is a hydrogen or hydrogen source, preferably hydrogen gas (this hydrogen gas is about 69 kPa (10 psi) to about 103 kPa ( 15 psi) in the presence of a catalyst such as Pd / C, Pt, Pd (sulfide) / C, etc., and ethyl acetate, THF, isopropyl acetate, 2-methyl-THF, methyl It can be deprotected by reacting in an organic solvent such as t-butyl ether, ethanol and the like. Wherein Pg ¹ is an SEM or silyl protecting group, formula (XIV) is deprotected by reacting with a fluoride source such as tetrabutylammonium fluoride in an organic solvent such as THF. be able to. A person skilled in the art, for example, T.W. W. Greene & P. G. M.M. It will be appreciated that other methods for removing protecting groups are known in the art, as described in Wuts' “Protective Groups in Organic Synthesis” (John Wiley & Sons, 1991). Let's go.

  One skilled in the art will recognize that the reagent selected for deprotection of the compound of formula (XIV) is selected to be substantially non-reactive with respect to the epoxy group of the compound of formula (XIV). You will understand.

The compound of formula (XV) is NaOCH ₃ , Kt-butoxide, sodium carbonate and the like, preferably an organic or inorganic base such as NaOCH ₃ (this base is preferably in an amount of about 1 molar equivalent or more, More preferably present in excess), methanol, ethanol, THF, acetonitrile, etc., preferably reacted in an organic solvent such as methanol, preferably at about room temperature, resulting in a compound corresponding to formula (V) .

  One skilled in the art will recognize that when the epoxy-methylene source is enantiomerically enriched with one of the enantiomers, the compound of formula (V) will have its corresponding enantiomerically enriched upon opening the epoxide. It will be understood that it is prepared as a compound. For example, when enantiomerically enriched (R) -glycidyl-m-nosylate or (R) -glycidyl tosylate is reacted with a compound of formula (XIII), the process described in Scheme 1 above can be represented by formula (V),

に対応する化合物を、星印（「^*」）の付された位置で鏡像異性的に濃縮な（Ｓ）鏡像異性体としてもたらす。

To the enantiomerically enriched (S) enantiomer at the position marked with an asterisk (" ^* ").

Preferably, the process described in Scheme 1 above applies to the preparation of compounds of formula (V) where each R ⁵ is other than nitro. One skilled in the art, when one or more R ⁵ groups are nitro, the compound of formula (V) is a compound of formula (V) where the substituent at which one or more nitro groups are desired is hydrogen. Converting this hydrogen to the corresponding nitro group from the corresponding compound in a known manner, for example by reacting a mixture of nitric acid and sulfuric acid or a mixture of nitric acid and acetic acid, or reacting potassium nitrate and sulfuric acid. Will understand that it can be prepared.

  The present invention is further directed to a process for preparing compounds of formula (V) as detailed in Scheme 2 below.

Accordingly, Q is selected from the group consisting of —C (O) — (C _1-4 alkyl), wherein C _1-4 alkyl is primary C _1-4 alkyl, more preferably —C (O) —CH _{3 and the} like. A suitably substituted compound of formula (XVI), a known compound, or a compound prepared by a known method is glycidyl-m-nosylate, glycidyl-tosylate, epichlorohydrin, epibromohydrin, etc. Yes, preferably glycidyl-m-nosylate or glycidyl-tosylate, preferably an enantiomerically enriched epoxy-methylene source, more preferably an epoxy such as (R) -glycidyl-m-nosylate or (R) -glycidyl-tosylate A methylene source (ie

）（このエポキシ−メチレン源は、好ましくは約１〜約５モル当量の範囲の量で、より好ましくは約１〜約２モル当量の範囲の量で、より好ましくは約１．１〜約１．５モル当量の範囲の量で存在する）と、Ｋ₂ＣＯ₃、Ｎａ₂ＣＯ₃、Ｃｓ₂ＣＯ₃、ＮａＨ、ＫＨなどであり好ましくはＫ₂ＣＯ₃のような無機塩基の存在下で（この無機塩基は、好ましくは約１モル当量以上の量で、より好ましくは過剰量で存在する）、ほぼ室温以上の温度、好ましくはほぼ室温〜約１００℃の範囲の温度、より好ましくは約４０℃〜約６０℃の範囲の温度、最も好ましくは約４０℃の温度で、ＤＭＦ、ＴＨＦ、Ｎ−メチルピロリジノンなどであり好ましくはＤＭＦのような有機溶媒中で、反応されて、式（ＸＶＩＩ）に対応する化合物をもたらす。

(The epoxy-methylene source is preferably in an amount ranging from about 1 to about 5 molar equivalents, more preferably in an amount ranging from about 1 to about 2 molar equivalents, more preferably from about 1.1 to about 1). 0.5 molar equivalents) and K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH, etc., preferably in the presence of an inorganic base such as K ₂ CO ₃ (The inorganic base is preferably present in an amount of about 1 molar equivalent or more, more preferably in excess) at a temperature above about room temperature, preferably in the range of about room temperature to about 100 ° C., more preferably about Reaction in an organic solvent such as DMF, THF, N-methylpyrrolidinone and preferably in an organic solvent such as DMF at a temperature in the range of 40 ° C. to about 60 ° C., most preferably about 40 ° C. ) Is obtained.

The compound of formula (XVII) is m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably a suitably selected oxidizing agent such as m-CPBA (the oxidizing agent is at least about 1 molar equivalent) , Preferably in an amount of about 1-2 molar equivalents) and is reacted in an organic solvent such as DCE, DCM, chloroform, acetonitrile, NMP, etc., preferably in DCM, preferably at about room temperature. This results in the compound corresponding to (XVIII). When Q is —C (O) — (CH ₃ ), the compound of formula (XVII) is reacted in DMF under conditions other than monomagnesium peroxyphthalate.

The compound of formula (XVIII) is NaOCH ₃ , Kt-butoxide, sodium carbonate and the like, preferably an organic or inorganic base such as NaOCH ₃ (this base is preferably in an amount of about 1 molar equivalent or more, More preferably present in excess), methanol, ethanol, THF, acetonitrile, etc., preferably reacted in an organic solvent such as methanol, preferably at about room temperature, resulting in a compound corresponding to formula (V) .

  One skilled in the art will recognize that when the epoxy-methylene source is enantiomerically enriched with one of the enantiomers, the compound of formula (V) will have its corresponding enantiomerically enriched upon opening the epoxide. It will be understood that it is prepared as a compound. For example, when enantiomerically enriched (R) -glycidyl-m-nosylate or (R) -glycidyl tosylate is reacted with a compound of formula (XIII), the process described in Scheme 2 above can be represented by formula (Va)

に対応する化合物を、星印（「^*」）の付された位置で鏡像異性的に濃縮な（Ｓ）鏡像異性体としてもたらす。

To the enantiomerically enriched (S) enantiomer at the position marked with an asterisk (" ^* ").

  The compound of formula (V) can be further purified by known methods (eg, US Patent Publication No. 2006/0041008 A1 (McComsey, D. et al., February 23, 2006) and US Patent Publication No. 2005/0282887 A1 ( McComsey, D. et al., Dated December 22, 2005)) to give compounds corresponding to formula (I).

For example, compounds of formula (I) where R ⁴ is hydrogen can be prepared according to the process outlined in Scheme 3.

  Thus, a suitably substituted compound of formula (V), prepared for example as outlined in Scheme 1 or 2 above, is activated by known methods so that J is Cl, Br, I, mesylate, triflate. This results in a compound corresponding to formula (XIX) which is a suitable leaving group such as a rate.

  The compound of formula (XIX) is more preferably in a phthalimide salt such as potassium phthalimide, sodium phthalimide and the like in an organic solvent such as DMF, DMSO, acetonitrile, etc., preferably at a high temperature in the range of 50 ° C. to about 200 ° C. Preferably, the reaction is carried out at a temperature of about 50 ° C. to about 150 ° C. when the organic solvent is DMF, DMSO or the like, and at about the reflux temperature when the organic solvent is acetonitrile or the like to obtain a compound corresponding to the formula (XX). Bring.

The compound of the formula (XX) is reacted with N ₂ H ₄ which is a known compound in an organic solvent such as ethanol, methanol, etc. at about 50 ° C. to about 100 ° C., more preferably at about reflux temperature. , Resulting in a compound corresponding to formula (XXI).

The compound of formula (XXI) is a known compound, sulfamide (NH ₂ —SO ₂ —NH ₂ ) (preferably the sulfamide is present in an amount ranging from about 2 to about 5 equivalents), THF, dioxane, etc. In an organic solvent such as, preferably at an elevated temperature in the range of about 50 ° C. to about 100 ° C., more preferably at about reflux temperature, to give compounds corresponding to formula (Ia), ie R ¹ and R ² Resulting in compounds of formula (I) wherein each is hydrogen.

  Alternatively, the compound of formula (XXI) is combined with a suitably substituted compound of formula (XXII), which is a known compound or a compound prepared by a known method, in the presence of a base such as TEA, DIPEA, pyridine, etc. Reaction in an organic solvent such as DMF, DMSO and the like yields compounds corresponding to formula (Ib).

