JP2008285486A - Short-acting sedative hypnotic agent for anesthesia and sedation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide compounds, compositions, and methods useful for inducing or maintaining general anesthesia or sedation in mammals. <P>SOLUTION: The compounds of formula (I) and the compounds of formula (II) can be used for preparing drugs useful for inducing or maintaining anesthesia or sedation in mammals. The drugs can further comprise a therapeutic agent selected from the group consisting of another sedative hypnotic agent, an analgesic, and a paralytic agent. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

(Field of Invention)
The present invention relates to novel substituted phenylacetate compounds that are useful as short acting sedative hypnotics for anesthesia and sedation. The invention also relates to pharmaceutical compositions comprising such compounds; methods for using such compounds for inducing or maintaining anesthesia or sedation; and intermediates for preparing such compounds .

(Background of the Invention)
Propofol, 2,6-diisopropylphenol, (Diprivan® Injectable Emulsion, AstraZeneca) is an injectable anesthetic with hypnotic properties. It can be used to induce and maintain general anesthesia and sedation. Propofol is a widely used anesthetic, but its usefulness is somewhat limited due to its long and unpredictable duration of activity after infusion. This unpredictable duration of activity leads to undesirable irregular and often long patient recovery times.

  Propanizide ([4-[(N, N-diethylcarbamoyl) methoxy] -3-methoxyphenyl] acetic acid propyl ester) is another injectable anesthetic that has been approved for use in some countries other than the United States. It is a medicine. Propanizide is much shorter than propofol and provides a predictable recovery time, but is not a potent anesthetic. In addition, an injectable emulsion formulation of Epontol®, propanide was provided by Bayer and was pulled from the Great Britain market in 1983 due to interest in anaphylactoid reactions. Therefore, propanide was not widely accepted as an injectable anesthetic, despite the fact that it provides a shorter and more predictable recovery time than propofol.

  There is currently a need for new injectable anesthetics. Preferred agents have a shorter and more predictable duration of activity than propofol. Preferred agents are also more potent than propanide.

(Summary of the Invention)
The Applicant has discovered a novel substituted phenylacetate compound that is effective as a short-acting sedative hypnotic. This drug has a shorter and more predictable duration of activity than propofol and is also more potent than propanide.

The present invention provides the following.
(Item 1)
  Compound of formula (I):

Where
  R ¹ (C ₂ ~ C ₆ ) Alkyl, (C ₂ ~ C ₆ ) Alkenyl, and (C ₂ ~ C ₆ ) Alkynyl, (C ₃ ~ C ₆ ) Cycloalkyl (C ₁ ~ C ₆ ) Selected from the group consisting of alkyl, phenyl, and benzyl;
  R ² And R ³ (C ₁ ~ C ₆ ) Alkyl, (C ₂ ~ C ₆ ) Alkenyl, and (C ₂ ~ C ₆ ) Each independently selected from the group consisting of alkynyl or R ² And R ³ Are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring having 5-7 atoms, and
  R ⁴ (C ₁ ~ C ₆ ) Alkyl, (C ₂ ~ C ₆ ) Alkenyl, and (C ₂ ~ C ₆ ) Selected from the group consisting of alkynyl;
  However, R ¹ , R ² , R ³ And R ⁴ The total number of carbon atoms in the compound exceeds 7.
(Item 2)
  A compound according to item 1, wherein R ¹ (C ₂ ~ C ₆ ) Alkyl, (C ₂ ~ C ₆ ) Alkenyl, and (C ₂ ~ C ₆ ) A compound selected from the group consisting of alkynyl.
(Item 3)
  A compound according to item 1, wherein R ¹ (C ₃ ~ C ₆ ) A compound selected from the group consisting of cycloalkyl, phenyl, and benzyl.
(Item 4)
  A compound according to item 1, wherein R ¹ (C ₂ ~ C ₄ ) A compound that is alkyl.
(Item 5)
  A compound according to item 4, wherein R is ¹ Is a compound which is ethyl or propyl.
(Item 6)
  6. The compound according to any one of items 1 to 5, wherein R ² (C ₁ ~ C ₄ ) Alkyl, (C ₂ ~ C ₄ ) Alkenyl, and (C ₂ ~ C ₄ ) A compound selected from the group consisting of alkynyl.
(Item 7)
  Item 7. The compound according to any one of Items 1 to 6, wherein R ² (C ₁ ~ C ₄ ) A compound that is alkyl.
(Item 8)
  8. The compound according to any one of items 1 to 7, wherein R ³ (C ₁ ~ C ₄ ) Alkyl, (C ₂ ~ C ₄ ) Alkenyl, and (C ₂ ~ C ₄ ) A compound selected from the group consisting of alkynyl.
(Item 9)
  Item 9. The compound according to any one of Items 1 to 8, wherein R ³ (C ₁ ~ C ₄ ) A compound that is alkyl.
(Item 10)
  Item 10. The compound according to any one of Items 1 to 9, wherein R is ⁴ (C ₁ ~ C ₄ ) Alkyl, (C ₂ ~ C ₄ ) Alkenyl, and (C ₂ ~ C ₄ ) A compound selected from the group consisting of alkynyl.
(Item 11)
  Item 11. The compound according to any one of Items 1 to 10, wherein R is ⁴ (C ₁ ~ C ₄ ) A compound that is alkyl.
(Item 12)
  A compound according to item 1, wherein R ¹ , R ² , R ³ And R ⁴ The total number of carbon atoms in the compound is in the range of 8-15.
(Item 13)
  13. A compound according to item 12, wherein R ¹ (C ₂ ~ C ₄ ) Alkyl; R ² , R ³ And R ⁴ Are each independently (C ₁ ~ C ₄ ) Alkyl; and R ¹ , R ² , R ³ And R ⁴ The total number of carbon atoms in the compound is in the range of 8-12.
(Item 14)
  14. A compound according to item 13, wherein R ¹ Is ethyl or isopropyl; R ² , R ³ And R ⁴ Are each independently selected from the group consisting of methyl, ethyl, and isopropyl; and R ¹ , R ² , R ³ And R ⁴ The total number of carbon atoms in the compound is in the range of 8-11.
(Item 15)
  15. A compound according to item 14, wherein R ¹ , R ² , R ³ And R ⁴ Wherein the sum of the number of carbon atoms is 9, 10, or 11.
(Item 16)
  15. A compound according to item 14, wherein R ² And R ³ Are each ethyl and R ⁴ Is propyl, the compound.
(Item 17)
  2. The compound according to item 1, wherein the compound is [4-[(N, N-diethylcarbamoyl) methoxy] -3-ethoxyphenyl] acetic acid propyl ester.
(Item 18)
  Compound of formula (II):

Where
    R ¹ (C ₂ ~ C ₆ ) Alkyl, (C ₂ ~ C ₆ ) Alkenyl, and (C ₂ ~ C ₆ ) Alkynyl, (C ₃ ~ C ₆ ) Cycloalkyl (C ₁ ~ C ₆ ) Selected from the group consisting of alkyl, phenyl, and benzyl;
  R ⁴ (C ₁ ~ C ₆ ) Alkyl, (C ₂ ~ C ₆ ) Alkenyl, and (C ₂ ~ C ₆ ) Selected from the group consisting of alkynyl; and
  R ⁵ Is a compound that is hydrogen or hydroxyl.
(Item 19)
  18. A pharmaceutical composition comprising a compound according to any one of items 1 to 17 and a pharmaceutically acceptable carrier.
(Item 20)
  20. The composition of item 19, further comprising a therapeutic agent selected from the group consisting of another sedative hypnotic, analgesic, and paralytic.
(Item 21)
  Item 20. The composition according to Item 19, further comprising an analgesic.
(Item 22)
  22. The composition according to item 21, wherein the analgesic is an opioid.
(Item 23)
  A compound according to any one of items 1 to 17 for use in pharmaceutical therapy.
(Item 24)
  18. Use of a compound according to any one of items 1 to 17 for the preparation of a medicament useful for inducing or maintaining anesthesia or sedation for a mammal.
(Item 25)
  25. Use according to item 24, wherein the medicament further comprises a therapeutic agent selected from the group consisting of another sedative hypnotic, analgesic and paralytic.
(Item 26)
  The use according to item 24, wherein the medicament further comprises an analgesic.
(Item 27)
  27. Use according to item 26, wherein the analgesic is an opioid.
(Item 28)
  A method for inducing or maintaining anesthesia or sedation for a mammal, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound according to any one of items 1-17. Administering a step of administering.
(Item 29)
  A method for inducing or maintaining anesthesia or sedation for a mammal, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound according to item 19. Method.
(Item 30)
  29. The method of item 28, wherein the method comprises administering to the mammal a therapeutically effective amount of a therapeutic agent selected from the group consisting of another sedative hypnotic, analgesic, and paralytic agent. The method further comprising the step of:

  Accordingly, the present invention provides a compound of formula (I):

を提供し、ここで：
Ｒ^１は、（Ｃ_２〜Ｃ_６）アルキル、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニル、（Ｃ_３〜Ｃ_６）シクロアルキル（Ｃ_１〜Ｃ_６）アルキル、フェニル、およびベンジルからなる群から選択され；
Ｒ^２およびＲ^３は、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_２〜Ｃ_６）アルケニル、および（Ｃ_２〜Ｃ_６）アルキニルからなる群から各々独立して選択されるか、またはＲ^２およびＲ^３は、それらが、結合する窒素原子とともに、５〜７原子を有するヘテロ環を形成し；そして
Ｒ^４は、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_２〜Ｃ_６）アルケニル、および（Ｃ_２〜Ｃ_６）アルキニルからなる群から選択され；
但し、Ｒ^１、Ｒ^２、Ｒ^３、およびＲ^４における炭素原子の合計が、７より多い。

Provide here:
R ¹ is (C ₂ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₆ ) alkyl, phenyl And selected from the group consisting of benzyl;
R ² and R ³ are each independently selected from the group consisting of (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, and (C ₂ -C ₆ ) alkynyl, or R ² And R ³ together with the nitrogen atom to which they are attached form a heterocycle having 5 to 7 atoms; and R ⁴ is (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, and Selected from the group consisting of (C ₂ -C ₆ ) alkynyl;
However, the total number of carbon atoms in R ¹ , R ² , R ³ , and R ⁴ is more than 7.

  The invention also relates to intermediates useful for preparing compounds of formula (I). Accordingly, the present invention provides a compound of formula (II):

を提供し、ここで、Ｒ^１およびＲ^４は、本明細書中において規定される通りであり、そしてＲ^５は、水素またはヒドロキシルである。

Where R ¹ and R ⁴ are as defined herein and R ⁵ is hydrogen or hydroxyl.

  The present invention further provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).

