Prodrugs of ketamine, compositions and uses thereof

文档序号：1026577 发布日期：2020-10-27 浏览：19次中文

阅读说明：本技术 ***的前药、其组合物和用途 (Prodrugs of ketamine, compositions and uses thereof ) 是由向家宁徐雪松伍维思施皓維于 2019-01-08 设计创作，主要内容包括：提供了(S)-或(R)-氯胺酮(包括同位素标记的氯胺酮)的前药、其组合物和用途。作为(S)-或(R)-氯胺酮的前药(包括同位素标记的氯胺酮)的前药的具有式(Ia)或(Ib)的化合物以及包含本文中提供的化合物的药物组合物用于治疗或预防CNS疾病。更特别地,相关的疾病包括抑郁症和疼痛。<Image he="279" wi="700" file="DDA0002671276460000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Provide (S) -Or (R) -ketamine (including isotopically labeled ketamine), compositions and uses thereof. Compounds having formula (Ia) or (Ib) that are prodrugs of (S) -or (R) -ketamine (including isotopically labeled ketamine) and pharmaceutical compositions comprising the compounds provided herein are useful for treating or preventing CNS disorders. More particularly, related disorders include depression and pain.)

1. A compound having a structure of formula (Ia) or (Ib), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

wherein R is-C (═ O) R¹、-C(＝O)OR²、-C(＝O)O(CHR³)OC(＝O)R⁴or-CD₃(ii) a And X is-CH₃or-CD₃。

2. A compound having the structure of formula (IIa) or (IIb), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

wherein R is¹Is optionally substituted or unsubstituted aryl-OH, aryl-NH₂alkenyl-OH, alkenyl-NH₂alkyl-NH₂alkyl-OH, carbocyclyl or heterocyclyl containing one or more N or O; and X is-CH₃or-CD₃。

3. The compound of claim 2, wherein R¹Is amino C_1-6Alkyl, -R^1aNHCOR^1b、-R^1aOCOR^1b、-R^1aCOOR^1b、Or C_3-6A heterocyclic group,

wherein R is¹Optionally substituted by C_1-6Alkyl, -OH or oxo (═ O),

wherein R is^1aAnd R^1bIndependently is H, C_1-6Alkyl or C_2-6Alkenyl radical and

R^1cis-OH, C_1-3Hydroxyalkyl, -OCOR^1bor-CH₂OCOR^1b。

4. The compound of claim 2, wherein said heterocyclyl containing one or more N or O is

5. A compound selected from the group consisting of:

wherein X is-CH₃or-CD₃。

6. A compound having a structure of formula (IIIa) or (IIIb), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

wherein R is²Is optionally substituted or unsubstituted alkyl, aryl, carbocyclyl or heterocyclyl containing one or more O; and X is-CH₃or-CD₃。

7. The compound of claim 6, wherein R²Is C_1-6Alkyl radical, C_1-6Hydroxyalkyl, amino C_1-6Alkyl, -R^2aS(O)_n1R^2b、-R^2aCOOR^2b、C_3-6Aryl or C_3-6A heterocyclic group,

wherein R is²Optionally substituted by C_1-6Alkyl, -OH, C_1-6A hydroxyalkyl group,

R^2aIs C_1-6Alkyl radical, wherein R^2aOptionally substituted by C_1-6Alkyl or-NH₂；

R^2bIs H or C_1-6An alkyl group; and is

n₁Are 0, 1, 2.

8. A compound selected from the group consisting of:

wherein X is-CH₃or-CD₃。

9. A compound having the structure of formula (IVa) or (IVb), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

wherein R is⁴Independently substituted or unsubstituted alkyl, aryl, azaaryl, carbocyclylOr a heterocyclic group containing one or more O or N, and R³Is H or substituted or unsubstituted alkyl; and X is-CH₃or-CD₃。

10. The compound of claim 9, wherein R³Is H or C_1-6An alkyl group.

11. The compound of claim 9, wherein R⁴Is C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Hydroxyalkyl, -R^4aNCOR^4b、-R^4aOCOR^4b、-R^4aS(O)_n2R^4b、C_1-6Heterocyclic group, C_1-5Azaaryl or

Wherein R is⁴Optionally substituted by C_1-6Alkyl, -NH₂Oxo (═ O), C_1-6A hydroxyalkyl group,Provided that C is_1-6Alkyl substituted with

Wherein R is^4aIs C_1-6Alkyl radical, R^4bIs C_1-6Alkyl or C_1-6A haloalkyl group;

R^4cis benzyl, R^4dIs H, or R^4cAnd R^4dTogether with the carbon atom to which they are attached form C_5-6A heterocyclic group; and is

n₂Is 0, 1 or 2.