  In one embodiment, the present invention is directed to a process for the preparation of a compound of formula (VS) as outlined in Scheme 4 below.

Accordingly, a suitably substituted compound of formula (XS), a known compound, or a compound prepared by a known method may be converted to a suitable protecting agent (ie, subsequent reaction conditions such as hydrolysis and oxidation). Benzyl bromides substituted with benzyl bromide, allyl bromide, 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl), t-butyl-diphenylsilyl chloride, methoxy, or nitro , 4-nitro-benzyl bromide, 4-methoxybenzyl bromide, etc.), 1- (C _1-4 alkoxy) methyl halide or 1- (C _1-4 alkoxy) ethyl halide (this halide is Cl, Br, or I (for example, MOM-Cl, ethoxyethyl chloride or the like) is) and the like, K ₂ C _{3, Na 2 CO 3, Cs} 2 CO 3, tetramethylguanidine, such as TEA, preferably in the presence of an organic or inorganic base is K ₂ CO ₃ (in this base is preferably about 1 molar equivalent or more More preferably in excess) at a temperature above about room temperature, preferably at a temperature of about 40 ° C. to about 100 ° C., more preferably at a temperature of about 60 ° C. to about 80 ° C., most preferably about Corresponding to a compound of formula (XI-S) in which Pg ¹ is the corresponding alcohol protecting group when reacted and protected in an organic solvent such as DMF, THF, N-methylpyrrolidinone at a temperature of 60 ° C. Resulting in a compound. For example, when the protective agent is benzyl bromide, Pg ¹ is benzyl whose protective agent is allyl bromide, Pg ¹ is allyl whose protective agent is MOM-Cl, and Pg ¹ is methoxymethyl ether. A person skilled in the art, for example, T.W. W. Greene & P. G. M.M. To incorporate other protecting groups and those protecting groups as described in Wuts' Protective Groups in Organic Synthesis (John Wiley & Sons, 1991, which is incorporated herein by reference in its entirety). It will be understood that these methods are known in the art.

  The compound of formula (XI-S) is m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably a suitably selected oxidizing agent such as m-CPBA (the oxidizing agent is at least about 1 And is reacted in an organic solvent such as DCM, preferably at about room temperature, preferably DCE, DCM, chloroform, acetonitrile, NMP, etc. To give the compound corresponding to formula (XII-S).

The compound of formula (XII-S) is NaOCH ₃ , Kt-butoxide, sodium carbonate, potassium hydrogen carbonate and the like, preferably an organic or inorganic base such as NaOCH ₃ (this base is preferably about 1 to about Present in an amount in the range of 5 molar equivalents, more preferably in an amount in the range of about 2 to about 3 molar equivalents) and an inorganic solvent, such as methanol, ethanol, propanol, a mixture of THF and alcohol, or the like In a mixture of one or more organic solvents and water, preferably in an alcohol, more preferably in methanol, preferably at a temperature in the range from about room temperature to about reflux temperature, more preferably at about room temperature. To give the compound corresponding to formula (XIII-S).

  The compound of formula (XIII) is (R) -glycidyl-m-nosylate, (R) -glycidyl-tosylate, (R) -epichlorohydrin, (R) -epibromohydrin, etc. ) -Glycidyl-m-nosylate or (R) -epoxy-methylene source such as (R) -glycidyl-tosylate (ie

）（エポキシ−メチレン源は好ましくは約１〜約５モル当量の範囲の量、より好ましくは約１〜約２モル当量の範囲の量、より好ましくは約１．１〜約１．５モル当量の範囲の量で存在する）と、Ｋ₂ＣＯ₃、Ｎａ₂ＣＯ₃、Ｃｓ₂ＣＯ₃、ＮａＨ、ＫＨなどであり好ましくはＫ₂ＣＯ₃のような無機塩基（この無機塩基は、好ましくは約１モル当量以上の量で、より好ましくは過剰量で存在する）の存在下で、ほぼ室温より高い温度で、好ましくはほぼ室温〜約１００℃の範囲の温度で、より好ましくは約４０℃〜約６０℃の範囲の温度で、最も好ましくは４０℃の温度で、ＤＭＦ、ＴＨＦ、Ｎ−メチルピロリジノンなどであり好ましくはＤＭＦであるような有機溶媒中で反応されて、式（ＸＩＶ−Ｓ）に対応する化合物をもたらす。

) (Epoxy-methylene source is preferably in an amount ranging from about 1 to about 5 molar equivalents, more preferably in an amount ranging from about 1 to about 2 molar equivalents, more preferably from about 1.1 to about 1.5 molar equivalents. And an inorganic base such as K ₂ CO ₃ , preferably K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH, etc. In the presence of about 1 molar equivalent or more, more preferably in excess) at a temperature above about room temperature, preferably at a temperature in the range of about room temperature to about 100 ° C., more preferably about 40 ° C. Reaction in an organic solvent such as DMF, THF, N-methylpyrrolidinone, etc., preferably DMF, at a temperature in the range of ˜about 60 ° C., most preferably 40 ° C. ) Is obtained.

The compound of formula (XIV-S) is deprotected according to known methods to give the compound corresponding to formula (XV-S). For example, in the compound of formula (XIV-S), Pg ¹ is benzyl, allyl, etc., and the compound of formula (XIV-S) is hydrogen or a hydrogen source, preferably hydrogen gas (this hydrogen gas is about 69 kPa (10 psi)) In the presence of a catalyst such as Pd / C, Pt, Pd (sulfide) / C, etc., and ethyl acetate, THF, isopropyl acetate, 2-methyl It can be deprotected by reaction in an organic solvent such as THF, methyl-t-butyl ether, ethanol and the like. Wherein Pg ¹ is SEM or a silyl protecting group, the formula (XIV-S) can be removed by reacting a fluoride source such as tetrabutylammonium fluoride in an organic solvent such as THF. Can be protected. A person skilled in the art, for example, T.W. W. Greene & P. G. M.M. It will be understood that other methods for removing protecting groups are known in the art, such as described in Wuts' “Protective Groups in Organic Synthesis” (John Wiley & Sons, 1991). .

  One skilled in the art will select a reagent that is substantially non-reactive with the epoxy group of the compound of formula (XIV-S) as the reagent selected for deprotection of the compound of formula (XIV-S). You will understand that

The compound of formula (XV-S) is NaOCH ₃ , Kt-butoxide, sodium carbonate and the like, preferably an organic or inorganic base such as NaOCH ₃ (this base is preferably in an amount of about 1 molar equivalent or more). More preferably present in excess) methanol, ethanol, THF, acetonitrile, etc., preferably in an organic solvent such as methanol, preferably at about room temperature, corresponding to formula (V-S) Resulting in a compound.

  In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (VS) as outlined in Scheme 5 below.

Thus, Q is selected from —C (O) — (C _1-4 alkyl), where C _1-4 alkyl is preferably primary C _1-4 alkyl, more preferably —C (O) —CH _{3 and the} like. A suitably substituted compound of formula (XVI-S), a known compound, or a compound prepared by a known method is (R) -glycidyl-m-nosylate, (R) -glycidyl-tosylate, ( R) -epichlorohydrin, (R) -epibromohydrin, etc., preferably a (R) -epoxy-methylene source such as (R) -glycidyl-m-nosylate or (R) -glycidyl-tosylate ( That is,

）（このエポキシ−メチレン源は、好ましくは、約１〜約５モル当量の範囲の量で、より好ましくは約１〜約２モル当量の範囲の量で、より好ましくは約１．１〜約１．５モル当量の範囲の量で存在する）と、Ｋ₂ＣＯ₃、Ｎａ₂ＣＯ₃、Ｃｓ₂ＣＯ₃、ＮａＨ、ＫＨなどであり好ましくはＫ₂ＣＯ₃のような無機塩基の存在下で（この無機塩基は、好ましくは、約１モル当量で、より好ましくは過剰量で存在する）、ほぼ室温の温度、より好ましくはほぼ室温〜約１００℃の範囲の温度、より好ましくは約４０℃〜約６０℃の範囲の温度、最も好ましくは約４０℃の温度で、ＤＭＦ、ＴＨＦ、Ｎ−メチルピロリジノンなどであり好ましくはＤＭＦのような有機溶媒中で、反応されて、式（ＸＶＩＩ−Ｓ）に対応する化合物をもたらす。

(The epoxy-methylene source is preferably in an amount ranging from about 1 to about 5 molar equivalents, more preferably in an amount ranging from about 1 to about 2 molar equivalents, more preferably from about 1.1 to about In the range of 1.5 molar equivalents) and K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH, etc., preferably in the presence of an inorganic base such as K ₂ CO ₃ (This inorganic base is preferably present in about 1 molar equivalent, more preferably in excess) at a temperature of about room temperature, more preferably a temperature in the range of about room temperature to about 100 ° C., more preferably about 40 Reaction in an organic solvent such as DMF, THF, N-methylpyrrolidinone, etc., preferably DMF, at a temperature in the range of from about 60 ° C. to about 60 ° C., most preferably about 40 ° C. Resulting in the compound corresponding to S).