  The compounds of the present invention are highly effective short acting sedative sleep agents for use in the induction and maintenance of anesthesia and sedation. Thus, the present invention also provides a method for inducing or maintaining anesthesia or sedation in a mammal, comprising administering to the mammal an effective amount of a compound of the present invention. The present invention also provides a method for inducing or maintaining anesthesia or sedation for a mammal, the method comprising administering to the mammal an effective amount of a pharmaceutical composition of the present invention.

(Detailed description of the invention)
When describing compounds, the compounds and methods of the present invention, the following terms have the following meanings unless otherwise indicated.

The term “(C ₁ -C ₆ ) alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl and the like. As used herein, “Me” represents methyl, “Et” represents ethyl, “propyl” and “Pr” represent n-propyl, and “iPr” represents iso -Indicates propyl.

The term “(C ₂ -C ₆ ) alkenyl” refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having 2 to 6 carbon atoms and at least one site of vinyl unsaturation. Preferred alkenyl groups include ethenyl (—CH═CH ₂ ), n-propenyl (—CH ₂ CH═CH ₂ ), iso-propenyl (—C (CH ₃ ) ═CH ₂ ) and the like.

The term “(C ₂ -C ₆ ) alkynyl” refers to an unsaturated hydrocarbon monoradical having 2 to 6 carbon atoms and at least one triple bond. Preferred alkynyl groups include ethynyl (—C≡CH), propargyl (—CH ₂ C≡CH), and the like.

The term “(C ₃ -C ₆ ) cycloalkyl” refers to a cyclic alkyl group of 3 to 6 carbon atoms having a single ring. Examples of such cycloalkyl groups include monocyclic structures (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.).

The term “(C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₆ ) alkyl” refers to a group of formula (C ₃ -C ₆ ) cycloalkyl (C ₁ -C ₆ ) alkyl, where ( C ₃ -C ₆₎ cycloalkyl and _(C 1 ~C ₆₎ alkyl is as defined above.

  The compounds of the present invention may contain one or more chiral centers. Accordingly, the present invention is intended to include racemic mixtures, diastereomers, enantiomers and mixtures enriched with one or more stereoisomers. As described and claimed, the scope of the present invention includes the racemic forms of the compounds as well as the individual enantiomers and non-racemic mixtures thereof.

  The term “hypnotic” generally refers to a compound that promotes sleep. As used in pharmacology, the term “hypnotic” refers to an agent used to induce or maintain anesthesia, sedation, or sleep.

  As used herein, the term “anesthesia” refers to a loss of sensation or consciousness resulting from a pharmacological decrease in nerve function.

  The term “sedation” is defined herein as sedation of mental excitement or a decrease in physiological function by administration of a drug.

  The term “effective amount” refers to an amount that, when administered to a mammal, is sufficient to induce or maintain anesthesia or sedation. Effective amounts will vary depending on the subject and the mode of administration and can be routinely determined by one skilled in the art.

  The term “analgesic” refers to a compound that reduces pain by altering the perception of nociceptive stimuli without causing significant anesthesia or loss of consciousness.

  The term “opioid” refers to a synthetic narcotic that has opiate-like activity (eg, analgesia) but is not derived from opium.

  As used herein, the term “short acting” refers to an agent that responds pharmacokinetically. When a short acting drug is administered by infusion, the effect of the drug ends quickly upon termination of the infusion.

  While a broad definition of the invention is set forth in the summary of the invention, certain drugs or certain compositions may be preferred. Specific values and preferred values are listed herein for radicals, substitutions, and ranges are for illustration only; they are within the ranges specified for other defined values or radicals and substitutions. Do not exclude other values.

Preferred agents incorporated into the compositions of the present invention and that can be administered according to the methods of the present invention are compounds of formula (I) as described above, wherein R ¹ , R ² , R ³ , and The total number of carbon atoms in R ⁴ is in the range of 8-15.

More preferably, the total number of carbon atoms of R ¹ , R ² , R ³ , and R ⁴ is in the range of 8-12.

Preferably, R ¹ is selected from the group consisting of (C ₂ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, and (C ₂ -C ₆ ) alkynyl.

In another preferred embodiment, R ¹ is selected from the group consisting of (C ₃ -C ₆ ) cycloalkyl, phenyl, and benzyl.

In another more preferred embodiment, R ¹ is selected from the group consisting of (C ₂ -C ₄ ) alkyl, (C ₂ -C ₄ ) alkenyl, and (C ₂ -C ₄ ) alkynyl.

In another more preferred embodiment, R ¹ is selected from the group consisting of (C ₂ -C ₄ ) alkyl, cyclopropyl, and cyclobutyl.

Even more preferably, R ¹ is (C ₂ -C ₄ ) alkyl.

Most preferably R ¹ is ethyl or propyl.

Preferably, R ² is selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₂ -C ₄ ) alkenyl, and (C ₂ -C ₄ ) alkynyl.

In an alternative preferred embodiment, R ² and R ³ together with the nitrogen atom to which they are attached form a piperidinyl ring.

More preferably, R ² is (C ₁ -C ₄ ) alkyl.

Preferably, R ³ is selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₂ -C ₄ ) alkenyl, and (C ₂ -C ₄ ) alkynyl.

More preferably, R ³ is (C ₁ -C ₄ ) alkyl.

Preferably, R ⁴ is selected from the group consisting of (C ₁ -C ₄ ) alkyl, (C ₂ -C ₄ ) alkenyl, and (C ₂ -C ₄ ) alkynyl.

More preferably, R ⁴ is (C ₁ -C ₄ ) alkyl.

In a preferred embodiment, R ¹ is (C ₂ -C ₄ ) alkyl; R ² and R ³ are each independently (C ₁ -C ₄ ) alkyl; and R ⁴ is (C ₁ ~C ₄₎ alkyl.

A preferred subgroup of compounds is where R ¹ is (C ₂ -C ₄ ) alkyl; R ² and R ³ are each independently (C ₁ -C ₄ ) alkyl; R ⁴ is (C ₁ -C ₄ ) alkyl; and the total number of carbon atoms of R ¹ , R ² , R ³ , and R ⁴ is a subgroup that ranges from 8-12.

Within this subgroup, preferably R ¹ is ethyl or propyl; R ² , R ³ , and R ⁴ are each independently selected from the group consisting of methyl, ethyl, and propyl; and R The total number of carbon atoms for ¹ , R ² , R ³ , and R ⁴ is in the range of 8-11. Particularly preferred values for the total number of carbon atoms are 9, 10, and 11.

Preferred compounds of the invention are those compounds of formula (I) wherein R ¹ , R ² , R ³ , and R ⁴ exhibit the values shown in Table I below.

特に好ましくは、Ｒ^１がエチルまたはプロピルであり、Ｒ^２およびＲ^３が各々エチルであり、そしてＲ^４がプロピルである、化合物である。化合物１は、特に最も好ましい。

Particularly preferred are compounds wherein R ¹ is ethyl or propyl, R ² and R ³ are each ethyl, and R ⁴ is propyl. Compound 1 is most particularly preferred.

(General synthesis process)
The intermediates and compounds of the invention can be prepared from readily available starting materials using known synthetic processes. For example, the compound can be prepared as outlined below and further described in the examples. It is understood that typical or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, and that other process conditions can also be used unless otherwise specified. . Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization processes.

Further, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of appropriate protecting groups for particular functional groups and appropriate conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T.W. W. Greene and
G. M.M. Wuts, Protecting Groups in Organic Synthesis, Volume 3, Wiley, New York, 1999 and references cited therein.

  This synthesis method is of formula (II), in particular (IIa) or (IIb):

の新規な中間体を使用する。合成の第一の方法において、式（Ｉ）の化合物は、式Ｘ−ＣＨ_２Ｃ（＝Ｏ）ＮＲ^２Ｒ^３の不可欠な化合物を用いて、式（ＩＩａ）の化合物のアルキル化によって調製され、ここで、Ｘは、適切な脱離基（例えば、クロロ、ブロモ、トシル、またはメシル）である。

The novel intermediate of In the first method of synthesis, a compound of formula (I) is prepared by alkylation of a compound of formula (IIa) using an essential compound of formula X—CH ₂ C (═O) NR ² R ^3. Where X is a suitable leaving group (eg, chloro, bromo, tosyl, or mesyl).

In the second method of synthesis, a compound of formula (IIb) is alkylated with an essential acetamide compound of formula X—CH ₂ C (═O) NR ² R ³ to give a compound of formula (III):

の化合物を生じ、そして式（Ｉ）の化合物を形成するために還元される。実施例４Ａ、４Ｂ、および１０〜１３に例示されるように、還元プロセスの有用な方法は、２工程反応により進行し、水素との反応前に、式（ＩＩＩ）のヒドロキシルは、最初にアセチル化される。

And is reduced to form a compound of formula (I). As illustrated in Examples 4A, 4B, and 10-13, a useful method of the reduction process proceeds by a two-step reaction, prior to reaction with hydrogen, the hydroxyl of formula (III) is initially acetylated. It becomes.

  The intermediate of formula (IIb) used in the above process is prepared from commercially available starting materials and reactants using conventional processes. For example, intermediates can be prepared as shown in Scheme A:

上記に示されるように、カテコールは、式Ｒ^１Ｘの化合物と結合され、ここで、Ｘは、脱離基であり、エーテル（ＩＶ）を形成し、これは、グリオキシル酸と反応され、化合物（Ｖ）を生じる。過剰のアルコールＲ^４ＯＨとの（Ｖ）の次の反応は、式（ＩＩｂ）の中間体を提供する。中間体（ＩＩｂ）は、上記のようにアルキル化され得、式（ＩＩＩ）の化合物を生じる。

As indicated above, catechol is coupled with a compound of formula R ¹ X, where X is a leaving group to form ether (IV), which is reacted with glyoxylic acid to form a compound (V) is produced. Subsequent reaction of (V) with excess alcohol R ⁴ OH provides an intermediate of formula (IIb). Intermediate (IIb) can be alkylated as described above to give compounds of formula (III).

  Intermediates of formula (Ia) can be prepared (for example as described in subpart (1) of Example 1 and also shown in Scheme B of subpart (2) of Example 1 below. like).

(Pharmaceutical composition)
The compounds of formula I can be formulated as pharmaceutical compositions and are adapted to the chosen route of administration (ie, orally or parenterally, intravenously, intramuscularly, topically, or by a subordinate route). In various forms, it can be administered to a mammalian host (eg, an animal or human patient).