12. The compound of claim 11, wherein C_1-6The heterocyclic radical is

13. The compound of claim 11, wherein C_1-5The nitrogen heteroaryl group isWherein

14. The compound of claim 11, whereinIs that

15. A compound selected from the group consisting of:

wherein X is-CH₃or-CD₃。

16. A compound having the structure of formula (Va) or (Vb) or (Vc) or (Vd), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

17. a pharmaceutical composition comprising a compound according to any one of claims 1 to 16.

18. The pharmaceutical composition of claim 17, further comprising at least one pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.

19. The pharmaceutical composition of claim 18, further comprising one or more pharmaceutically effective amounts of an adjunctive therapeutic agent, and wherein the adjunctive therapeutic agent is for the treatment of neurological and psychiatric disorders or diseases of the central nervous system.

20. The pharmaceutical composition according to claim 19, wherein the neurological and psychiatric disorder or disease of the central nervous system is depression or pain.

21. The pharmaceutical composition of claim 19, wherein the adjunctive therapeutic agent is selected from the group consisting of lithium, drug or herbal antidepressants, anticonvulsants, mood stabilizers, antipsychotics, and benzodiazepines

22. Use of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 21 in the manufacture of a medicament for the prevention, management, treatment or alleviation of a neurological and psychiatric disorder or disease of the central nervous system of a patient.

23. Use of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 21 in the manufacture of a medicament for antagonising NMDA receptors.

24. A compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 21 for use in the prevention, management, treatment or alleviation of a neurological and psychiatric disorder or disease of the central nervous system of a patient.

25. A compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 21 for use in antagonising an NMDA receptor.

26. A method of preventing, managing, treating or alleviating a neurological and psychiatric disorder or disease of the central nervous system in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 21.

27. A method of antagonizing an NMDA receptor in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 21.

Technical Field

The present invention relates to the field of pharmaceutical technology, and more particularly to prodrugs of (S) -or (R) -ketamine (including isotopically labeled ketamine), compositions and uses thereof. More specifically, the compounds disclosed herein may be useful as NMDA (N-methyl-D-aspartate) receptor antagonists for the treatment, prevention or alleviation of neurological and psychiatric disorders or diseases of the central nervous system associated with NMDA receptors, and the pharmaceutical compositions disclosed herein also have the function of preventing, treating or alleviating diseases associated with NMDA receptors. More particularly, related disorders include depression and pain.

Background

Antidepressants are central nervous system therapeutics used to treat diseases such as Major Depressive Disorder (MDD), mood disorders, and seasonal affective disorder. MDD, also known as clinical depression, is a condition that lasts for two weeks or more and interferes with one's ability to perform daily tasks and enjoy activities that previously had fun.

Glutamate is the major excitatory neurotransmitter in the brain. Like classical neurotransmitters, glutamate is released from nerve cells, binds to receptors and is removed by reuptake transporters. Glutamate receptor systems are very complex and can be divided into various receptor subtypes based on their molecular and pharmacological properties. Most clinical studies on various CNS indications have focused on drugs that modulate glutamate function via NMDA receptors. Glutamate and its receptor subtypes play a fundamental role in synaptic plasticity and influence the human emotional, cognitive and rewarding processes. Additional effects include neurodevelopment and neurotrophic effects as well as neurodegeneration.

Ketamine is classified as an NMDA receptor antagonist, although its pharmacological actions are complex and it binds to multiple receptors. It was first approved by the FDA in the united states as a general anesthetic 50 years ago. Chemically, ketamine is a racemic mixture of (R) -ketamine and (S) -ketamine. In 1998, (S) -ketamine was approved in the european union for general anesthesia.

Repeated administration of ketamine is an effective antidepressant, continuous therapeutic strategy for patients who show an initial response to ketamine infusion. In ten patients with TRD who failed to respond lifelong to an average of eight antidepressants, repeated intravenous (i.v.) administration of ketamine over two weeks (six infusions) resulted in an average 85% reduction in the MADRS (mongmery-Asberg depression scale) score after the sixth infusion.