The compound of formula (XIII-S) is m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably a suitably selected oxidizing agent such as m-CPBA (the oxidizing agent is at least about 1 And is reacted in an organic solvent such as DCM, preferably at about room temperature, preferably DCE, DCM, chloroform, acetonitrile, NMP, etc. To give the compound corresponding to formula (XIII-S). When Q is —C (O) — (CH ₃ ), the compound of formula (XVII-S) is reacted in DMF under conditions other than monomagnesium peroxyphthalate.

The compound of formula (XVIII-S) is NaOCH ₃ , Kt-butoxide, sodium carbonate and the like, preferably with an organic or inorganic base such as NaOCH ₃ (this base is preferably in an amount of about 1 molar equivalent or more). More preferably present in excess) methanol, ethanol, THF, acetonitrile, etc., preferably in an organic solvent such as methanol, preferably at about room temperature, corresponding to formula (V-S) Resulting in a compound.

  Compounds of formula (V-S) can be further prepared by known methods (eg, US Patent Publication No. 2006/0041008 A1 (McComsey, D. et al., February 23, 2006) and US Patent Publication No. 2005/0282887 A1. (Disclosed in McComsey, D. et al., December 22, 2005)) to provide compounds corresponding to formula (IS).

  For example, compounds of formula (IS) can be prepared according to the process outlined in Scheme 6 below.

  Thus, for example, a suitably substituted compound of formula (VS), prepared as outlined in Scheme 1, 2, 4 or 5 above, is activated by known methods such that J is tosylate, This results in compounds corresponding to formula (XIX-S) which are suitable leaving groups such as Cl, Br, I, mesylate, triflate and the like.

  The compound of formula (XIX-S) is preferably used in a phthalimide salt such as potassium phthalimide, sodium phthalimide and the like in an organic solvent such as DMF, DMSO, acetonitrile, etc., preferably at a high temperature in the range of 50 ° C. to about 200 ° C. More preferably, when the organic solvent is DMF, DMSO or the like, the reaction is performed at a temperature of about 50 ° C. to about 150 ° C., and when the organic solvent is acetonitrile or the like, the reaction is performed at about the reflux temperature. This gives the corresponding compound.

The compound of the formula (XX-S) reacts with N ₂ H ₄ which is a known compound in an organic solvent such as ethanol and methanol at about 50 ° C. to about 100 ° C., more preferably at about reflux temperature. To give the compound corresponding to formula (XXI-S).

The compound of formula (XXI-S) is a known compound, sulfamide (NH ₂ —SO ₂ —NH ₂ ) (preferably the sulfamide is present in an amount ranging from about 2 to about 5 equivalents), THF, Reacted in an organic solvent such as dioxane, preferably at an elevated temperature in the range of about 50 ° C. to about 100 ° C., more preferably at about reflux temperature, to provide a compound corresponding to formula (IS).

  Alternatively, a compound of formula (XXI-S) is replaced with a suitably substituted compound of formula (XXII-S), which is a known compound also known as sulfamoyl chloride, and a base such as TEA, DIPEA, pyridine, etc. Is reacted in an organic solvent such as DMF, DMSO, etc. to give the corresponding compound of formula (IS).

  The present invention is further directed to crystalline forms of the compound of formula (IS) (hereinafter referred to as crystalline forms (IS-SA) and (I-SB)). The crystalline forms of the compounds of formula (IS) can be characterized by their powder X-ray diffraction (PXRD) spectrum.

  In one embodiment, the crystalline forms of the compounds of formula (IS) can be characterized by their corresponding PXRD peaks, which peaks have a relative intensity greater than or equal to about 10%. Preferably, these peaks have a relative intensity of about 25% or greater. In one embodiment, the crystalline form of the compound of formula (IS) can be characterized by its corresponding PXRD peak, which has a position (° 2θ), d-spacing (Å) and relative intensity. (%). In another embodiment, the crystalline form of the compound of formula (IS) can be characterized by a corresponding PXRD peak, which is defined by position (° 2θ) and d-spacing (Å). Is done.

  The powder XRD spectrum was measured on a representative sample of the crystalline form of the compound of formula (IS) having the peaks described in Tables 2 and 3 below. The PXRD spectrum consists of an X-Celerator detector, scan form 3 to 35 ° 2θ, step size 0.0165 ° 2θ, 10.16 sec / step, effective scan rate 0.2067 ° / sec, instrument voltage 45 kV and current setting 40 mA. Was measured using.

  The crystalline form (I-SA) can be prepared, for example, as described in Example 13 below. The melting point of the crystalline form (I-SA) was measured on a representative sample and showed an onset of melting point of 98.6 ° C to 100.8 ° C. The crystalline form (I-SA) can be characterized by a powder XRD peak as described in Table XRD-1 below.

  Crystalline form (I-SB) can be prepared by recrystallizing the compound of formula (IS) from water according to known methods, for example, as described in Example 14 below. The melting point of crystalline form (I-SA) was measured on a representative sample and showed onset of melting at 100.7 ° C. and 102.8 ° C. The crystalline form (I-SB) can be characterized by a powder XRD peak as described in Table 3 below.

  FIG. 1 illustrates representative powder X-ray diffraction patterns corresponding to the following samples. (A) The top scan corresponds to a representative sample of crystalline form (I-SB), and (b) the middle and bottom scans are of two separately prepared crystalline forms (I-SA). Corresponds to the sample.

  The present invention further includes pharmaceutical compositions containing one or more compounds prepared according to any method described herein, together with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as active ingredients can be prepared by intimately mixing the compound (s) with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the desired route of administration (eg, oral, parenteral). Thus, for liquid oral formulations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, colorants and the like. For solid oral formulations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. Solid oral preparations may be coated with a substance such as sugar or enteric coated to control the primary site of absorption. For parenteral administration, the carrier usually consists of sterile water and other ingredients may be added for increased solubility or storage. Injectable suspensions or solutions can also be prepared using aqueous carriers with suitable additives.

  To produce a pharmaceutical composition of the present invention, one or more compounds of the present invention as an active ingredient are intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, such as oral or muscle Various forms may be taken depending on the form of the formulation desired for parenteral administration, such as internal or internal. Any conventional pharmaceutical vehicle can be used for the manufacture of the composition in an oral dosage form. Thus, for example, in liquid oral formulations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, colorants and the like, For solid oral formulations such as powders, capsules, caplets, gelcaps, and tablets, suitable carriers and additives include starch, sugar, diluents, granulating agents, lubricants, binders, disintegrants. Etc. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. Optionally, the tablets may be sugar coated or enteric coated by standard techniques. When parenterally, the carrier usually contains sterile water, but may contain other ingredients for purposes such as, for example, to aid solubility or for storage. Suspensions for injection can also be prepared, in which case appropriate liquid carriers, suspending agents and the like can be used. The pharmaceutical compositions herein include the amount of active ingredient necessary to deliver the effective dosages described above per dosage unit, eg, tablets, capsules, powders, injections, teaspoonfuls, etc. It is. The pharmaceutical composition herein comprises a dosage unit such as a tablet, capsule, powder, injection, suppository, teaspoonful, etc., at about 1-1000 mg / kg / day, or about 0.01-300 mg / day. kg / day, or any range therein, preferably about 0.5-100 mg / kg / day, or any range therein, more preferably about 1.0-25.0 mg / kg / day, or It can be given in any range of dosages therein. However, the dosage may vary depending on the patient's requirements, the severity of the condition being treated and the compound employed. Either daily administration or post-cycle administration may be used.

  Preferably, these compositions are for oral, parenteral, intranasal, sublingual or rectal administration, or administration by inhalation or insufflation, eg tablets, pills, capsules, powders, granules, sterile parenteral solutions Or a unit dosage form such as a suspension, metered dose aerosol or liquid propellant, drop, ampoule, autoinjector, or suppository. Alternatively, the composition can be present in a form suitable for once-weekly or monthly administration, for example, an insoluble salt of the active compound such as decanoate provides a depot preparation for intramuscular injection. Can be adapted to. For the preparation of solid compositions such as tablets, the main active ingredient can be a pharmaceutical carrier such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum. These are mixed with conventional tableting ingredients and other pharmaceutical diluents such as water to form solid preformulation compositions containing a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable salt thereof. When these pre-formulated compositions are referred to as homogeneous, this means that the active ingredient is evenly dispersed throughout the composition so that the composition is equally effective, such as tablets, pills and capsules. It means that it can be easily divided into shapes. This solid pre-blended composition is then divided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the new composition can be coated or otherwise formulated to provide a dosage form that offers the advantage of long-term action. For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form of the former jacket. The two components can be separated by an enteric layer that prevents disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. Various materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

  Liquid forms that may incorporate the novel compositions of the present invention for oral or infusion administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and cottonseed oil, sesame oil, coconut oil or peanut oil Flavored emulsions containing edible oils, as well as elixirs and similar pharmaceutical excipients. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