  Thus, the compounds can be administered systemically, for example, orally, in combination with a pharmaceutically acceptable vehicle such as an inert excipient or edible carrier. They can be placed together in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly with the food of the patient's diet. For the purpose of oral therapeutic administration, the active compound can be combined with one or more excipients and in the form of ingestible tablets, sublingual tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. Can be used in Such compositions and preparations should contain at least 0.1% of active compound. The percentages of the compositions and preparations can of course vary and can conveniently be between about 2 and about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

  Tablets, troches, pills, capsules and the like also contain: a binder (eg, tragacanth gum, acacia, corn starch or gelatin); an excipient (eg, dicalcium phosphate); a disintegrant (eg, corn starch, potato) Starch, alginic acid, etc.); lubricants (eg, magnesium stearate); and sweeteners (eg, sucrose, fructose, lactose or aspartame) or flavoring agents (eg, peppermint, wintergreen oil, or cherry flavoring), Can be added. Where the unit dosage form is a capsule, it can contain, in addition to a substance of the above type, a liquid carrier such as a vegetable oil or polyethylene glycol. A variety of other materials can be present as coatings or otherwise improve the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange scent. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into retention-release preparations and devices.

  The active agents described herein are typically formulated as pharmaceutical compositions that are suitable for intravenous administration. The active agent is relatively insoluble in water. Thus, for intravenous administration, agents are typically formulated in an aqueous medium using one or more water-immiscible solvents and one or more emulsifiers. Some emulsifiers are surfactants variously expressed in the literature. Individual formulations may contain one or more additional ingredients such as stabilizers, tonicity modifiers, bases or acids to adjust pH, and solubilizers. The formulations can also optionally contain a preservative (eg, ethylenediaminetetraacetic acid (EDTA) or sodium metabisulfite, to name only a few.

  A wide range of water-immiscible solvents can be used in the compositions of the present invention. The water-immiscible solvent can be a vegetable oil (eg, soybean oil, safflower oil, cottonseed oil, corn oil, sunflower oil, peanut oil, or olive oil). Alternatively, the water-immiscible solvent is an ester of a medium or long chain fatty acid (eg, a monoglyceride, diglyceride, or triglyceride); an ester of a combination of a medium and a long chain fatty acid, or chemically modified Or a manufactured material (eg ethyl oleate, isopropyl myristate, isopropyl palmitate, glycerol ester, polyoxyl or hydrogenated castor oil). The water-immiscible solvent can also be a marine oil (eg cod liver oil, another fish-derived oil). Suitable solvents also include fractionated oils such as coconut oil or improved soybean oil.

  The composition may also include an emulsifier. Suitable emulsifiers include synthetic nonionic emulsifiers such as ethoxylated ethers and esters and polyoxypropylene-polyoxyethylene block copolymers, and phospholipids. Naturally occurring phospholipids (eg, egg and soy phospholipids) and / or improved or artificially manipulated phospholipids (eg, prepared by physical fractionation and / or chromatography) or A mixture of can be used. Phospholipids are alternatively referred to as phosphatides. Preferred emulsifiers are egg phospholipid and soybean phospholipid. Egg yolk phospholipids are mainly composed of phosphatidylcholine and phosphatidylethanolamine. Lecithin, which is classified as phosphatidylcholine and can be derived from egg yolk or soybean, is another commonly used emulsifier.

  The pharmaceutical formulation may also contain stabilizers that may alternatively be considered co-emulsifiers. Anionic stabilizers contain phosphatidylglycerol, which is a special example of phosphatidylethanolamine (PEG-PE) and dimyristol phosphatidylglycerol (DMPG) conjugated with polyethylene glycol. Further examples of useful stabilizers include oleic acid and its sodium salt, cholic acid and deoxycholic acid and their respective salts, cationic lipids (eg, stearylamine and oleylamine), and 3β- [N- (N ', N'-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol).

The pharmaceutical compositions of the invention can be made isotonic with blood by incorporating an appropriate tonicity modifying agent. Glycerol is most often used as a tonicity modifier. Alternatively, tonicity modifying agents include xylitol, mannitol, and sorbitol. The pharmaceutical composition is typically formulated to be at a physiologically neutral pH (typically in the range of 6.0 to 8.5). The pH can be adjusted by the addition of a base (eg, NaOH or NaHCO ₃ ) or, in some cases, an acid (eg, HCl).

  Pharmaceutically safe oil-water emulsions containing vegetable oils, phosphatide emulsifiers (typically egg lecithin or soybean lecithin) and tonicity modifying substances are commercially available for parenteral nutrition (eg, the trademark Liposyn). ® II and Liposyn ® III (Abbott Laboratories, North Chicago, IL) and Intralipid ® (under Fresenius Kabi AB, Uppsala, Sweden). The agents described herein may be formulated with these or other similar oil-water emulsions, for example, as shown in injections 5-9 of Example 16 below.

The compounds of the present invention may also be formulated in triglycerides containing esters of at least one medium chain length (C ₆ -C ₁₂ ) fatty acid. Preferably, _{triglycerides,} containing an ester of C 8 _{-C 10} fatty acids. Suitable triglycerides for formulating the compounds of the invention are provided by Condea Chemie GmbH (Witten, Germany) under the trademark Miglyol®. For example, Miglyol® 810 or 812 (capryl (C ₁₀ ) / caprin (C ₈ ) glyceride) is useful for the formulation of the drug. Injection 11 of Example 16 below shows a formulation containing egg yolk phosphatide as an emulsifier, DMPG as an anionic stabilizer, and glycerol as a tonicity modifying agent, where Miglyol® is Used as oil phase.

  Further, the agents described herein can be formulated in the same manner as the pharmaceutical compositions of propanide known in the art. For example, the compounds of the present invention can be formulated in a mixture containing esters of medium chain length fatty acids, as discussed in US Pat. No. 4,711,902. Further, the compounds described herein can be synthesized, for example, as described in US Pat. Nos. 4,056,635; 4,452,817; and 4,798,846. It can be formulated similar to propofol compositions known in the art.

  In yet another alternative, the compound can be formulated using a solubilizer (eg, hydroxypropyl-β-cyclodextrin) to form an inclusion complex.

  Other formulations that are more suitable for use in the present invention may be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th (1985).

The compounds according to the invention are potent hypnotics that are rapidly metabolized in vivo to inert and well-accepted carboxylic acid metabolites (Formula I where R ⁴ is hydrogen). The compound exhibits one or more of the following beneficial properties compared to previous drugs: increased potency, shorter recovery time, reduced cardiovascular effects, lower toxicity, and higher therapeutic index ( Here, the therapeutic index is defined as the ratio of the maximum tolerated dose to the effective dose).

  Thus, the compounds of the present invention are for the induction and / or maintenance of general anesthesia, for the initiation and / or maintenance of conscious sedation in spontaneously breathing patients, and intubated, mechanically ventilated It can be used for induction and / or maintenance of sedation for patients.

  The amount of active agent required for use in the methods of the invention will vary with the route of administration, the age and condition of the patient, and the degree of anesthesia or sedation required, and ultimately will be responsible It is the judgment of a physician or clinician.

  In general, the drug can be administered as the first bolus dose to produce anesthesia or sedation, followed by continuous infusion of the drug at a rate that is sufficient to achieve and maintain the desired level of anesthesia or sedation. Can be done. Alternatively, continuous infusion of an agent of the invention may be used to maintain anesthesia or sedation following induction, or another sedative hypnotic (eg, propofol, barbiturate (eg, nembutal® (pentobarbital sodium)) or brevital ( ®) sodium (methhexital sodium), or benzodiazepine (eg, Valium®)) can be used to induce and maintain.

  For example, suitable bolus doses of the agent for human patients are typically in the range of about 0.1 to about 50 milligrams / kilogram (mg / kg), preferably about 0.5 to about 20 mg / kg. It is. The rate of infusion typically ranges from about 5 to about 5000 micrograms / kilogram / min (μg / kg / min), preferably from about 10 to about 2000 μg / kg / min.

  The compounds of the present invention may also be used in other therapeutic agents (eg, other sedative hypnotics, analgesics (eg, opioids such as the μ-opioid agonists remifentanil, fentanyl, sulfentanil, or alfentanil), or paralytic agents. (Eg, atracurium besylate or pancuronium bromide) Thus, the compositions of the present invention may require another therapeutic agent (eg, a sedative hypnotic, analgesic, or paralytic) as needed. Similarly, the treatment methods of the invention can also optionally include the step of administering another therapeutic agent (eg, a sedative hypnotic, analgesic, or paralytic) to the mammal.

  The ability of an agent to function as an anesthetic or sedative is determined by assays known in the art (eg, US Pat. No. 5,908,869, or R. James and J. Glen, J. Med Chem., 23, 1350 (1980)) or using the assay described in Test A below.

(Test A)
(Method)
(Prescription)
Test compounds, eg, representative compounds of the present invention as well as comparative compounds, propanide, are (1) 10% cremophor EL / 90% D5W (5% dextrose in dilute water;) (2) 10% Liposyn® Trademark) III (available from Intravenous Fat Emulsion, including 10 g soybean oil, 1.2 g egg phosphatide and 25 g glycerol, per 100 mL), Abbott Laboratories, North Chicago, IL; and (3) Miglyol® 810 ( Formulated with infusion (10) or (11) (as described in Example 16) with (capric / capringlyceride). Typically, the above formulation (1) was used for bolus dosing and formulation (2) or (3) was used for infusion dosing. The compounds of the invention and propanizide were synthesized as described in Examples 1-15 below. Propofol formulated with soybean oil, sold as a Diprivan® infusion emulsion, was obtained from AstraZeneca (Wilmington, DE).

(Bolus administration (rat))
Rats (adult male Sprague-Dawley) were placed in windshield suppression and injected with the compound of interest (1 or 2 mL / kg over about 3 seconds) via the tail vein. Anesthesia onset time (defined as loss of upright reflex), duration of anesthesia (ie duration of loss of upright reflex), and behavior recovery (ie, ataxia, sedation and / or following recurrence of upright reflex) The duration of lethargy) was recorded. The duration of anesthesia was measured by placing the rat in the back after the start of anesthesia and the time to recovery of the bounce reflex was recorded using a stopwatch. The depth of anesthesia was assessed intermittently by observing the extent of the pull reflex to the hind paw harmful knob. Behavioral recovery was assessed by visual observation.

(Bolus administration (guinea pig))
Adult male guinea pigs were administered by bolus administration (0.1-0.25 mL volume) via the ear vein. The duration of loss of bounce reflex was measured as described above for rats.

(Administration by injection (rat))
Rats (adult Sprague-Dawley) are placed in a windshield suppressor and bolus injection via the tail vein (approximately 3 seconds at a dose estimated from an earlier bolus experiment to produce anesthesia with a duration of about 2 minutes) Anesthesia was induced by 0.15-1 mL / kg). Immediately after bolus administration, infusion via the tail vein (typically having a duration of 20 minutes, 180 minutes or 300 minutes) was initiated (0.075-0.5 mL / kg / half at half the bolus dose / minute). Min). In certain embodiments, the initial infusion rate is maintained throughout, while for others the rate is adjusted as necessary to maintain a constant depth of anesthesia (adjusted foot retracted in response to a harmful knob) Modified as specified). Following completion of the infusion, the duration of anesthesia (ie, the duration of loss of the bounce reflex) and behavioral recovery (ie, duration of ataxia, sedation or drowsiness following recovery of the bounce reflex) were recorded.