Although ketamine has an effective effect via i.v. infusion and is in a favorable position compared to other drugs in the treatment of treatment-refractory depression, this dosing regimen requires the patient to obtain treatment in the clinic. Ketamine has been studied in humans to evaluate its oral bioavailability. Ketamine was found to show only 17% oral bioavailability in humans due to extensive first pass metabolism, which prevented its development into an oral regimen. In addition, side effects of ketamine may be associated with high Cmax after iv bolus administration.

To overcome the pharmacokinetic deficiencies of ketamine, a prodrug approach will be employed to identify viable ketamine derivatives that can significantly improve the pharmacokinetic properties of ketamine via oral administration. In order to avoid potential side effects, sustained release formulations may be desirable to eliminate peaks and minima in drug plasma concentrations.

Disclosure of Invention

The following is merely a summary of some aspects of the invention, but the invention is not limited thereto. All references to the present specification are incorporated herein by reference in their entirety. When the disclosure of the present specification is different from that of the cited reference, the disclosure of the present specification shall control. The present invention provides compounds and pharmaceutical compositions that modulate antagonism of the NMDA receptor, their preparation and corresponding pharmaceutical compositions. The compounds and/or pharmaceutical compositions of the present invention may potentially be used in the preparation of medicaments for the prevention, treatment, amelioration of certain conditions or diseases associated with the NMDA receptor, including depression and pain, in a patient.

In particular, in one aspect, the present invention relates to compounds having the structure of formula (Ia) or (Ib), or stereoisomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof:

wherein R is-C (═ O) R¹、-C(＝O)OR²、-C(＝O)O(CHR³)OC(＝O)R⁴or-CD₃(ii) a And X is-CH₃or-CD₃；

Wherein R is¹Is optionally substituted or unsubstituted aryl-OH, aryl-NH₂alkenyl-OH, alkenyl-NH₂alkyl-NH₂alkyl-OH, carbocyclyl or heterocyclyl containing one or more N or O; and X is-CH₃or-CD₃；

Wherein R is²Is optionally substituted or unsubstituted alkyl, aryl, carbocyclyl or heterocyclyl containing one or more O; and X is-CH₃or-CD₃；

Wherein R is⁴Independently is a substituted or unsubstituted alkyl, aryl, azaaryl, carbocyclyl, or heterocyclyl containing one or more O or N, andR³is H or substituted or unsubstituted alkyl; and X is-CH₃or-CD₃。

It is an object of the present invention that the compounds having the structure of formula (Ia) or (Ib) are prodrugs of (S) -or (R) -ketamine, wherein the moiety "N-R" can be cleaved in vivo by chemical hydrolysis or metabolic processes via endogenous enzymes. The compounds having formula (Ia) or (Ib) may have the following properties: i) significantly improved oral bioavailability compared to ketamine; and ii) adapting sustained release formulations suitable for QD or BID to meet patient compliance and convenience.

In another aspect, provided herein is a compound having the structure of formula (IIa) or (IIb), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

In one embodiment, R¹Is amino C_1-6Alkyl, -R^1aNHCOR^1b、-R^1aOCOR^1b、-R^1aCOOR^1b、Or C_3-6A heterocyclic group,

wherein R is¹Optionally substituted by C_1-6Alkyl, -OH or oxo (═ O),

wherein R is^1aAnd R^1bIndependently is H, C_1-6Alkyl or C_2-6Alkenyl radical and

R^1cis-OH, C_1-3Hydroxyalkyl, -OCOR^1bor-CH₂OCOR^1b。

In one embodiment, heterocyclyl containing one or more N or O is

In another aspect, provided herein is a compound having a structure of formula (IIIa) or (IIIb), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

wherein R is²Is optionally substituted or unsubstituted alkyl, aryl, carbocyclyl or heterocyclyl containing one or more O; and X is-CH₃or-CD₃。

In one embodiment, R²Is C_1-6Alkyl radical, C_1-6Hydroxyalkyl, amino C_1-6Alkyl, -R^2aS(O)_n1R^2b、-R^2aCOOR^2b、C_3-6Aryl or C_3-6A heterocyclic group,

wherein R is²Optionally substituted by C_1-6Alkyl, -OH, C_1-6A hydroxyalkyl group, or-R^2aCOOR^2bProvided that C is_1-6Alkyl substituted with

R^2aIs C_1-6Alkyl radical, wherein R^2aOptionally substituted by C_1-6Alkyl or-NH₂；

R^2bIs H or C_1-6An alkyl group; and is

n₁Are 0, 1, 2.