  The methods for treating epilepsy or related disorders described in the present invention can also be performed using a pharmaceutical composition comprising any compound as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain about 0.1 mg to 1000 mg of the compound, preferably about 50 to 500 mg or any range thereof, and can be configured in any form suitable for the selected dosage form. Carriers include necessary and inert pharmaceutical excipients including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (including rapid release, timed release and sustained release formulations, respectively), granules, and powders, as well as liquids, Liquid forms such as syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

  Advantageously, the compounds of the invention may be administered in a daily dose, or the total daily dose may be administered in two, three or four divided doses per day. Furthermore, the compounds for the present invention may be administered in nasal dosage forms by topical use of suitable intranasal excipients well known to those skilled in the art or via transdermal skin patches. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

  For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. . In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, benzoic acid Examples thereof include sodium acid, sodium acetate, and sodium chloride, but are not limited thereto. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

  The liquid takes the form of suitably flavored suspending or dispersing agents such as synthetic and natural gums such as tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

  To prepare the pharmaceutical compositions of the invention, the compound of formula (I) as the active ingredient is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, but the carrier is administered ( For example, it can take a wide variety of forms depending on the form of the formulation desired (orally or parenterally). Suitable pharmaceutically acceptable carriers are well known in the art. Some descriptions of these pharmaceutically acceptable carriers can be found in “Handbook of Pharmaceutical Excitents” published by American Pharmaceutical Association and Pharmaceutical Society of Great Britain.

  Methods for formulating pharmaceutical compositions are described, for example, in the publication of Marcel Dekker, Inc, edited by Lieberman et al., “Pharmaceutical Dosage Forms: Tables”, 2nd edition, revised and expanded, Vols 1-3, Avis et al., “Pharmaceutical. Dosage Forms: Parental Medicines ", Volumes 1 and 2, and published in numerous publications such as Liberman et al.," Pharmaceutical Dosage Forms: Disperse Systems ", Volumes 1 and 2.

  The compounds of the present invention can be administered in any of the aforementioned compositions according to established dosage regimes in the art whenever treatment of sputum or related disorder conditions is required.

  The daily dose of the product may vary over a wide range of 0.01 to 10,000 mg per day for a human adult, or any range therein. For oral administration, the composition is preferably 0.01, 0.05, 0.1, 0.5, 1.0, 2.5 for symptomatic adjustment of the dose to the patient to be treated. , 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient are preferably provided. An effective amount of the drug is usually provided at a dosage level of about 0.01 mg / kg body weight to about 500 mg / kg body weight per day, or any range therein. More preferably, the range is from about 0.05 to about 100.0 mg / kg body weight / day or any range therein, even more preferably from about 1.0 to about 50.0 mg / kg body weight / day or It is an arbitrary range among them. The compounds can be administered on a regimen of 1 to 4 times per day.

  The optimal dosage to be administered can be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the formulation, the mode of administration, and the progression of disease symptoms. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

  One skilled in the art will recognize that both in vivo and in vitro testing using suitable, known and generally accepted cells and / or animal models can predict the ability of a test compound to treat or prevent a given disease. Will do.

  Those skilled in the art will be able to conduct human clinical trials, including first-in-human studies, dose determination studies, and efficacy studies in healthy patients and / or patients suffering from certain diseases. It will be further appreciated that it can be accomplished according to methods well known in the clinical and medical fields.

  The following examples are set forth to assist in understanding the invention, and are not intended and should not be construed in any way as limiting the invention described in the following claims. is not.

  In the following examples, some synthesis products are listed as isolated as a residue. One skilled in the art will appreciate that the term “residue” is not intended to limit the physical state in which the product is isolated, but may include, for example, solids, oils, foams, gums, syrups, and the like. Let's go.

Example 1
2-Benzyloxy-5-chloro-benzaldehyde

An A2L three-necked flask (with a mechanical stirrer, nitrogen inlet, and thermocouple) was charged with 5-chlorosalicylaldehyde (7.23 g, 0.147 mol), benzyl bromide (25.1 g, 0.147 mol). ), Potassium carbonate (20.3 g, 0.147 mol), and N, N-dimethylformamide (650 mL). The reaction mixture was heated to 60 ° C. for 18 hours (overnight). The reaction mixture was poured into water (700 mL) and then extracted with ethyl ether (3 × 300 mL). The combined organics were washed with brine (2 × 200 mL), dried (MgSO ₄ ) and concentrated to give the crude product. The crude product was dissolved in 1: 1 heptane-dichloromethane and loaded onto Biotage 75S (200 g silica gel), heptane (1 L), then 1: 9 (3 L), and 3: 7 (2 L) ethyl acetate-heptane. Elution gave the title compound as a solid.

¹ H NMR (CDCl ₃ ) δ ppm: 10.48 (s, 1H), 7.81 (d, J = 3.1 Hz, 1H), 7.42 (m, 6H), 7.01 (d, J = 8.9 Hz, 1H), 5.19 (s, 2H).

(Example 2)
Formic acid, 2-benzyloxy-5-chloro-phenyl ester

A 1 L one-necked flask (with a magnetic stirrer and nitrogen inlet) was charged with 2-benzyloxy-5-chloro-benzaldehyde (8, 28.1 g, 0.114 mol) and dichloromethane (360 mL). To this solution was added m-CPBA (˜75%, 31.4 g, 0.137 mol). The reaction mixture was stirred at room temperature for 17 hours (overnight) to give a white slurry. This white solid was filtered off and then the 10% (w / w) filtrate was washed with sodium bisulfite (200 mL) and each phase was tested with iodine starch paper to see if there was residual oxidant. did. The test was negative and the organic phase was washed with saturated sodium bicarbonate (2 × 150 mL), dried (MgSO ₄ ) and concentrated to give the crude product as a solid. The crude product was used in the subsequent step without further purification.

¹ H NMR (CDCl ₃ ) δ ppm: 8.25 (s, 1H), 7.37 (m, 5H), 7.15 (m, 2H), 6.95 (d, J = 8.7 Hz, 1H) , 5.09 (s, 2H).

(Example 3)
2-Benzyloxy-5-chloro-phenol

A one-necked flask (with a magnetic stirrer and nitrogen inlet) was charged with crude formic acid, 2-benzyloxy-5-chloro-phenyl ester (9.28 g, 0.107 mol), sodium methoxide (25% in methanol (w / w)). w) Charged 26.5 mL, 0.123 mol), and methanol (175 mL). The reaction mixture was stirred for 18 hours (overnight). The reaction mixture was concentrated to a red oil and partitioned between saturated ammonium chloride (200 mL) and ethyl ether (200 mL). The aqueous solution was extracted with ethyl ether (100 mL) and the combined organics were washed with brine, dried (MgSO ₄ ) and concentrated to give the title compound as an oil. The product was used in the subsequent step without further purification.

¹ H NMR (CDCl ₃ ) δ ppm: 7.41 (m, 5H), 6.95 (d, J = 1.8 Hz, 1H), 6.82 (m, 2H), 5.71 (s, 1H) , 5.09 (s, 2H).

Example 4
(R) -2- (2-Benzyloxy-5-chloro-phenoxymethyl) -oxirane

A 500 mL three-necked flask (with a magnetic stir bar, thermocouple, and nitrogen inlet) was charged with 2-benzyloxy-5-chloro-phenol (10, 11.3 g, 48.2 mmol), (R) -glycidyl m- Nitrophenyl sulfonate (11.3 g, 43.8 mmol) and N, N-dimethylformamide (200 mL) were charged. The reaction mixture was heated to 40 ° C. for 12 hours, then cooled to room temperature and poured into water (300 mL). The aqueous phase was extracted with ethyl ether (3 × 200 mL). The combined organic phases were washed with 1M sodium hydroxide (aq), brine (3 × 100 mL), dried (MgSO ₄ ) and concentrated under reduced pressure to give the crude product as an oil. The oil was dissolved in heptane-dichloromethane 1: 1 and eluted on an Isco cartridge (120 g silica gel) to give the title compound as an oil.

¹ H NMR (CDCl ₃ ) δ ppm: 7.38 (m, 5H), 6.94 (d, J = 2.5 Hz, 1H), 6.85 (m, 2H), 5.11 (s, 2H) 4.28 (dd, J = 11.4, 3.3 Hz, 1H), 4.01 (dd, J = 11.3, 5.5 Hz, 1H), 3.38 (m, 1H), 2. 89 (dd, J = 5.1, 4.9 Hz, 1H), 2.77 (dd, J = 5.0, 2.6 Hz, 1H).

(Example 5)
(R) -4-Chloro-2-oxiranylmethoxy-phenol

  A Parr reaction vessel was charged with 5% palladium on carbon (dry, 1.0 g), (R) -2- (2-benzyloxy-5-chloro-phenoxymethyl) -oxirane (11, 11.7 g, 40.2). Mmol) and ethyl acetate (250 mL). The reaction mixture was stirred on a Parr shaker at room temperature under 5 to 7 psi hydrogen gas for 2.5 hours. The catalyst was filtered off and ethyl acetate was removed under reduced pressure to give the title compound as a solidified oil. The product was used in the subsequent step without further purification.