(result)
Bolus administration (rat): A dose response curve was determined for the duration of loss of bounce reflex in rats resulting from a bolus injection of the test compound prepared in formula (1). To quantify anesthesia efficacy, the dose of test compound that produced an average loss of a 2-minute bounce reflex was calculated. FIG. 1 compares a bolus dose (mg / kg) of a compound of the invention that results in a 2 minute loss of upright reflex and the required dose of a comparative compound, propanide.

(Bolus administration (guinea pig))
The efficacy of Compound 1 was also tested in guinea pigs by a similar process. The dose of Compound 1 required to produce a 2 minute bounce reflex in guinea pigs was calculated to be 8 mg / kg compared to the 13 mg / kg dose for propanidide.

(Administration by injection (rat))
Recovery time after termination of administration by injection into rats was determined for Compound 1 and the comparative compounds propofol and propanide. The duration (in minutes) of loss of bounce after the end of the infusion is given as a function of the duration of the infusion in Table 2 below.

  (Table 2. Duration of loss of bounce reflex after completion of infusion (in minutes))

図２は、表２において得られるような、立ち直り反射の喪失の持続時間の合計として、ラットにおける特定の持続時間の注入の終了後の全回復時間（分で）、および立ち直り反射の回復後の行動回復の持続時間を示す。

Figure 2 shows the total recovery time (in minutes) after the end of a specific duration infusion in rats, as the total duration of loss of the bounce reflex as obtained in Table 2, and after the recovery of the bounce reflex Indicates the duration of behavior recovery.

  As shown by the above data in rat and guinea pig animal models, the compounds of the present invention tested are more potent general anesthetics than propanidide and even after prolonged (5 hours) infusions Provides a significantly shorter overall recovery rate than propofol. Furthermore, the duration of loss of bounce reflex after the end of injection for the tested compounds of the present invention was within the uncertainty of the experimental results and was independent of the duration of the injection.

  In vitro stability of representative compounds of the invention can be determined as shown in Test B.

(Test B)
(Whole blood sample source)
Rat and guinea pig whole blood samples obtained by cardiac puncture were collected in vacutainer tubes containing sodium heparin. Samples were kept in ice and used on the same day as collection. Dog, monkey and human whole blood purchased from commercial vendors was kept on wet ice and used the next day of collection.

(Metabolic assay)
The test compound propanizide and a representative compound of the invention were spiked into a final concentration of 100 μM in a 300 μL whole blood sample. The protein was immediately precipitated by addition of 2 volumes of ice-cold ethanol and vortex mixing. This constituted the zero time point. In the same 300 μL incubation, the spiked whole blood sample was then incubated at 37 ° C. for 30 seconds to 60 minutes. At predetermined time points, 600 μL ice-cold ethanol was added to the mixture to terminate the incubation. At the end of the incubation, the sample was centrifuged and the supernatant was dried at room temperature under a stream of nitrogen. The residue was reconstituted in 150 μL of sterile water and then centrifuged. An aliquot (50 μL) of the supernatant was injected into HPLC-UV for analysis.

(HPLC method)
C ₁₈ , 5 μm, 2 × 150 mm A D (Luna, Phenomenex) reverse phase HPLC column was used, and a gradient of 10% to 68% acetonitrile with no gradient with 10% acetonitrile over 15 min followed by 5 min. The mobile phase component contained 0.1% TFA. Analytes were monitored by UV detection at 214 nm.

(Data analysis)
The concentration of substrate in the incubation was measured as a peak area ratio using an internal standard method, and the percent resolution was measured with respect to the zero time value.

(result)
Test compounds of formula (I) were rapidly metabolized to the corresponding carboxylic acid (formula (I), where R ⁴ = hydrogen). The acid metabolite was found to be inactive as an anesthetic in Test A. The rapid conversion of compounds of formula (I) to these acid metabolites, and the inactivity of these acid metabolites as anesthetics, is the shorter and more predictable recovery observed for compounds of formula (I) Speed can be at least partially due.

  The invention will now be illustrated by the following non-limiting examples.

  In the examples below, the following abbreviations have the following meanings. Any abbreviations not defined have their generally accepted meanings. Unless otherwise noted, all temperatures are in degrees Celsius.

DMSO = dimethyl sulfoxide EtOAc = ethyl acetate DCM = dichloromethane PPTS = pyridinium p-toluenesulfonic acid DMF = dimethylformamide (Overview :)
Unless otherwise specified, reagents, starting materials and solvents are purchased from commercial vendors (eg, Sigma-Aldrich (St. Louis, MO) and Trans World Chemicals, Inc. (TCI) (Rockville, MD)), and Used without purification; reaction was carried out under nitrogen atmosphere; reaction mixture was monitored by thin layer chromatography (silica TLC), analytical high performance liquid chromatography (analyl. HPLC), or mass spectrometry; reaction mixture was Purified by flash column chromatography, generally on silica gel, or by vacuum distillation; NMR samples were dissolved in deuterated solvents (CD ₃ OD, CDCl ₃ , or DMSO-d6) and others Unless indicated in Use has been solvent described as part standard, Varian
Spectra were obtained using a Gemini 2000 instrument (300 MHz); and mass spectrometric identification was performed by electrospray ionization (ESMS) using a Perkin Elmer instrument (PE SCIEX API 150 EX).

  (Example 1 Compound 1: [4-[(N, N-diethylcarbamoyl) methoxy] -3-ethoxyphenyl] acetic acid propyl ester)

磁気攪拌棒を備えた５０ｍＬの丸底フラスコにおいて、３−エトキシ−４−ヒドロキシフェニル酢酸プロピルエステル（８００ｍｇ、３．４ｍｍｏｌ、１．０当量）を乾燥アセトン（２０ｍＬ）中に溶解した。この溶液に、Ｋ_２ＣＯ_３（７０５ｍｇ、５．１ｍｍｏｌ、１．５当量）、続いて２−クロロ−Ｎ，Ｎ−ジエチルアセトアミド（０．５５ｍＬ、４．０ｍｍｏｌ、１．２当量、Ａｌｄｒｉｃｈから入手可能）を添加した。激しい攪拌下で、懸濁液を還流まで温め、そしてそれらの条件下で１５時間維持した。室温もで冷却した後、この反応混合物を折りたたんだ濾紙を用いて濾過し、そして残った溶液は、減圧下で溶媒を含まなかった。油性生成物を、カラムクロマトグラフィー（ＳｉＯ_２、５０％ ＥｔＯＡｃ／ヘキサン）を用いて精製し、６３０ｍｇ（理論値の５３％）の無色の油状物を得、これは、ＨＰＬＣにより９９．６％の純度であった。

In a 50 mL round bottom flask equipped with a magnetic stir bar, 3-ethoxy-4-hydroxyphenylacetic acid propyl ester (800 mg, 3.4 mmol, 1.0 equiv) was dissolved in dry acetone (20 mL). Get the _{solution, K 2 CO 3 (705mg,} 5.1mmol, 1.5 eq) followed by 2-chloro -N, N-diethylacetamide (0.55 mL, 4.0 mmol, 1.2 equiv, from Aldrich Possible) was added. Under vigorous stirring, the suspension was warmed to reflux and maintained under those conditions for 15 hours. After cooling also at room temperature, the reaction mixture was filtered using a folded filter paper and the remaining solution was free of solvent under reduced pressure. The oily product was purified using column chromatography (SiO ₂ , 50% EtOAc / hexanes) to give 630 mg (53% of theory) of a colorless oil, which was 99.6% by HPLC. It was purity.

（（１）式（ＩＩａ）Ｒ^１＝エチルおよびＲ^４＝プロピル（３−エトキシ−４−ヒドロキシフェニル酢酸プロピルエステル）の中間体の調製）
テフロン（登録商標）のスクリューキャップを有する３０ｍＬのガラス圧力管に、磁気攪拌棒を備え、そしてこれに３−エトキシ−４−ヒドロキシフェニル酢酸（２．５ｇ、１２．７ｍｍｏｌ、１．０当量、Ｔｒａｎｓ Ｗｏｒｌｄ Ｃｈｅｍｉｃａｌｓから入手可能）を充填した。１−プロパノール（２０ｍＬ、２７０ｍｍｏｌ、約２０当量）を添加し、そしてこの混合物を攪拌して溶解した。濃硫酸（２滴）を添加した。チューブキャップを手で固くスクリューダウンし、そしてチューブをオイル浴中に浸けた。この反応物を９０℃で１５分間攪拌した。チューブを室温まで冷却し、その後、この内容物を丸底フラスコに移し、そして過剰のアルコールを減圧中で蒸留した。残った油状物を酢酸エチル（５０ｍＬ）中に集め、そして飽和炭酸水素ナトリウム溶液で洗浄した。硫酸マグネシウムで乾燥し、濾過した後、この溶媒を減圧下で蒸留し、淡黄色油状物として２．６ｇ（８５％収量）のエステルが残った。

(1) Preparation of intermediate of formula (IIa) R ¹ = ethyl and R ⁴ = propyl (3-ethoxy-4-hydroxyphenylacetic acid propyl ester)
A 30 mL glass pressure tube with a Teflon® screw cap was equipped with a magnetic stir bar and was equipped with 3-ethoxy-4-hydroxyphenylacetic acid (2.5 g, 12.7 mmol, 1.0 eq, Trans (Available from World Chemicals). 1-propanol (20 mL, 270 mmol, ca. 20 eq) was added and the mixture was stirred to dissolve. Concentrated sulfuric acid (2 drops) was added. The tube cap was screwed down by hand and the tube was immersed in an oil bath. The reaction was stirred at 90 ° C. for 15 minutes. The tube was cooled to room temperature, after which the contents were transferred to a round bottom flask and excess alcohol was distilled in vacuo. The remaining oil was collected in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution. After drying over magnesium sulfate and filtration, the solvent was distilled under reduced pressure leaving 2.6 g (85% yield) of ester as a pale yellow oil.

(2) Preparation of intermediate of formula (IIa) R ¹ = ethyl and R ⁴ = propyl (3-ethoxy-4-hydroxyphenylacetic acid propyl ester)
The title intermediate was also prepared according to Scheme B below.