In another aspect, provided herein is a compound having the structure of formula (IVa) or (IVb), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

wherein R is⁴Independently is a substituted or unsubstituted alkyl, aryl, azaaryl, carbocyclyl, or heterocyclyl containing one or more O or N, and R³Is H or substituted or unsubstituted alkyl; and X is-CH₃or-CD₃。

In one embodiment, R³Is H or C_1-6An alkyl group.

In one embodiment, R⁴Is C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Hydroxyalkyl, -R^4aNCOR^4b、-R^4aOCOR^4b、-R^4aS(O)_n2R^4b、C_1-6Heterocyclic group, C_1-5Azaaryl or

Wherein R is⁴Optionally substituted by C_1-6Alkyl, -NH₂Oxo (═ O), C_1-6A hydroxyalkyl group,

Provided that C is_1-6Alkyl substituted with

Wherein R is^4aIs C_1-6Alkyl radical, R^4bIs C_1-6Alkyl or C_1-6A haloalkyl group;

R^4cis benzyl, R^4dIs H, or R^4cAnd R^4dTogether with the carbon atom to which they are attached form C_5-6A heterocyclic group; and is

n₂Is 0, 1 or 2.

In one embodiment, C_1-6The heterocyclic radical is

In one embodiment, C_1-5The nitrogen heteroaryl group isWhereinOptionally substituted with one or more methyl groups or-NH₂Or a combination thereof.

In one embodiment of the process of the present invention,is that

In another aspect, provided herein is a compound having the structure of formula (Va) or (Vb) or (Vc) or (Vd), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

in another aspect, provided herein is a pharmaceutical composition comprising a compound of the invention.

In one embodiment, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.

In one embodiment, the pharmaceutical composition further comprises one or more pharmaceutically effective amounts of an adjunctive therapeutic agent, and wherein the adjunctive therapeutic agent is for the treatment of a neurological and psychiatric disorder or disease of the central nervous system.

In one embodiment, the neurological and psychiatric disorder or disease of the central nervous system is depression or pain.

In one embodiment, the adjunctive therapeutic agent is selected from the group consisting of lithium, drug or herbal antidepressants, anticonvulsants, mood stabilizers, antipsychotics, and benzodiazepinesAt least one of (a).

In another aspect, provided herein is the use of the compound or pharmaceutical composition in the manufacture of a medicament for the prevention, management, treatment, or amelioration of a neurological and psychiatric disorder or disease of the central nervous system in a patient.

In another aspect, provided herein is the use of the compound or pharmaceutical composition in the manufacture of a medicament for antagonizing NMDA receptors.

In another aspect, provided herein is the compound or pharmaceutical composition for use in preventing, managing, treating or ameliorating a neurological and psychiatric disorder or disease of the central nervous system in a patient.

In another aspect, provided herein is the compound or pharmaceutical composition for use in antagonizing NMDA receptors.

In another aspect, provided herein is a method of preventing, managing, treating or ameliorating a neurological and psychiatric disorder or disease of the central nervous system in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the compound or pharmaceutical composition.

In another aspect, provided herein is a method of antagonizing NMDA receptors in a patient comprising administering to a patient in need thereof a therapeutically effective amount of the compound or pharmaceutical composition.

In another aspect, provided herein is a method for preparing, isolating and purifying a compound represented by formulae (Ia) to (Vd).

Biological test results show that the compounds provided herein have good antagonism against NMDA receptors and exhibit better pharmacokinetic properties and bioavailability.

In certain embodiments of the compounds, pharmaceutical compositions and methods of the present invention, the compounds of formulae (Ia) to (Vd) are compounds selected from those species described or exemplified in the following detailed description, or are pharmaceutically acceptable salts of such compounds.

In another preferred embodiment, the present invention relates to a process for preparing pharmaceutical compositions each comprising an effective amount of at least one compound of formulae (Ia) to (Vd) or a pharmaceutically acceptable salt of a compound of formulae (Ia) to (Vd). The pharmaceutical composition according to the present invention may further comprise at least one pharmaceutically acceptable excipient, carrier, adjuvant, solvent, support or combination thereof.

If formulated as a fixed dose, such combination products employ the compounds of the present invention within the dosage ranges described herein (or as known to those of skill in the art) as well as other pharmaceutically active or therapeutic agents within their dosage ranges. The compounds of the present invention may also be administered sequentially with known antidepressants and analgesics when a combined preparation is not appropriate. In any combination therapy, the present invention is not limited in the order of administration; the compounds of formulae (Ia) to (Vd) may be administered before or after administration of known antidepressants and analgesics. Such techniques are within the skill of those in the art as well as of the attending physician.