¹ H NMR (CDCl ₃ ) δ ppm: 6.87 (m, 3H), 6.09 (bs, 1H), 4.25 (dd, J = 11.4, 2.6 Hz, 1H), 3.98 ( dd, J = 11.3, 5.7 Hz, 1H), 3.39 (m, 1H), 2.96 (t, J = 4.6 Hz, 1H), 2.85 (dd, J = 5.2) , 2.7 Hz, 1 H).

(Example 6)
(S)-(6-Chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methanol

To a one-necked flask (with a magnetic stirrer and nitrogen inlet) was added (R) -4-chloro-2-oxiranylmethoxy-phenol (12, 8.1 g, 40.4 mmol), sodium methoxide (in methanol). 25% (w / w), 10.5 mL, 48.4 mmol), and methanol (90 mL) were charged. The reaction mixture was stirred for 18 hours (overnight). The reaction mixture was concentrated to a red oil and partitioned between water (250 mL) and ethyl ether (200 mL). The aqueous layer was extracted with ethyl ether (2 × 100 mL) and the combined organics were washed with 1M aqueous sodium hydroxide (150 mL), brine (2 × 100 mL), dried (MgSO ₄ ) and concentrated, A crude product was obtained. The crude product was dissolved in dichloromethane, loaded onto Biotage 40M (silica gel 90 g) and eluted with dichloromethane (250 mL) and ethyl acetate-dichloromethane (1 L) 1:19 to give the title compound as a white solid. (19415-132A).

  Melting point: 73-75 ° C.

Light pressure rotation: [α] _D = −58.0 ° (c1.99, MeOH, 23 ° C.)
¹ H NMR (CDCl ₃ ) δ ppm: 6.82 (m, 3H), 4.30 (dd, J = 11.1, 2.2 Hz, 1H), 4.24 (m, 1H), 4.10 ( dd, J = 11.2, 7.4 Hz, 1H), 3.87 (m, 2H), 1.95 (t, J = 6.6 Hz, 1H).

(Example 7)
(R) -1- (4-Chloro-2-oxiranylmethoxy-phenyl) -ethanone

A 22 L four-necked flask (with a mechanical stirrer, thermocouple, Teflon stopper, and argon inlet) was charged with 4-chloro-2-hydroxy-acetophenone (13, 687.2 g, 4.03 mol) and N, N-dimethylformamide (14.0 L) was charged. To this solution was added potassium carbonate (613 g, 4.43 mol) and (R) -glycidyl m-nitrophenyl sulfonate (1.045 kg, 4.03 mol). The reaction mixture was heated to 40 ° C. over 20 hours (overnight), then cooled to room temperature and divided into two parts. Each portion was poured into water (9 L) and extracted with methyl tert-butyl ether (3 × 2 L). The two organic phases were each washed with brine (2 × 4 L), dried (MgSO ₄ ) and concentrated under reduced pressure to use the crude product obtained in the subsequent step without further purification. did.

¹ H NMR (CDCl ₃ ) δ ppm: 7.71 (d, J = 8.5 Hz, 1H), 7.02 (dd, J = 8.8, 1.7 Hz, 1H), 6.95 (d, J = 1.8 Hz, 1H), 4.39 (dd, J = 11.0, 2.8 Hz, 1H), 3.98 (dd, J = 10.8, 6.1 Hz, 1H), 3.41 ( m, 1H), 2.96 (t, J = 4.4 Hz, 1H), 2.78 (dd, J = 5.1, 2.7 Hz, 1H), 2.64 (s, 3H).

A small amount of the product prepared as described above was chromatographed (Isco silica-40 g) to give a white powder.
MP: 79-80 ° C.
Light pressure rotation: [a] _D = -19.4 ° (c2.02, MeOH, 23 ° C).
High resolution MS: (as C ₁₁ H ₁₂ O ₃ Cl, M ^{+ H} ): Calculated: 227.48, Measured: 227.05

(Example 8)
(R) -acetic acid, 4-chloro-2-oxiranylmethoxy-phenyl ester

A 22 L four-necked flask (with a mechanical stirrer, two stoppers, and a condenser with an argon inlet) was charged with (R) -1- (4-chloro-2-oxiranylmethoxy-phenyl) -ethanone ( 14,815 g, 3.60 mol) and dichloromethane (8.8 L) were charged. To this solution was added m-CPBA (˜75% Lancaster, 993 g, 4.31 mol oxidant). The reaction mixture was warmed at warm reflux over 3 days for 22 hours (heated only under supervision). Then additional m-CPBA (100 g, ˜0.36 mol) was added and reflux was continued for another 8 hours. The reaction mixture was then cooled overnight to give a white slurry upon cooling. The white solid was removed by filtration and the filtrate was partitioned into 4 portions. Each part was washed with 10% (w / w) sodium bisulfite (1 L) and both phases were tested on iodine starch paper to see if there was any residual oxidant. The test result was negative, the aqueous phase was back extracted with dichloromethane (2 × 250 mL) and the combined organic phases (4 portions) were washed with saturated sodium bicarbonate (3 × 500 mL) and dried (MgSO ₄ ) And the crude product obtained by concentration was used in the subsequent step without further purification.

¹ H NMR (CDCl ₃ ) δ ppm: 6.96 (m, 3H), 4.25 (dd, J = 10.9, 2.4 Hz, 1H), 3.94 (dd, J = 11.5, 5 .6 Hz, 1H), 3.30 (m, 1H), 2.88 (t, J = 4.8 Hz, 1H), 2.71 (dd, J = 4.8, 2.6 Hz, 1H), 2 .31 (s, 3H).

A small amount of the crude product prepared as described above was chromatographed (Isco silica-12g) to give a clear oil.
Light pressure rotation: [α] _D = −8.29 ° (c2.05, MeOH, 23 ° C.).
High resolution MS: (as C ₁₁ H ₁₁ O ₃ Cl, M ⁺ ): calculated value: 242.03, measured value: 242.03

Example 9
(S)-(6-Chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methanol

A 12 L four-necked flask (with a mechanical stirrer, two stoppers, and a nitrogen inlet) was charged with (R) -acetic acid, 4-chloro-2-oxiranylmethoxy-phenyl ester (15, 1.019 kg ( Impure), hypothetical 874 g, 3.60 mol), sodium methoxide (25% in methanol (w / w), 972 mL, 4.50 mol) and methanol (6.0 L) were charged. The reaction mixture was stirred for 20 hours (overnight), then treated with 3M aqueous sodium hydroxide (500 mL) and stirred for an additional 6 days. The red oil obtained by concentrating the reaction mixture was diluted with water to a volume of 4.0 L. This material was partitioned into two portions and each aqueous phase was extracted with methyl tert-butyl ether (2 × 1.0) and ethyl ether (1 L). These organic phases were washed with 10% aqueous sodium bisulfite (500 mL), saturated sodium bicarbonate (500 mL), brine (2 × 500 mL), dried (MgSO ₄ ) and concentrated to give the crude product. . The crude product was used in the subsequent step without further purification.

¹ H NMR (CDCl ₃ ) δ ppm: 6.89 (m, 1H), 6.2 (m, 2H), 4.30 (dd, J = 11.3, 2.2 Hz, 1H), 4.23 ( m, 1H), 4.10 (dd, J = 10.9, 7.6 Hz, 1H), 3.91 (dd, J = 12.0, 4.2 Hz, 1H), 3.83 (dd, J = 12.1, 5.4 Hz, 1H).

A small amount of the crude product prepared as described above was chromatographed (Isco silica-12g) to give a white solid.
Melting point: 79-81 ° C.
Light pressure rotation: [α] _D = −58.2 ° (c 2.05, MeOH, 23 ° C.),
Chiral HPLC: Chiralpak AS-H, hexane / IPA (97: 3), R t = 16.095 min,> 99% ee.
High resolution MS: (as C ₉ H ₉ O ₃ Cl, M ⁺ ): calculated value: 200.02: measured value: 200.02

(Example 10)
(R) -Toluene-4-sulfonic acid, 6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl-methyl ester

A 12 L four-necked flask (with a mechanical stirrer, nitrogen inlet, and two stoppers) was charged with (S)-(6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl. ) -Methanol (2,300 g, 1.50 mol) and 4.5 L of tetrahydrofuran / dichloromethane (9: 1) were charged. This solution was treated with N-methylmorpholine (362 mL, 3.29 mol), N, N-dimethylaminopyridine (36.4 g, 0.298 mol), and paratoluenesulfonyl chloride (341 g, 1.79 mol). . The reaction mixture was stirred at room temperature under nitrogen for 10 days (˜4 days later, the reaction was apparently complete). The reaction mixture was filtered to remove amine hydrochloride and partitioned into two portions. Each portion was stirred with 20% aqueous potassium bicarbonate (3 L) for 2.5 hours. Each portion was then extracted with isopropylacetic acid (2 × 1.5 L) and the organics were washed with 2M hydrochloric acid (2 × 1 L), saturated sodium bicarbonate (2 × 1 L), brine (500 mL) and dried ( MgSO ₄ ). The resulting mixture was concentrated to give a crude product. The crude product was dissolved in dichloromethane / heptane (1: 3) and loaded onto Biotage 150 L (silica gel 5 kg), heptane (8 L), 1: 9 ethyl acetate-heptane (24 L), 15:85 ethyl acetate-heptane ( 48L) and eluted with 1: 2 ethyl acetate-heptane (18 L) (207 kPa (30 psi)) to give the title compound as an off-white solid.