（（ａ）化合物Ｂ１の調製）
２−エトキシフェノール（５６．６、０．４０１ｍｍｏｌ、１当量）、グリオキシル酸（５０％水溶液）（４１．０ｍＬ、０．３９６ｍｏｌ、０．９９当量）、および蒸留水（１１０ｍＬ）を合わせた。この混合物を氷浴で冷却し、そして１０％ ＮａＯＨの溶液（３００ｍＬの蒸留水中３２．２ｇ ＮａＯＨ、０．８０５ｍｏｌ、２当量）を、添加漏斗を介して、ゆっくり添加した。この反応物を室温までゆっくり温め、そして約１８時間後、この溶液を酢酸エチル（４×２５０ｍＬ）で洗浄し、次いで６Ｎ ＨＣｌを用いて、約ｐＨ３まで酸性化した。ＮａＣｌを添加し、次いで生成物を酢酸エチル（４×２００ｍＬ）中で抽出した。有機相をブラインで洗浄し、硫酸マグネシウムで乾燥し、そして溶媒を減圧下で除去し、淡いピンク色の固体として、５１．８ｇのＢ１を得た。

((A) Preparation of Compound B1)
2-Ethoxyphenol (56.6, 0.401 mmol, 1 equivalent), glyoxylic acid (50% aqueous solution) (41.0 mL, 0.396 mol, 0.99 equivalent), and distilled water (110 mL) were combined. The mixture was cooled in an ice bath and a solution of 10% NaOH (32.2 g NaOH in 300 mL distilled water, 0.805 mol, 2 eq) was added slowly via an addition funnel. The reaction was slowly warmed to room temperature and after about 18 hours, the solution was washed with ethyl acetate (4 × 250 mL) and then acidified to about pH 3 with 6N HCl. NaCl was added and the product was then extracted in ethyl acetate (4 × 200 mL). The organic phase was washed with brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give 51.8 g of B1 as a pale pink solid.

（（ｂ）化合物Ｂ２の調製）
化合物Ｂ１（４５．０ｇ、０．２１２ｍｏｌ、１当量）をＤＣＭ（２２５ｍＬ）中に溶解し、ピリジン（８０ｍＬ、０．９８９ｍｏｌ、６当量）を添加し、そしてこの混合物を氷浴中、窒素下で冷却した。無水酢酸（１００ｍＬ、１．０６ｍｏｌ、４当量）を添加漏斗を介して、ゆっくり添加した。反応が完了するまでこの混合物を攪拌し（約３時間）、次いでジエチルエーテル（５００ｍＬ）で希釈し、そして１Ｎ ＨＣｌ（４×２５０ｍＬ）で洗浄した。この混合物を８％の炭酸水素ナトリウム溶液（４×８０ｍＬ）中で抽出し、６Ｎ ＨＣｌを用いて約ｐＨ４に酸性化し、そして生成物をジエチルエーテル中に抽出し、白色の結晶性固体として、４１．１ｇのＢ２を得た。

((B) Preparation of Compound B2)
Compound B1 (45.0 g, 0.212 mol, 1 eq) is dissolved in DCM (225 mL), pyridine (80 mL, 0.989 mol, 6 eq) is added and the mixture is placed in an ice bath under nitrogen. Cooled down. Acetic anhydride (100 mL, 1.06 mol, 4 eq) was added slowly via the addition funnel. The mixture was stirred until the reaction was complete (about 3 hours), then diluted with diethyl ether (500 mL) and washed with 1N HCl (4 × 250 mL). This mixture is extracted in 8% sodium bicarbonate solution (4 × 80 mL), acidified to about pH 4 with 6N HCl, and the product is extracted into diethyl ether to give 41 as a white crystalline solid. Obtained 1 g of B2.

（（ｃ）化合物Ｂ３の調製）
化合物Ｂ２（３０．９ｇ、０．１０４ｍｏｌ）をメタノール（５００ｍＬ）中に溶解し、蒸留水で湿ったＰｄ（ＯＨ）_２（５．０ｇ）を添加し、そしてこの混合物を水素下３０ｐｓｉで振盪しながら配置した。４８時間後、Ｐｄ（ＯＨ）_２を濾過により除去し、そして溶媒を減圧下で除去し、黄色の油状物として２２ｇのＢ３を得た。

((C) Preparation of Compound B3)
Compound B2 (30.9 g, 0.104 mol) is dissolved in methanol (500 mL), Pd (OH) ₂ (5.0 g) moistened with distilled water is added, and the mixture is shaken at 30 psi under hydrogen. Arranged while. After 48 hours, Pd (OH) ₂ was removed by filtration and the solvent was removed under reduced pressure to give 22 g of B3 as a yellow oil.

（（ｄ）４−ヒドロキシフェニル酢酸プロピルエステルの調製）
化合物Ｂ３（１．４０ｇ、５．８７ｍｍｏｌ）を過剰の１−プロパノール（５０ｍＬ）に溶解し、濃Ｈ_２ＳＯ_４（３滴）を添加し、そしてこの混合物を９０℃で約１８時間加熱した。１−プロパノールの容量を減圧下で減少させ、次いでこの混合物をジエチルエーテルで希釈し、飽和炭酸水素ナトリウム溶液（２×）、蒸留水（１×）、ブライン（１×）で洗浄し、硫酸マグネシウムで乾燥し、そして減圧下で溶媒を除去し、黄色の油状物として４−ヒドロキシフェニル酢酸プロピルエステルを得た。

((D) Preparation of 4-hydroxyphenylacetic acid propyl ester)
Compound B3 (1.40 g, 5.87 mmol) was dissolved in excess 1-propanol (50 mL), concentrated H ₂ SO ₄ (3 drops) was added, and the mixture was heated at 90 ° C. for about 18 hours. The volume of 1-propanol is reduced under reduced pressure, then the mixture is diluted with diethyl ether, washed with saturated sodium bicarbonate solution (2 ×), distilled water (1 ×), brine (1 ×), magnesium sulfate And dried under reduced pressure to give 4-hydroxyphenylacetic acid propyl ester as a yellow oil.

（実施例２ 化合物２：［４−［（Ｎ，Ｎ−ジエチルカルバモイル）メトキシ］−３−エトキシフェニル］酢酸エチルエステル）

Example 2: Compound 2: [4-[(N, N-diethylcarbamoyl) methoxy] -3-ethoxyphenyl] acetic acid ethyl ester

中間体の合成において、１−プロパノールをエタノールに変えることを除いて、実施例１に記載した手順と類似の手順を使用して、Ｒ^１＝エチルおよびＲ^４＝プロピルを有する式（ＩＩａ）の中間体を生成し、表題の化合物を８１％の収量で、無色の油状物として、調製し、これは、ＨＰＬＣにより９６％の純度であった。

In the synthesis of the intermediate, using a procedure similar to that described in Example 1 except that 1-propanol is changed to ethanol, the compound of formula (IIa) having R ¹ = ethyl and R ⁴ = propyl is used. The intermediate was produced and the title compound was prepared as a colorless oil in 81% yield, which was 96% pure by HPLC.

（実施例３ 化合物３：［４−［（Ｎ，Ｎ−ジエチルカルバモイル）メトキシ］−３−エトキシフェニル］酢酸イソプロピルエステル）

(Example 3 Compound 3: [4-[(N, N-diethylcarbamoyl) methoxy] -3-ethoxyphenyl] acetic acid isopropyl ester)

中間体の合成において、１−プロパノールをイソプロパノールに変えることを除いて、実施例１に記載した手順と類似の手順を使用して、Ｒ^１＝エチルおよびＲ^４＝イソプロピルを有する式（ＩＩａ）の中間体を生成し、表題の化合物を６３％の収量で、これは、無色の油状物として調製し、ＨＰＬＣにより９９％の純度であった。

In the synthesis of the intermediate, using a procedure similar to that described in Example 1 except that 1-propanol is changed to isopropanol, the compound of formula (IIa) having R ¹ = ethyl and R ⁴ = isopropyl is used. An intermediate was produced and the title compound was prepared in 63% yield, which was prepared as a colorless oil and was 99% pure by HPLC.

（実施例４Ａ 化合物４：［４−［（Ｎ，Ｎ−ジエチルカルバモイル）メトキシ］−３−プロポキシフェニル］酢酸プロピルエステル）
化合物４を以下のスキームＣに従って、調製した。

Example 4A Compound 4: [4-[(N, N-diethylcarbamoyl) methoxy] -3-propoxyphenyl] acetic acid propyl ester
Compound 4 was prepared according to Scheme C below.

（（１）化合物Ｃ１（式（ＩＶ）Ｒ^１＝プロピル）の調製）
オーバーヘッドスターラーを備える３ＬのフラスコにおいてＤＭＦ（１．５ｍＬ）中のカテコールの溶液（８１．０ｇ、０．７４ｍｏｌ）を調製し、氷浴中で冷却した。ＮａＨ（オイル中６０％）（２９ｇ、０．７３ｍｏｌ）をこの溶液にゆっくり添加し、一旦完全に反応し（最後の添加後約１時間）、１−ブロモプロパン（７２ｍＬ、０．７４ｍｏｌ）を添加した。この反応混合物を一晩攪拌し、そして室温までゆっくり温めた。

(Preparation of (1) Compound C1 (Formula (IV) R ¹ = Propyl))
A solution of catechol (81.0 g, 0.74 mol) in DMF (1.5 mL) was prepared in a 3 L flask equipped with an overhead stirrer and cooled in an ice bath. Slowly add NaH (60% in oil) (29 g, 0.73 mol) to this solution, once completely reacted (about 1 hour after the last addition), add 1-bromopropane (72 mL, 0.74 mol) did. The reaction mixture was stirred overnight and slowly warmed to room temperature.

  The reaction mixture is poured into a separatory funnel containing diethyl ether and washed with water (3 ×) and then extracted into 1N NaOH (3 ×), the aqueous portion acidified to about pH 1 with 6N HCl, The product was then extracted in DCM (3x). The DCM was washed with brine (1 ×), dried over magnesium sulfate, and the solvent was removed under reduced pressure to give a red oil. The oil was purified through a 6 "silica gel plug, washed with 10% ethyl acetate / hexane, and then the solvent was removed under reduced pressure to give 26.8 g of a colorless oil C1.

(Preparation of (2) Compound C2 (Formula (V) R ¹ = Propyl))
To a mixture of C1 (26.8 g, 0.176 mol) and glyoxylic acid (50% solution in water) (17.6 mL, 0.160 mmol) cooled in an ice bath, a solution of 10% NaOH (128 mL, 0.320 mol) Was added. The mixture was stirred overnight and allowed to warm slowly to room temperature. After about 15 hours, 150 mL of distilled water was added to solubilize the mixture, and the reaction was again stirred overnight at room temperature.

  The reaction mixture was washed with ethyl acetate (4 ×), the aqueous portion was acidified with glacial acetic acid to about pH 3, and the product was extracted in ethyl acetate (3 ×). The ethyl acetate was washed with brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give 12 g of white solid C2.