Another embodiment is a method for administering a compound of the invention to a subject (e.g., a human) in need thereof by administering to the subject a pharmaceutical formulation of the invention.

Another embodiment is a method of preparing a pharmaceutical formulation of the invention by mixing at least one pharmaceutically acceptable compound of the invention and optionally one or more pharmaceutically acceptable additives or excipients.

For the preparation of pharmaceutical compositions from the compounds described herein, pharmaceutically acceptable inert carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, beads, cachets (cachets), and suppositories. Powders and tablets may contain from about 5 to about 95% active ingredient. Suitable solid carriers are known in the art, for example magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of preparation for use in the various compositions can be found in a.gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th edition, (1990), Mack Publishing co.

Liquid form preparations include solutions, suspensions, and emulsions. For example, there are water or water-propylene glycol solutions for parenteral injection or the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol formulations suitable for inhalation may include solutions and solids in powder form, which may be combined with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the present invention may also be delivered transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions, and may be included in a matrix or reservoir type transdermal patch, as is conventional in the art for this purpose.

The compounds of the invention may also be delivered subcutaneously.

Preferably, the compound is administered orally or intravenously.

Preferably, the pharmaceutical formulation is in unit dosage form. In this form, the preparation is subdivided into unit doses of appropriate size containing appropriate quantities of the active ingredient, e.g., an effective amount to achieve the desired purpose.

The amount of active compound in a unit dose of the formulation may vary or be adjusted between about 1mg to about 1000mg, preferably about 1mg to about 500mg, more preferably about 1mg to about 300mg, still more preferably about 1mg to about 200mg, depending on the particular application.

The actual dosage employed may vary depending upon the patient's needs and the severity of the condition being treated. Determining an appropriate dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dose may be divided into several portions and administered in portions throughout the day, as required. The amount and frequency of administration of the compound of the present invention and/or its pharmaceutically acceptable salt will be adjusted according to the judgment of the attending physician, taking into account such factors as the age, condition and size of the patient and the severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration may range from about 1 mg/day to about 300 mg/day, preferably from 10 mg/day to 200 mg/day in about one to two divided doses.

Any embodiments disclosed herein can be combined with other embodiments, even if they are described under different aspects of the invention, as long as they do not contradict each other. In addition, any technical feature in one embodiment may be applied to a corresponding technical feature in other embodiments, even if the embodiments are described under different aspects of the present invention, as long as they are not contradictory to each other.

The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting. These aspects, as well as other aspects and embodiments, are described more fully below.

Detailed description and specific embodiments

For the sake of brevity, the disclosures of the publications (including patents and patent applications) cited in this specification are hereby incorporated by reference in their entirety.

Most chemical names are generated using IUPAC nomenclature. Some chemical names are generated using different nomenclature or alternative or commercial names known in the art. In the case of a conflict between a name and a structure, the structure controls.

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulae. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terms, usage of terms, described techniques, etc.), this application controls.

It is also to be understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are identified according to the CAS version of the periodic Table of the elements and the 75 th edition (1994) of the Handbook of Chemistry and Physics. Furthermore, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltio: 1999, and Michael B.Smith and Jerry March, John Wiley & Sons, "March's Advanced Organic Chemistry", New York: 2007, which is incorporated herein by reference in its entirety.

As used above, and throughout this disclosure, the following terms are to be understood to have the following meanings, unless otherwise indicated. In the absence of a definition, the conventional definition known to those skilled in the art prevails. In the event that a definition provided herein conflicts with or is different from the definition provided in any cited publication, the definition provided herein controls.

As used herein, the terms "comprising," "including," and "containing" are used in their open, non-limiting sense.

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

To provide a more concise description, some of the quantitative expressions given herein are not defined by the term "about". It is understood that each quantity given herein is meant to refer to the actual given value, and also to the approximation of such given value that would reasonably be inferred based on the ordinary skill in the art, whether or not the term "about" is explicitly used, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given in percent, such yield refers to the mass of the same entity relative to the yield obtained for the maximum amount of entity that can be obtained under the particular stoichiometric conditions. Unless otherwise indicated, concentrations given in percentages refer to mass ratios.

The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

The terms "optionally substituted" and "unsubstituted or substituted" are used interchangeably herein to mean that the structure is unsubstituted or substituted with one or more substituents disclosed herein, wherein the substitution occurs at any valency-allowed and reasonable position of the structure or group provided herein.