¹ H NMR (DMSO-d6) δ ppm: 7.79 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 2. 5 Hz, 1 H), 6.87 (dd, J = 8.8, 2.5 Hz, 1 H), 6.8 (d, J = 8.8 Hz, 1 H), 4.46 (m, 1 H), 4. 35 (dd, J = 11.7, 3.1 Hz, 1H), 4.29 (dd, J = 11.7, 2.5 Hz, 1H), 4.20 (dd, J = 11.3, 6. 4 Hz, 1 H), 3.99 (dd, J = 11.5, 6.2 Hz, 1 H), 2.42 (s, 1 H).

Light pressure rotation: [α] _D = −34.73 ° (c2.02, MeOH, 23 ° C.).

(Example 11)
(S) -2- (6-Chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -isoindolin-1,3-dione

  A 12 L four-necked flask (with a mechanical stirrer, an air condenser with a nitrogen inlet on top, and two stoppers) was charged with (R) -toluene-4-sulfonic acid, 6-chloro-2,3-dihydro. Filled with benzo [1,4] dioxin-2-yl-methyl ester (3,443 g, 1.25 mol), potassium phthalimido (301 g, 1.62 mol) and N, N-dimethylformamide (5 L). The reaction mixture was heated to 100 ° C. over 2 hours and then cooled to room temperature over 16 hours (overnight). The reaction mixture was diluted with water (6 L) and stirred for 2.5 hours. The resulting white solid was collected by vacuum filtration and dried in a 55 ° C. vacuum oven to give the title compound as an off-white solid.

¹ H NMR (DMSO-d6) δ ppm: 7.84 (m, 4H), 6.98 (d, J = 2.9 Hz, 1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.49 (qd, J = 6.1, 2.2, 1H), 4.36 (dd, J = 11.4, 2 .7 Hz, 1 H), 4.13 (dd, J = 11.9, 2.5 Hz, 1 H), 3.88 (m, 2 H).

  Melting point: 126-127 ° C.

(Example 12)
(S)-(6-Chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamide

A 12 L four-necked flask (with a mechanical stirrer, a water condenser with a nitrogen inlet at the top, and two stoppers) was charged with (S) -2- (6-chloro-2,3-dihydro-benzo [ 1,4] dioxin-2-ylmethyl) -isoindolin-1,3-dione (4,370 g, 1.12 mol), hydrazine (65.2 mL, 2.08 mol), and ethanol (4 L) were charged. The reaction mixture was heated at reflux for 1.5 hours and then cooled to room temperature. The reaction mixture was acidified with 1M hydrochloric acid (2 L) and filtered. The filtrate was concentrated to remove ethanol, then basified with 3M sodium hydroxide (1 L) and extracted with ethyl ether (2 L, then 2 × 1 L). The combined organics were washed with brine (2 × 600 mL), dried (MgSO ₄ ) and concentrated to give the title compound as a white solid that was used in the subsequent step without further purification. did.

¹ H NMR (DMSO-d6) δ ppm: 6.95 (d, J = 1.9 Hz, 1H), 6.87 (m, 2H), 4.37 (dd, J = 11.5, 2.6, 1H), 4.07 (m, 1H), 3.98 (dd, J = 10.9, 7.7 Hz, 1H), 2.83 (dd, J = 12.7, 5.4, 1H), 2.77 (dd, J = 12.7, 6.1, 1H).

Melting point: 70-71 ° C.
Light pressure rotation: [α] _D = −81.0 ° (c2.00, MeOH, 23 ° C.).

(Example 13)
(S) -N- (6-Chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide

In a 12 L four-necked flask (with a mechanical stirrer, a water condenser with a nitrogen inlet at the top, and two stoppers), (S)-(6-chloro-2,3-dihydro-benzo [1, 4] Dioxin-2-yl) -methylamine (5,214 g, 1.07 mol), sulfamide (412 g, 4.29 mol), and isopropyl acetate (4 L) were charged. The reaction mixture was then heated to reflux over 3 days for a total of 15 hours and then cooled to room temperature. The reaction mixture was cooled in an ice bath and the residue was collected by filtration and washed with isopropyl acetate. The filtrate was washed with 1M hydrochloric acid (3 L), dried (MgSO ₄ ) and concentrated to give the crude product. All of the crude product is dissolved in ethyl acetate, absorbed onto silica gel (600 g), loaded onto a Biotage sample induction module, then heptane (2 L), 1: 9 ethyl acetate-heptane (4 L), 3: 7 ethyl acetate. Elution into Biotage 150M (silica gel 2.5 g) using heptane (12 L), 1: 1 ethyl acetate-heptane (16 L) gave the product along with the mixed fractions. The mixed fraction was purified using Biotage 75L (1 L), 1: 9 ethyl acetate-heptane (4 L), 3: 7 ethyl acetate-heptane (6 L), 1: 1 ethyl acetate-heptane (8 L). 800g silica) was rechromatographed to give additional product. These two product lots were combined to give the title compound as an off-white solid.

  The title compound prepared by the procedure described in this example is of the formula (I-SA).

¹ H NMR (DMSO-d6) δ ppm: 6.98 (d, J = 1.9 Hz, 1H), 6.89 (m, 3H), 6.67 (bs, 2H), 4.36 (dd, J = 11.7, 1.6, 1H), 4.28 (m, 1H), 4.00 (dd, J = 11.5, 6.8 Hz, 1H), 3.19 (m, 1H), 3 .11 (m, 1H).

Melting point: 99-100 ° C.
Light pressure rotation: [α] _D = −57.6 ° (c2.14, MeOH, 23 ° C.).
Chiral HPLC: Chiralpak AD-H, hexane (0.1% TEA) / IPA (80:20), R _t = 11.407 min,> 99% ee.

Elemental analysis of C ₉ H ₁₁ ClN ₂ O ₄ S.
Calculated:% C 38.78,% H 3.98,% Cl 12.72,% N 10.05,% S 11.51.
Measurements:% C 38.81,% H 3.74,% Cl 12.83,% N 9.93,% S 11.53.

(Example 14)
Water recrystallization of (S) -N- (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide
Obtained by adding distilled water (5 mL) to (S) -N- (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide (0.050 g) in a test tube. The resulting mixture was heated. It was observed that the white solid dissolved in water before the water boiled. As the water cooled, the material precipitated out as a suspension and white needles formed over 2 hours. The crystals were removed by filtration, rinsed with water, air dried and recovered to give the crystalline form (I-SB) as defined herein.

(Example 15)
(R) -Toluene-4-sulfonic acid, (7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methyl ester

(S)-(7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl) methanol {[α] _D = −35.6 ° (c = 1.45, EtOH), 7. 12 g, 35.4 mmol} (prepared by the method disclosed in AM Birch et al., Journal of Medicinal Chemistry 1999, 42, 3342-3355) was dissolved in pyridine (50 mL) and cooled to 0 ° C. To the resulting mixture was added para-toluenesulfonyl chloride (6.68 g, 35.5 mmol) and the reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was then cooled in an ice bath and 1N HCl (750 mL) was added. The reaction mixture was extracted with diethyl ether (3x, 200 mL). The combined diethyl ether was washed with 1N HCl (2 ×, 250 mL), water, brine (2 ×), dried (MgSO ₄ ) and evaporated under reduced pressure to give the title compound as a white solid. .

¹ H NMR (CDCl ₃ ) δ 7.79 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 6.76 (m, 3H), 4.40 ( m, 1H), 4.21 (m, 3H), 4.03 (dd, J = 6.2, 11.6 Hz, 1H), 2.61 (s, 3H).

(Example 16)
(S) -2- (7-Chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -isoindolin-1,3-dione

  (R) -Toluene-4-sulfonic acid, (7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methyl ester (10.65 g) (as in Example 15 above) Prepared) in potassium phthalimido (8.90 g, 48 mmol) and DMF (100 mL) and the resulting mixture was heated to reflux for 1 hour, then cooled to room temperature and vigorously stirred ice water ( 750 mL) and stirred for 30 minutes. The resulting white solid was filtered, washed several times with water, and then dried under reduced pressure (16 hours) to give the title compound as a white powdery solid.

¹ H NMR (CDCl ₃ ) δ 7.89 (m, 2H), 7.75 (m, 2H), 6.82 (m, 3H), 4.50 (m, 1H), 4.29 (dd, J = 2.3, 11.6 Hz, 1H), 4.05 (m, 2H), 3.89 (dd, J = 5.4, 14.2 Hz, 1H).