((3) Preparation of Compound C3 (Formula (IIb) R ¹ and R ⁴ = Propyl))
PPTS (0.47 g, 1.87 mmol) was added to a solution of C2 (3.27 g, 1.44 mmol) dissolved in excess 1-propanol (90 mL). The solution was heated at 50 ° C. overnight.

  The volume of 1-propanol is reduced under reduced pressure, diluted with ethyl acetate and washed with 1N HCl (3 ×), saturated sodium bicarbonate (3 ×), and brine (1 ×) and dried over magnesium sulfate. did. The solvent was removed under reduced pressure and the mixture was purified by column chromatography to give 1.7 g of a colorless oil C3.

((4) Preparation of Compound C4 (Formula (III) R ¹ and R ⁴ = Propyl, R ² and R ³ = Ethyl))
Cesium carbonate (10 g, 30.7 mmol) was added to a solution of C3 (1.70 g, 6.36. Mmol) dissolved in acetone (100 mL). After stirring for 10 minutes, 2-chloro-N, N-diethylacetamide (0.95 mL, 6.91 mmol) was added and the reaction mixture was heated at 60 ° C. overnight.

  When the reaction was complete, the cesium carbonate was filtered and the solvent was removed under reduced pressure and the mixture was purified by column chromatography to give 0.82 g of a colorless oil C4.

((5) Preparation of Compound C5)
To a solution of C4 (0.512 g, 1.40 mmol) dissolved in DCM (50 mL) and pyridine (0.35 mL, 4.33 mmol) and cooled in an ice bath was added acetyl bromide (0.21 mL, 2.84 mmol). ) Was added. The reaction mixture was stirred overnight and slowly warmed to room temperature.

  The mixture is poured into diethyl ether and washed with 1N HCl (3 ×), saturated sodium bicarbonate (3 ×), distilled water (1 ×), and brine (1 ×), then dried over magnesium sulfate, and The solvent was removed under reduced pressure to give 0.517 g of a pink oil C5.

((6) Synthesis of Compound 4)
To a solution of C5 (0.167 g, 0.394 mmol) in 1-propanol (25 mL) was added 10% Pd / C (20 mg) moistened with 1-propanol and treated at 28 psi under hydrogen. . After 1 hour, the Pd / C was removed and replaced with another portion of 1-propanol moistened with 10% Pd / C (20 mg) and treated again under hydrogen at 28 psi for 3 hours. Pd / C was removed by filtration and the solvent was removed under reduced pressure, then the mixture was purified by column chromatography to give 90 mg of a colorless oil 4.

  Alternatively, compound 4 can be prepared as in the following examples.

Example 4B Compound 4: [4-[(N, N-diethylcarbamoyl) methoxy] -3-propoxyphenyl] acetic acid propyl ester
(Preparation of (1) Compound C1 (Formula (IV) R ¹ = Propyl))
To a solution of catechol (100.1 g, 0.91 mol) dissolved in acetone (1 L), potassium carbonate (125.1 g, 0.91 mol) was slowly added with vigorous stirring; 1-bromopropane (90.0 mL) 0.92 mol) was added during heating and the mixture was refluxed overnight.

  Once the reaction was cooled to room temperature, the potassium carbonate was removed by filtration and the solvent was removed under reduced pressure. The product was then diluted with diethyl ether, washed with distilled water (4 ×) and then extracted in 1N NaOH. The aqueous solution was collected, acidified with 6N HCl to about pH 1, and the product was extracted in diethyl ether, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The product was purified through a 6 ″ silica gel plug, washed with 10% ethyl acetate / hexane, and the solvent was removed under reduced pressure to yield 45 g (0.30 mol, 32% yield) of off-white. Of C1 was obtained.

（（２）化合物Ｃ２（式（Ｖ）Ｒ^１＝プロピル）の調製）
氷浴中で冷却した、１Ｌの蒸留水中のＣ１（１００ｇ、０．６５７ｍｏｌ）およびグリオキシル酸（水中５０％溶液）（６７ｍＬ、０．６４８ｍｏｌ）の混合物に、１０％のＮａＯＨ溶液（５００ｍｌの脱イオン水中５２ｇのＮａＯＨ、１．３ｍｏｌ）を添加漏斗を介して、ゆっくり添加した。この混合物を、室温までゆっくり温める間、一晩攪拌した。

(Preparation of (2) Compound C2 (Formula (V) R ¹ = Propyl))
To a mixture of C1 (100 g, 0.657 mol) and glyoxylic acid (50% solution in water) (67 mL, 0.648 mol) in 1 L distilled water cooled in an ice bath was added 10% NaOH solution (500 ml deionized). 52 g NaOH in water, 1.3 mol) was added slowly via an addition funnel. The mixture was stirred overnight while slowly warming to room temperature.

  The reaction mixture was washed with ethyl acetate (4 ×), the aqueous portion was collected and acidified with 6N HCl to about pH 3, then the product was extracted in ethyl acetate (3 ×). The ethyl acetate was washed with brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give 70 g (0.31 mol, 47% yield) of a light pink solid C2.

（（３）化合物Ｃ３（式（ＩＩｂ）Ｒ^１およびＲ^４＝プロピル）の調製）
過剰の１−プロパノール（５５０ｍＬ）に溶解したＣ２（７０ｇ、０．２８９ｍｏｌ）の溶液に、ＰＰＴＳ（７．５ｇ、２９．８ｍｍｏｌ）を添加し、そして５０℃で一晩加熱した。

((3) Preparation of Compound C3 (Formula (IIb) R ¹ and R ⁴ = Propyl))
To a solution of C2 (70 g, 0.289 mol) dissolved in excess 1-propanol (550 mL) was added PPTS (7.5 g, 29.8 mmol) and heated at 50 ° C. overnight.

The volume of 1-propanol is reduced under reduced pressure, then diluted with ethyl acetate and 1N
Washed with HCl (3x), saturated aqueous sodium bicarbonate (3x), and brine (1x), then dried over magnesium sulfate. The solvent was removed under reduced pressure and the mixture was then purified by column chromatography to give 55 g (0.20 mol, 71% yield) of an off-white solid C3.

（（４）化合物Ｃ４（式（ＩＩＩ）Ｒ^１およびＲ^４＝プロピル、Ｒ^２およびＲ^３＝エチル）の調製）
炭酸カリウム（９５ｇ、０．６９ｍｏｌ）をアセトン（５００ｍＬ）に溶解したＣ３（８５ｇ、０．３２ｍｏｌ）の溶液にゆっくり添加した。次いで、この混合物を６０℃まで加熱し、１時間攪拌した後、２−クロロ−Ｎ，Ｎ−ジエチルアセトアミド（４３．５ｍＬ、０．３２ｍｏｌ）を添加し、そしてこの反応混合物を６０℃で４８時間加熱した。

((4) Preparation of Compound C4 (Formula (III) R ¹ and R ⁴ = Propyl, R ² and R ³ = Ethyl))
Potassium carbonate (95 g, 0.69 mol) was slowly added to a solution of C3 (85 g, 0.32 mol) dissolved in acetone (500 mL). The mixture was then heated to 60 ° C. and stirred for 1 hour before 2-chloro-N, N-diethylacetamide (43.5 mL, 0.32 mol) was added and the reaction mixture was stirred at 60 ° C. for 48 hours. Heated.

  When the reaction is complete, potassium carbonate is removed by filtration and the solvent is removed under reduced pressure and the mixture is purified by column chromatography to give 50 g (0.13 mol, 46% yield) of a colorless oil. Product C4 was obtained.

（（５）化合物Ｃ５の調製）
ＤＣＭ（６００ｍｌ）およびピリジン（３０ｍｌ、０．３７ｍｏｌ）に溶解し、氷浴中で冷却したＣ４（５０ｇ、０．１３ｍｏｌ）溶液に、アセチルブロミド（２０ｍｌ、０．２７ｍｏｌ）を添加した。ゆっくり室温まで温めながら、反応混合物を一晩攪拌した。

((5) Preparation of Compound C5)
To a solution of C4 (50 g, 0.13 mol) dissolved in DCM (600 ml) and pyridine (30 ml, 0.37 mol) and cooled in an ice bath, acetyl bromide (20 ml, 0.27 mol) was added. The reaction mixture was stirred overnight while slowly warming to room temperature.

  The solvent was reduced in vacuo then diluted with diethyl ether and washed with 1N HCl (5 ×), saturated sodium bicarbonate (4 ×), and brine (1 ×), then dried over magnesium sulfate. . The solvent was removed under vacuum to give a yellow oil. The oil was then purified by column chromatography to give 50 g of a yellow oil C5 (0.12 mol, 91% yield).

。

.

((6) Synthesis of Compound 4)
To a solution of C5 (50 g, 0.12 mol) in 1-propanol (200 mL) was added 10% Pd / C (5 g) moistened with 1-propanol and treated with shaking under 32 psi of hydrogen for 48 hours. . Pd / C was removed, replaced with another portion of 10% Pd / C (2 g) moistened with 1-propanol and treated again with shaking under 30 psi of hydrogen for 4 hours. Pd / C was removed by filtration through a Millipore filter, the solvent was removed in vacuo, and the product was then purified by column chromatography to give 38 g of colorless oil 4 (0.10 mol, yield). Rate 87%).

ＨＰＬＣ（ＲＰ、１０〜７０％ アセトニトリル／水、６分実行、２１４ｎｍ）保持時間４．７５分、純度１００％（ＨＰＬＣによる）。

HPLC (RP, 10-70% acetonitrile / water, 6 min run, 214 nm) Retention time 4.75 min, purity 100% (by HPLC).

Example 5 Compound 5: [4-[(N, N-dipropylcarbamoyl) methoxy] -3-ethoxyphenyl] acetic acid ethyl ester
Using the process of Example 2, 2-chloro-N, N-diethylacetamide was replaced with 2-chloro-N, N-dipropylacetamide to prepare compound 5 (yield 54%).

ＨＰＬＣ（ＲＰ、３０〜９０％ アセトニトリル／水、６分実行、２１４ｎｍで検出）保持時間３．２０分、純度９７％（ＨＰＬＣによる）。

HPLC (RP, 30-90% acetonitrile / water, 6 min run, detected at 214 nm) Retention time 3.20 min, purity 97% (by HPLC).

Example 6 Compound 6: [4-[(N, N-dipropylcarbamoyl) methoxy] -3-ethoxyphenyl] acetic acid propyl ester
Using the process of Example 1, 2-chloro-N, N-diethylacetamide was replaced with 2-chloro-N, N-dipropylacetamide to prepare compound 6 (51% yield).