(Example 17)
(S)-(7-Chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine

(S) -2- (7-Chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -isoindolin-1,3-dione (8.1 g, 24.6 mmol, above example) 16) was combined with hydrazine (1.57 g, 49 mmol) in EtOH (120 mL) and heated at reflux for 2 h before cooling to room temperature. 1N HCl was then added to the reaction mixture until the pH was 2.0 and the resulting mixture was stirred for 45 minutes. The resulting white solid was filtered, washed several times with fresh EtOH, and the solid was discarded. The solid obtained by evaporating the filtrate under reduced pressure was partitioned between diethyl ether and dilute aqueous NaOH. The diethyl ether solution was washed once with brine, dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to give the title compound as a clear viscous oil.

MS200 (MH ⁺ )
¹ H NMR (CDCl ₃ ) δ 6.90 (dd, J = 1.54, 1.1 Hz, 1 H), 6.79 (m, 2 H), 4.26 (dd, J = 11.2, 2.2 Hz) , 1H), 4.13 (m, 1H), 3.98 (dd, J = 11.3,7.5Hz, 1H), 2.98 (m, 2H), 1.25 (bd s, NH 2 )

Light pressure rotation [α] _D = −54.2 ° (c = 1.55, CHCl ₃ )

(Example 18)
(S) -N- (7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide (compound of formula (IS))

  (S)-(7-Chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine (4.7 g, 23.5 mmol) and sulfamide (4.51 g, 47 mmol) Was refluxed in dioxane (125 mL) for 3 hours, then cooled to room temperature, filtered and evaporated under reduced pressure to give a solid. The solid (crude product) was purified by flash column chromatography (DCM: MeOH 20: 1) and the white solid obtained was recrystallized from ethyl acetate / hexane to give the title compound as white crystalline Obtained as a solid.

mp 118-119 ° C
MS 277 (M-1)
Light pressure rotation [α] _D = −40.0 ° (c = 1.20, MeOH)

¹ H NMR (DMSOd6) δ 6.97 (d, J = 2.2 Hz, 1H), 6.90 (m, 3H), 6.67 (s, 2H, NH2), 4.35 (m, 2H), 4.01 (m, 1H), 3.15 (m, 2H)

Chemical analysis:
Calculated values: C, 38.78, H, 3.98, N, 10.05, S, 11.51
Measurements: C, 38.83, H, 3.88, N, 10.08, S, 11.31

(Example 19)
Liquid formulation For example, the compound of formula (IS) prepared as described above was formulated by known methods to make 25 mg and 100 mg liquid formulations, respectively, with the components listed in Table 4 below.

Example 20-Desk Example As a specific embodiment of the oral composition, 100 mg of the compound prepared in Example 18 is blended with sufficient fine powdered lactose to obtain a total amount of 580 to 590 mg, a size O hard gel Filled capsule.

  While the foregoing specification teaches the principles of the invention, along with examples given for purposes of illustration, the practice of the invention is not limited to the following claims and all equivalents included in the equivalents of the following claims. It will be understood that variations, adaptations and / or modifications are encompassed.

Claims (89)

A process for preparing a compound of formula (V) comprising:

In the formula

Selected from the group consisting of
b is an integer of 0 to 4, c is an integer of 0 to 2,
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl, and nitro;

Protecting a compound of formula (X) to obtain a compound corresponding to formula (XI), wherein Pg ¹ is an alcohol protecting group;

Reacting a compound of formula (XI) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XII);

In order to obtain a compound corresponding to formula (XIII), the compound of formula (XII) is combined with an organic or inorganic base in an organic solvent, or in an organic solvent mixture, or in a mixture of one or more organic solvents and water. Reacting, and

Reacting a compound of formula (XIII) with an epoxy-methylene source in the presence of an inorganic base in an organic solvent at a temperature above about room temperature to obtain a compound corresponding to formula (XIV);

Deprotecting the compound of formula (XIV) to obtain a compound corresponding to formula (XV);

Reacting the compound of formula (XV) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V). Pg ¹ is selected from the group consisting of benzyl, allyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl-diphenylsilyl, 4-nitro-benzyl, 4-methoxybenzyl, methoxymethyl, and ethoxyethyl. The process according to 1. The process of claim 2 wherein Pg ¹ is selected from the group consisting of benzyl and allyl.   The process of claim 1, wherein the oxidant is m-CPBA. The process of claim 1, wherein the organic or inorganic base reacted with the compound of formula (XII) is NaOCH ₃ .   The process of claim 1, wherein the epoxy-methylene source is selected from the group consisting of glycidyl-m-nosylate and glycidyl-tosylate.   The process of claim 1, wherein the epoxy-methylene source is selected from the group consisting of (R) -glycidyl-m-nosylate and (R) -glycidyl tosylate.   4. The process of claim 3, wherein the compound of formula (XIV) is deprotected by reacting the compound of formula (XIV) with hydrogen or a hydrogen source. The organic or inorganic base is NaOCH _3, The process according to claim 1 is reacted with a compound of the formula (V).

The process of claim 1, wherein A process for preparing a compound of formula (I) comprising:

Where

Selected from the group consisting of
b is an integer of 0 to 4, c is an integer of 0 to 2,
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl, and nitro;
R ⁴ is selected from the group consisting of hydrogen and lower alkyl;
R ¹ and R ² are each independently hydrogen and lower alkyl,
Or selected from the group consisting of these pharmaceutically acceptable salts,

Protecting the compound of formula (X) to obtain a compound corresponding to formula (XI),

A protecting step, wherein Pg ¹ is an alcohol protecting group, selected from the group consisting of:

Reacting a compound of formula (XI) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XII);

To obtain a compound corresponding to formula (XIII), the compound of formula (XII) is reacted with an organic or inorganic base in an organic solvent, in an organic solvent mixture, or in a mixture of one or more organic solvents and water. A process of

Reacting a compound of formula (XIII) with an epoxy-methylene source in the presence of an inorganic base in an organic solvent at a temperature above about room temperature to obtain a compound corresponding to formula (XIV);

Deprotecting the compound of formula (XIV) to obtain a compound corresponding to formula (XV);

Reacting the compound of formula (XV) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V);

Reacting a compound of formula (V) to obtain a compound corresponding to formula (I). PG ¹ is selected from the group consisting of benzyl, allyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl-diphenylsilyl, 4-nitro-benzyl, 4-methoxybenzyl, methoxymethyl, and ethoxyethyl. 11. Process according to 11. Pg ¹ is selected from the group consisting of benzyl and allyl, A process according to claim 12.   The process of claim 11, wherein the oxidant is m-CPBA. Which is the organic or inorganic base is NaOCH ₃ is reacted with a compound of formula (XII), The process of claim 11.   The process of claim 11, wherein the epoxy-methylene source is selected from the group consisting of glycidyl-m-nosylate and glycidyl-tosylate.   The process of claim 11, wherein the epoxy-methylene source is selected from the group consisting of (R) -glycidyl-m-nosylate and (R) -glycidyl tosylate.   14. The process of claim 13, wherein the compound of formula (XIV) is deprotected by reacting the compound of formula (XIV) with hydrogen or a hydrogen source. The organic or inorganic base is NaOCH _3, The process according to claim 11 is reacted with a compound of the formula (V).

And
The process of claim 1, wherein R ¹ is hydrogen, R ² is hydrogen, and R ⁴ is hydrogen. A process for the preparation of a compound of formula (VS) comprising:

Protecting the compound of formula (XS) to obtain a compound corresponding to formula (XI-S), wherein Pg ¹ is an alcohol protecting group;

Reacting a compound of formula (XI-S) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XII-S);

In order to obtain a compound corresponding to formula (XIII-S), the compound of formula (XII-S) is organic or in an organic solvent mixture or in a mixture of one or more organic solvents and water. Reacting with an inorganic base;

To obtain the compound corresponding to formula (XIV-S), the compound of formula (XIII-S) is reacted with the (R) -epoxy-methylene source in the presence of an inorganic base in an organic solvent at a temperature above about room temperature. A process of

Deprotecting the compound of formula (XIV-S) to obtain a compound corresponding to formula (XV-S);

Reacting the compound of formula (XV-S) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V-S). Pg ¹ is selected from the group consisting of benzyl, allyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl-diphenylsilyl, 4-nitro-benzyl, 4-methoxybenzyl, methoxymethyl, and ethoxyethyl. 21. Process according to 21. Pg ¹ is selected from the group consisting of benzyl and allyl, The process of claim 22.   The process of claim 21, wherein the oxidant is m-CPBA. The organic or inorganic base is reacted with a compound of formula (XII-S) is NaOCH _3, The process of claim 21.   The process of claim 21, wherein the (R) -epoxy-methylene source is selected from the group consisting of (R) -glycidyl-m-nosylate and (R) -glycidyl tosylate.   24. The process of claim 23, wherein the compound of formula (XIV-S) is deprotected by reacting the compound of formula (XIV) with hydrogen or a hydrogen source. The organic or inorganic base is NaOCH _3, The process according to claim 21 is reacted with a compound of the formula (V-S). A process for the preparation of a compound of formula (IS) comprising the process of claim 21 comprising:

A process further comprising reacting the compound of formula (VS) to obtain a compound corresponding to formula (IS). Compound of formula (IS)

Or a process for preparing a pharmaceutically acceptable salt thereof,

Protecting the compound of formula (XS) to obtain a compound corresponding to formula (XI-S), wherein Pg ¹ is an alcohol protecting group;

Reacting a compound of formula (XI-S) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XII-S);

In order to obtain a compound corresponding to formula (XIII-S), the compound of formula (XII-S) is organic or in an organic solvent mixture or in a mixture of one or more organic solvents and water. Reacting with an inorganic base;

To obtain the compound corresponding to formula (XIV-S), the compound of formula (XIII-S) is reacted with the (R) -epoxy-methylene source in the presence of an inorganic base in an organic solvent at a temperature above about room temperature. A process of

Deprotecting the compound of formula (XIV-S) to obtain a compound corresponding to formula (XV-S);

Reacting the compound of formula (XV-S) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V-S);

Reacting a compound of formula (VS) to obtain a compound corresponding to formula (IS). Pg ¹ is selected from the group consisting of benzyl, allyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl-diphenylsilyl, 4-nitro-benzyl, 4-methoxybenzyl, methoxymethyl, and ethoxyethyl. 30. Process according to 30. Pg ¹ is selected from the group consisting of benzyl and allyl, A process according to claim 31.   32. The process of claim 30, wherein the oxidant is m-CPBA. The organic or inorganic base is reacted with a compound of formula (XII-S) is NaOCH _3, The process of claim 30.   31. The process of claim 30, wherein the (R) -epoxy-methylene source is selected from the group consisting of (R) -glycidyl-m-nosylate and (R) -glycidyl tosylate.   33. The process of claim 32, wherein the compound of formula (XIV-S) is deprotected by reacting the compound of formula (XIV) with hydrogen or a hydrogen source. The organic or inorganic base is NaOCH _3, The process of claim 30 is reacted with a compound of the formula (V-S).   A product prepared by the process of claim 11.   31. A product prepared by the process of claim 30.   40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of claim 39.   40. A pharmaceutical composition produced by mixing the product of claim 39 and a pharmaceutically acceptable carrier.   40. A process for producing a pharmaceutical composition comprising mixing the product of claim 39 and a pharmaceutically acceptable carrier.   40. A method of treating epilepsy or a related disorder comprising administering to a subject in need thereof a therapeutically effective amount of the product of claim 39.   44. The method of claim 43, wherein the disorder is epilepsy. A process for preparing a compound of formula (V) comprising:

Where

Selected from the group consisting of
b is an integer of 0 to 4, c is an integer of 0 to 2,
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl, and nitro;

A compound of formula (XVI) wherein Q is selected from the group consisting of —C (O) — (C _1-4 alkyl), from about room temperature in the presence of an epoxy-methylene source and an inorganic base; Reacting in an organic solvent at an elevated temperature to obtain a compound corresponding to formula (XVII);

Reacting a compound of formula (XVII) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XVIII);

Reacting the compound of formula (XVIII) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V). Q is -C (O) -CH _3, The process of claim 45.   46. The process of claim 45, wherein the epoxy-methylene source is selected from the group consisting of glycidyl-m-nosylate and glycidyl-tosylate.   48. The process of claim 47, wherein the epoxy-methylene source is selected from the group consisting of (R) -glycidyl-m-nosylate and (R) -glycidyl tosylate.   46. The process of claim 45, wherein the oxidant is m-CPBA. The organic or inorganic acid is NaOCH _3, The process according to claim 45 is reacted with a compound of formula (XVIII).

46. The process of claim 45, wherein A process for preparing a compound of formula (I) comprising:

Where

Selected from the group consisting of
b is an integer of 0 to 4, c is an integer of 0 to 2,
Each R ⁵ is independently selected from the group consisting of halogen, lower alkyl, and nitro;
R ⁴ is selected from the group consisting of hydrogen and lower alkyl;
R ¹ and R ² are
Each independently selected from the group consisting of hydrogen and lower alkyl, or a pharmaceutically acceptable salt thereof,

A compound of formula (XVI) wherein

Q is selected from the group consisting of —C (O) — (C _1-4 alkyl)) at a temperature above about room temperature in the presence of an epoxy-methylene source and an inorganic base. Reacting in an organic solvent to obtain a compound corresponding to formula (XVII);

Reacting a compound of formula (XII) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XIII);

Reacting a compound of formula (XVIII) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V);

Reacting a compound of formula (V) to obtain a compound corresponding to formula (I). Q is -C (O) -CH _3, The process of claim 52.   53. The process of claim 52, wherein the epoxy-methylene source is selected from the group consisting of glycidyl-m-nosylate and glycidyl-tosylate.   55. The process of claim 54, wherein the epoxy-methylene source is selected from the group consisting of (R) -glycidyl-m-nosylate and (R) -glycidyl tosylate.   53. The process of claim 52, wherein the oxidant is m-CPBA. The organic or inorganic acid is NaOCH _3, The process according to claim 52 is reacted with a compound of formula (XVIII).

53. The process of claim 52, wherein R ¹ is hydrogen, R ² is hydrogen, and R ⁴ is hydrogen. A process for the preparation of a compound of formula (VS) comprising:

A compound of formula (XVI-S) wherein Q is selected from the group consisting of —C (O) — (C _1-4 alkyl), the presence of an (R) -epoxy-methylene source and an inorganic base Reacting in an organic solvent at a temperature above about room temperature to obtain a compound corresponding to formula (XVII-S),

Reacting a compound of formula (XII-S) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XIII-S);

Reacting the compound of formula (XVIII-S) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V-S). The process of claim 15, wherein Q is —C (O) —CH ₃ .   16. The process of claim 15, wherein the (R) -epoxy-methylene source is selected from the group consisting of (R) -glycidyl-m-nosylate and (R) -glycidyl tosylate.   The process of claim 15, wherein the oxidant is m-CPBA. The organic or inorganic acid is NaOCH _3, The process of claim 15 is reacted with a compound of formula (XVIII-S). Compound of formula (IS)

Or a process for preparing a pharmaceutically acceptable salt thereof,

A compound of formula (XVI-S) wherein Q is selected from the group consisting of —C (O) — (C _1-4 alkyl), the presence of an (R) -epoxy-methylene source and an inorganic base Reacting in an organic solvent at a temperature above about room temperature to obtain a compound corresponding to formula (XVII-S),

Reacting a compound of formula (XII-S) with an oxidizing agent in an organic solvent to obtain a compound corresponding to formula (XIII-S);

Reacting a compound of formula (XVIII-S) with an organic or inorganic base in an organic solvent to obtain a compound corresponding to formula (V-S);

Reacting the compound of formula (VS) to obtain a compound corresponding to formula (IS). Q is -C (O) -CH _3, The process of claim 64.   65. The process of claim 64, wherein the (R) -epoxy-methylene source is selected from the group consisting of (R) -glycidyl-m-nosylate and (R) -glycidyl tosylate.   65. The process of claim 64, wherein the oxidant is m-CPBA. The organic or inorganic acid is NaOCH _3, The process according to claim 64 is reacted with a compound of formula (XVIII-S).   53. A product prepared by the process of claim 52.   65. A product prepared by the process of claim 64.   71. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of claim 70.   72. A pharmaceutical composition produced by mixing the product of claim 70 and a pharmaceutically acceptable carrier.   71. A process for producing a pharmaceutical composition comprising mixing the product of claim 70 and a pharmaceutically acceptable carrier.   71. A method of treating epilepsy or a related disorder comprising administering to a subject in need thereof a therapeutically effective amount of the product of claim 70.   75. The method of claim 74, wherein the disorder is epilepsy. Crystal form I-SA of the compound of formula (IS).

Crystalline form I-SA having the following powder X-ray diffraction peaks.

Crystalline form I-SB of the compound of formula (IS).

79. Crystalline Form I-SB of claim 78, wherein Crystalline Form I-SA has the following powder X-ray diffraction peak.

  77. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of claim 76.   77. A pharmaceutical composition produced by mixing the product of claim 76 and a pharmaceutically acceptable carrier.   77. A process for producing a pharmaceutical composition comprising mixing the product of claim 76 and a pharmaceutically acceptable carrier.   77. A method of treating epilepsy or a related disorder comprising administering to a subject in need thereof a therapeutically effective amount of the product of claim 76.   84. The method of claim 83, wherein the disorder is epilepsy.   79. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of claim 78.   79. A pharmaceutical composition produced by mixing the product of claim 78 and a pharmaceutically acceptable carrier.   79. A process for producing a pharmaceutical composition comprising mixing the product of claim 78 and a pharmaceutically acceptable carrier.   79. A method of treating epilepsy or a related disorder comprising administering to a subject in need thereof a therapeutically effective amount of the product of claim 78.   90. The method of claim 88, wherein the disorder is epilepsy.

Images