ＨＰＬＣ（ＲＰ、３０〜９０％ アセトニトリル／水、６分実行、２１４ｎｍで検出）保持時間３．５７分、純度１００％（ＨＰＬＣによる）。

HPLC (RP, 30-90% acetonitrile / water, 6 min run, detected at 214 nm) Retention time 3.57 min, purity 100% (by HPLC).

Example 7 Compound 7: [4-[(N-ethyl-N-methylcarbamoyl) methoxy] -3-ethoxyphenyl] acetic acid propyl ester
Using the process of Example 1, 2-chloro-N, N-diethylacetamide was replaced with 2-chloro-N-ethyl-N-methylacetamide to prepare compound 7 (88% yield).

ＨＰＬＣ（ＲＰ、３０〜９０％ アセトニトリル／水、６分実行、２１４ｎｍで検出）保持時間２．４５分、純度９９％（ＨＰＬＣによる）。

HPLC (RP, 30-90% acetonitrile / water, 6 min run, detected at 214 nm) Retention time 2.45 min, purity 99% (by HPLC).

Example 8 Compound 8: [4-[(N-ethyl-N-propylcarbamoyl) methoxy] -3-ethoxyphenyl] acetic acid ethyl ester
Using the process of Example 2, 2-chloro-N, N-diethylacetamide was replaced with 2-chloro-N-ethyl-N-propylacetamide to prepare compound 8 (64% yield).

ＨＰＬＣ（ＲＰ、３０〜９０％アセトニトリル／水、６分実行、２１４ｎｍで検出）保持時間２．８１分、純度９５％（ＨＰＬＣによる）。

HPLC (RP, 30-90% acetonitrile / water, 6 min run, detected at 214 nm) Retention time 2.81 min, purity 95% (by HPLC).

Example 9 Compound 9: [4-[(N-ethyl-N-propylcarbamoyl) methoxy] -3-ethoxyphenyl] acetic acid propyl ester
Using the process of Example 1, 2-chloro-N, N diethylacetamide was replaced with 2-chloro-N-ethyl-N-propylacetamide to prepare compound 9 (92% yield).

ＨＰＬＣ（ＲＰ、３０〜９０％ アセトニトリル／水、６分実行、２１４ｎｍで検出）保持時間２．９５分、純度１００％（ＨＰＬＣによる）。

HPLC (RP, 30-90% acetonitrile / water, 6 min run, detected at 214 nm) Retention time 2.95 min, purity 100% (by HPLC).

Example 10 Compound 10: [4-[(N, N-dimethylcarbamoyl) methoxy] -3-propoxyphenyl] acetic acid propyl ester
((1) Preparation of 2- [4-[(N, N-dimethylcarbamoyl) methoxy] -3-propoxyphenyl] -2-hydroxyacetic acid propyl ester (10-D))
Performed using reactant compound C (2.49 g, 9.28 mmol), acetone (60 mL), potassium carbonate (2.55 g, 18.5 mmol) and N, N-dimethylacetamide (1.42 g, 11.5 mmol). Compound 10-D was prepared using the process of Example 4B subpart (4) (1.4 g).

。

.

((2) Preparation of 2- [4-[(N, N-dimethylcarbamoyl) methoxy] -3-propoxyphenyl] -2-acetoxyacetic acid propyl ester (10-E))
Example 4B using reactant compound 10-D (1.4 g, 3.96 mmol), DCM (100 mL), pyridine (1.0 mL, 12.4 mmol), and acetyl bromide (0.55 mL, 7.44 mmol). Compound 10-E was prepared (1.4 g) using the process of subpart (5).

。

.

((3) Synthesis of Compound 10)
Compound 10-E was treated with hydrogen according to the process of Example 4B subpart (6) to prepare compound 10 as a white solid (0.80 g, 2.37 mmol).

ＨＰＬＣ（ＲＰ、１０〜７０％ アセトニトリル／水、６分実行、２１４ｎｍ）保持時間４．２３分、純度９９．２％（ＨＰＬＣによる）。

HPLC (RP, 10-70% acetonitrile / water, 6 min run, 214 nm) Retention time 4.23 min, purity 99.2% (by HPLC).

Example 11 Compound 11: [4-[(N-ethyl-N-propylcarbamoyl) methoxy] -3-propoxyphenyl] acetic acid propyl ester
(Preparation of (1) 2- [4-[(N-ethyl-N-propylcarbamoyl) methoxy] -3-propoxyphenyl] -2-hydroxyacetic acid propyl ester (11-D))
Reactant compound C (2.43 g, 9.06 mmol), acetone (60 mL), potassium carbonate (2.50 g, 18.1 mmol), and 2-chloro-N-ethyl-N-propylacetamide (1.94 g, 11 Compound 9-D was prepared using the process of Example 4B subpart (4) (1.75 g).

。

.

((2) Preparation of 2- [4-[(N-ethyl-N-propylcarbamoyl) methoxy] -3-propoxyphenyl] -2-acetoxyacetic acid propyl ester (11-E))
Example 4B using reactant compound 11-D (1.70 g, 4.29 mmol), DCM (100 mL), pyridine (1.0 mL, 12.4 mmol), and acetyl bromide (0.60 mL, 4.77 mmol). Compound 11-E was prepared (2.0 g) using the process of subpart (5).

。

.

((3) Synthesis of Compound 11)
Compound 11-E was treated with hydrogen according to the process of Example 4B subpart (6) to prepare compound 11 as a colorless oil (0.95 g, 2.50 mmol).

ＨＰＬＣ（ＲＰ、１０〜７０％ アセトニトリル／水、６分実行、２１４ｎｍ）保持時間５．２６分、純度１００％（ＨＰＬＣによる）。

HPLC (RP, 10-70% acetonitrile / water, 6 min run, 214 nm) Retention time 5.26 min, purity 100% (by HPLC).

Example 12 Compound 12: [4-[(N, N-dipropylcarbamoyl) methoxy] -3-propoxyphenyl] acetic acid propyl ester
(Preparation of (1) 2- [4-[(N, N-dipropylcarbamoyl) methoxy] -3-propoxyphenyl] -2-hydroxyacetic acid propyl ester (12-D))
Reactant compound C (2.27 g, 8.46 mmol), acetone (60 mL), potassium carbonate (2.50 g, 18.1 mmol), and 2-chloro-N, N-dipropylacetamide (1.65 g, 9. Compound 12-D was prepared (1.0 g) using the process of Example 4B subpart (4).

（（２）２−［４−［（Ｎ，Ｎ−ジプロピルカルバモイル）メトキシ］−３−プロポキシフェニル］−２−アセトキシ酢酸プロピルエステル（１２−Ｅ）の調製）
反応物化合物１２−Ｄ（１．７０ｇ、４．２９ｍｍｏｌ）、ＤＣＭ（１００ｍＬ）、ピリジン（１．０ｍＬ、１２．４ｍｍｏｌ）、およびアセチルブロミド（０．６０ｍＬ、４．７７ｍｍｏｌ）を用い、実施例４Ｂ下位部分（５）のプロセスを使用して、化合物１２−Ｅを調製した（１．０ｇ）。

((2) Preparation of 2- [4-[(N, N-dipropylcarbamoyl) methoxy] -3-propoxyphenyl] -2-acetoxyacetic acid propyl ester (12-E))
Example 4B using reactant compound 12-D (1.70 g, 4.29 mmol), DCM (100 mL), pyridine (1.0 mL, 12.4 mmol), and acetyl bromide (0.60 mL, 4.77 mmol). Compound 12-E was prepared using the process of subpart (5) (1.0 g).

。

.

((3) Synthesis of Compound 12)
Compound 12-E was treated with hydrogen according to the process of Example 4B subpart (6) to prepare compound 12 as a colorless oil (0.80 g, 2.03 mmol).

ＨＰＬＣ（ＲＰ、１０〜７０％ アセトニトリル／水、６分実行、２１４ｎｍ）保持時間５．４５分、純度１００％（ＨＰＬＣによる）。

HPLC (RP, 10-70% acetonitrile / water, 6 min run, 214 nm) Retention time 5.45 min, purity 100% (by HPLC).

Example 13 Compound 13: [4-[(N-ethyl-N-methylcarbamoyl) methoxy] -3-propoxyphenyl] acetic acid propyl ester
(Preparation of (1) 2- [4-[(N-ethyl-N-methylcarbamoyl) methoxy] -3-propoxyphenyl] -2-hydroxyacetic acid propyl ester (13-D))
Reactant compound C (2.26 g, 8.42 mmol), acetone (60 mL), potassium carbonate (2.50 g, 18.1 mmol), and 2-chloro-N-ethyl-N-methylacetamide (1.26 g, 9 Compound 13-D was prepared using the process of Example 4B subpart (4) (1.6 g).

。

.

((2) Preparation of 2- [4-[(N-ethyl-N-methylcarbamoyl) methoxy] -3-propoxyphenyl] -2-acetoxyacetic acid propyl ester (13-E))
Example 4B using reactant compound 13-D (1.60 g, 4.35 mmol), DCM (100 mL), pyridine (1.0 mL, 12.4 mmol), and acetyl bromide (0.60 mL, 4.77 mmol). Compound 13-E was prepared (1.9 g) using the process of subpart (5).

。

.

((3) Synthesis of Compound 13)
Compound 13-E was treated with hydrogen according to the process of Example 4B subpart (6) to prepare compound 13 as a colorless oil (1.5 g, 4.27 mmol).

ＨＰＬＣ（ＲＰ、１０〜７０％ アセトニトリル／水、６分実行、２１４ｎｍ）保持時間４．４７分、純度９９％（ＨＰＬＣによる）。

HPLC (RP, 10-70% acetonitrile / water, 6 min run, 214 nm) Retention time 4.47 min, purity 99% (by HPLC).

Example 14 Compound 14: [4-[(N-ethyl-N-propylcarbamoyl) methoxy] -3-propoxyphenyl] acetic acid ethyl ester
Compound 11 (0.201 g, 0.510 mmol) was saponified by dissolving in (1: 1) MeOH: deionized water (10 mL). While the mixture was immersed in an ice bath, 0.1 N NaOH (5.1 mL, 0.51 mmol) was added and the mixture was stirred overnight, diluted with deionized water, and washed with DCM. The aqueous portion was acidified with 1N HCl and the product was extracted into DCM and dried over magnesium sulfate. The solvent was removed under vacuum.

  The acid product was redissolved in ethanol (20 mL), sulfuric acid (2 drops) was added and the mixture was heated to 110 ° C. overnight. The solvent was removed in vacuo and the product was then purified by column chromatography to give compound 14 as a colorless oil (170 mg, 0.465 mmol).

ＨＰＬＣ（ＲＰ、１０〜７０％ アセトニトリル／水、６分実行、２１４ｎｍ）保持時間４．８８分、純度９５％（ＨＰＬＣによる）。

HPLC (RP, 10-70% acetonitrile / water, 6 min run, 214 nm) Retention time 4.88 min, purity 95% (by HPLC).

Example 15 Comparative Compound Propanidide: [4-[(N, N-Diethylcarbamoyl) methoxy] -3-methoxyphenyl] acetic acid propyl ester
(Preparation of (1) 3-methoxy-4-hydroxyphenylacetic acid propyl ester (15-A))
4-Hydroxy-3-methoxyphenethyl alcohol (Sigma-Aldrich) was dissolved in anhydrous 1-propanol. About 5 drops of concentrated sulfuric acid was added to the solution and the solution was heated in a pressure tube at 100 ° C. for 3-5 hours. After the reaction was complete, 1-propanol was removed under reduced pressure and the resulting oil was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, sterile water, and then with brine. The solution was dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 15-A as a red oil in almost quantitative yield.

。

.

((2) Preparation of [4-[(N, N-diethylcarbamoyl) methoxy] -3-methoxyphenyl] acetic acid propyl ester)
3-Methoxy-4-hydroxyphenylacetic acid propyl ester (15-A) was dissolved in acetone. To this solution was added 2 equivalents of K ₂ CO ₃ followed by 1.2 equivalents of 2-chloro-N, N-diethylacetamide. The suspension was warmed and perfused for about 15 minutes (60 ° C.) with vigorous stirring. After cooling to room temperature, the reaction mixture was filtered and the remaining solvent was removed under reduced pressure to give a 95% yield dark yellow oil. The oily product was purified by silica column chromatography to produce the title compound.

。
（実施例１６．以下は、本発明「化合物Ｘ」の化合物を含む、代表的な薬学的用量形態を示す。
（ｉ）注入１ 重量％
「化合物Ｘ」 ２．０
ダイズ油 １０．０
卵ホスファチド １．２
グリセロール ２．２５
エデト酸ニナトリウムニ水和物 ０．００５５
水酸化ナトリウム 十分量
注入のための水 １００まで

（ｉｉ）注入２ 重量％
「化合物Ｘ」 １．０
ダイズ油 ５．０
分画ココナッツ油 ５．０
卵ホスファチド １．２
グリセロール ２．２５
エデト酸ニナトリウムニ水和物 ０．００５５
水酸化ナトリウム 十分量
注入のための水 １００まで

（ｉｉｉ）注入３ 重量％
「化合物Ｘ」 １．０％ｗ／ｖ
Ｎ−メチルピロリジノン ３０％ｗ／ｖ
プロピレングリコール ４０％ｗ／ｖ
注入のための水

（ｉｖ）注入４ 重量％
「化合物Ｘ」 ２．０％ｗ／ｖ
Ｎ−メチルピロリジノン ３０％ｗ／ｖ
プロピレングリコール ４０％ｗ／ｖ
注入のための水

（ｖ）注入５ 重量％
「化合物Ｘ」 １．０
ダイズ油 １．０〜３．０
レシチン １．２
グリセロール ２．２５
水酸化ナトリウム 十分量
注入のための水 １００まで

（ｖｉ）注入６ 重量％
「化合物Ｘ」 １．０％ｗ／ｖ
ダイズ油 １０．０％ｗ／ｖ
ベニバナ油 １０．０％ｗ／ｖ
卵ホスファチド １．２％ｗ／ｖ
グリセロール ２．５％ｗ／ｖ
水酸化ナトリウム 十分量
注入のための水

（ｖｉｉ）注入７ 重量％
「化合物Ｘ」 １．０％ｗ／ｖ
ダイズ油 １０．０％ｗ／ｖ
卵ホスファチド １．２％ｗ／ｖ
グリセロール ２．５％ｗ／ｖ
水酸化ナトリウム 十分量
注入のための水

（ｖｉｉｉ）注入８ 重量％
「化合物Ｘ」 １．０％ｗ／ｖ
ダイズ油 ３０．０％ｗ／ｖ
卵黄由来の卵ホスファチジルコリン １．２％ｗ／ｖ
グリセロール １．６７％ｗ／ｖ
水酸化ナトリウム 十分量
注入のための水

（ｉｘ）注入９ 重量％
「化合物Ｘ」 ４．０％ｗ／ｖ
ダイズ油 ２０％ｗ／ｖ
レシチン ２．４％ｗ／ｖ
グリセロール ２．５％ｗ／ｖ
オレイン酸 ０．０３％ｗ／ｖ
０．１Ｎ 水酸化ナトリウム ｐＨ８になるまで十分量
注入のための水

（ｘ）注入１０ 重量％
「化合物Ｘ」 １０．０％ｗ／ｖ
カプリル酸／カプリン酸トリグリセリド １０．０％ｗ／ｖ
卵ホスファチジド １．２％ｗ／ｖ
グリセロール ２．５％ｗ／ｖ
水酸化ナトリウム 十分量
注入のための水

（ｘｉ）注入１１ 重量％
「化合物Ｘ」 ５．０％ｗ／ｖ
カプリル酸／カプリン酸トリグリセリド １５．０％ｗ／ｖ
卵ホスファチジド １．２％ｗ／ｖ
グリセロール ２．５％ｗ／ｖ
水酸化ナトリウム 十分量
注入のための水

（ｘｉｉ）注入１２ 重量％
「化合物Ｘ」 １０．０％ｗ／ｖ
Ｍｉｇｌｙｏｌ（登録商標）８１０ ５．０〜１０．０％ｗ／ｖ
卵黄ホスファチジド ０．５〜１．０％ｗ／ｖ
ＤＭＰＧ ０．１％ｗ／ｖ
グリセロール ２．２５％ｗ／ｖ
水酸化ナトリウム 十分量
注入のための水

上記処方物を、薬学的分野において周知である従来のプロセスによって監督し得る。例えば、注入９に従う化合物１の処方物を、以下のプロセスによって調製した。

.
Example 16. The following shows a representative pharmaceutical dosage form comprising a compound of the present invention “Compound X”.
(I) Injection 1 % by weight
“Compound X” 2.0
Soybean oil 10.0
Egg phosphatide 1.2
Glycerol 2.25
Edetate disodium dihydrate 0.0055
Sodium hydroxide water for injection up to 100

(Ii) Injection 2 % by weight
“Compound X” 1.0
Soybean oil 5.0
Fractionated coconut oil 5.0
Egg phosphatide 1.2
Glycerol 2.25
Edetate disodium dihydrate 0.0055
Sodium hydroxide water for injection up to 100

(Iii) Injection 3 % by weight
“Compound X” 1.0% w / v
N-methylpyrrolidinone 30% w / v
Propylene glycol 40% w / v
Water for injection

(Iv) 4 % by weight of injection
“Compound X” 2.0% w / v
N-methylpyrrolidinone 30% w / v
Propylene glycol 40% w / v
Water for injection

(V) 5 % by weight injected
“Compound X” 1.0
Soybean oil 1.0-3.0
Lecithin 1.2
Glycerol 2.25
Sodium hydroxide water for injection up to 100

(Vi) Injection 6 % by weight
“Compound X” 1.0% w / v
Soybean oil 10.0% w / v
Safflower oil 10.0% w / v
Egg phosphatide 1.2% w / v
Glycerol 2.5% w / v
Sodium hydroxide enough water for injection

(Vii) Injection 7 % by weight
“Compound X” 1.0% w / v
Soybean oil 10.0% w / v
Egg phosphatide 1.2% w / v
Glycerol 2.5% w / v
Sodium hydroxide enough water for injection

(Viii) 8 % by weight injected
“Compound X” 1.0% w / v
Soybean oil 30.0% w / v
Egg yolk-derived egg phosphatidylcholine 1.2% w / v
Glycerol 1.67% w / v
Sodium hydroxide enough water for injection

(Ix) Injection 9 % by weight
“Compound X” 4.0% w / v
Soybean oil 20% w / v
Lecithin 2.4% w / v
Glycerol 2.5% w / v
Oleic acid 0.03% w / v
0.1N sodium hydroxide enough water for injection until pH 8

(X) Injection 10 % by weight
“Compound X” 10.0% w / v
Caprylic acid / Capric acid triglyceride 10.0% w / v
Egg phosphatidide 1.2% w / v
Glycerol 2.5% w / v
Sodium hydroxide enough water for injection

(Xi) 11 % by weight of injection
“Compound X” 5.0% w / v
Caprylic acid / Capric acid triglyceride 15.0% w / v
Egg phosphatidide 1.2% w / v
Glycerol 2.5% w / v
Sodium hydroxide enough water for injection

(Xii) 12 % by weight injected
“Compound X” 10.0% w / v
Miglyol® 810 5.0-10.0% w / v
Egg yolk phosphatide 0.5-1.0% w / v
DMPG 0.1% w / v
Glycerol 2.25% w / v
Sodium hydroxide enough water for injection

The formulation can be supervised by conventional processes well known in the pharmaceutical art. For example, a formulation of Compound 1 according to Injection 9 was prepared by the following process.

  L-α-phosphatidylcholine 60% (lecithin) (2.40 g), glycerol (98%) (2.50 g) (both from Sigma-Aldrich), oleic acid (99%) (0.03 g) (Fluka- A mixture of Sigma-Aldrich, Buchs, Switzerland and deionized water (71.1 g) was heated at 60 ° C. until completely dissolved, resulting in an opaque solution. The pH was adjusted to pH 8 while the solution was warmed by the addition of 0.1 N NaOH. A mixture of Compound 1 (4.0 g) and soybean oil (Sigma-Aldrich) (20.0 g) was heated to 60 ° C. until blended and then added to the first mixture. The solution was stirred briefly at 60 ° C. and then transferred to a beaker and stirred with a Polytron tissue homogenizer at maximum speed for 5 minutes to provide a premixed solution.

  A microfluidizer (Microfluidics Corp., Newton, MA, model no. 110S) was washed with isopropanol and then deionized water. A microfluidizer was prepared with a minimum amount of premixed solution. The microfluidizer reservoir was filled with the premixed solution and the solution was circulated through the mixing chamber for 30 seconds at maximum pressure (about 12000-15000 psi). The first approximately 10 drops of the microfluidized solution were collected and discarded, then all subsequent fractions were collected in glass vials.

  All publications, patents, and patent documents are hereby incorporated by reference as if each were incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

FIG. 1 compares the desired dose of the prior art compound, propanide, and its dose in mg / kg of the compound of the present invention that produces an average 2-minute loss of upright reflex in rats. FIG. 2 shows the recovery time following the end of the infusion of the prior art compounds, propanide and propofol and the total recovery time (minutes) following the end of the infusion of 20 minutes, 3 hours and 5 hours in rats of Compound 1 of the invention. Compare

Claims (1)

  Compounds described in this example.

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