Generally, the term "substituted" refers to the replacement of one or more hydrogen radicals in a given structure or group with a radical of a specified substituent. Unless otherwise indicated, a substituent may have a substituent at each substitutable and reasonable position of the group. When more than one position in a given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Substituents disclosed herein include, but are not limited to, D, F, Cl, Br, I, -N₃、-CN、-NO₂、-OH、-SH、-NH₂Alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

Chemical definition

As used herein, "alkyl" refers to a saturated straight or branched hydrocarbon group having 1 to 12 carbon atoms. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-methyl-1-pentyl, 2-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-methyl-2-pentyl, and the, 2-ethyl-1-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like, and longer alkyl groups such as heptyl, octyl and the like.

Throughout the specification, substituents of the compounds disclosed herein are disclosed in groups or ranges. It is specifically intended that the invention include each and every individual subcombination of the various members of such groups and ranges. For example, the term "C_1-6Alkyl "is specifically intended to disclose methyl, ethyl, C individually₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

The term "D" refers to a single deuterium atom.

The term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon sp2 double bond, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. The alkenyl group may be optionally substituted with one or more substituents described herein.

The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon sp triple bond, wherein the alkynyl radical may be optionally substituted with one or more substituents described herein.

The terms "halogen" or "halo" are used interchangeably herein and refer to fluorine (F), chlorine (Cl), bromine (Br), or (I).

The term "alkoxy" means an alkyl group, as previously defined, appended to the parent molecular moiety through an oxygen atom. Unless otherwise specified, alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms. In other embodiments, alkoxy groups contain 1 to 4 carbon atoms. In yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. Alkoxy groups may be optionally substituted with one or more substituents disclosed herein. As used herein, "alkoxyalkyl" refers to- (alkylene) -O- (alkyl), wherein each "alkyl" is independently an alkyl as defined above.

"aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group, wherein all rings of the group are aromatic. For bicyclic or tricyclic systems, the individual aromatic rings are fused to one another. Exemplary aryl groups include, but are not limited to, phenyl, naphthalene, and anthracene.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, wherein alkyl is as defined herein. Some non-limiting examples of such groups include, but are not limited to, -CF₃、-CF₂CF₃、-CH₂CF₂CHF₂And the like. In one embodiment, "haloalkyl" refers to a lower C_1-4Haloalkyl, wherein the "C_1-4Haloalkyl "includes fluorine substituted C_1-4Haloalkyl, chloro-substituted C_1-4Haloalkyl, bromo-substituted C_1-4Haloalkyl, iodo substituted C_1-4Haloalkyl, and the like. In particular, fluorine substituted C_1-4Haloalkyl includes-CH₂F、-CHF₂、-CF₃、-CH₂Cl、-CHCl₂、-CCl₃、-CH₂Br、-CHBr₂、-CBr₃、-CH₂CH₂F、-CH₂CHF₂、-CH₂CF₃、-CF₂CH₂F、-CF₂CHF₂、-CF₂CF₃、-CHFCF₃、-CHFCHF₂、-CHFCH₂F、-CH₂CH₂CF₃、-CH₂CF₂CHF₂And the like. The haloalkyl group is optionally substituted with one or more substituents described herein.

The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, wherein alkyl is as defined herein, and amino is optionally substituted.

The term "hydroxy-substituted alkyl" or "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined herein. Some non-limiting examples of such groups include, but are not limited to, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, and the like.

The term "deuterium" as used herein refers to a stable isotope of hydrogen having one proton and one neutron.

The terms "carbocyclyl" and "carbocycle," used interchangeably herein, refer to a monovalent or multivalent ring having 3 to 12 carbon atoms that is saturated or contains one or more unsaturations, as a monocyclic, bicyclic or tricyclic ring system, but in which no aromatic ring can be present in the carbocyclyl.

The term "hydroxy" refers to an-OH group.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a mono-or polyvalent monocyclic, bicyclic or tricyclic ring containing 3 to 12 carbon atoms in which one or more atoms in the ring are each independently replaced by a heteroatom, as defined herein, and which ring may be saturated or contain one or more unsaturations, but no aromatic ring may be present in the aromatic ring.

The term "cycloalkyl" refers to a monovalent or polyvalent saturated ring having 3 to 12 ring carbon atoms as a monocyclic, bicyclic, or tricyclic ring system.

Those skilled in the art will recognize that the species of heteroaryl and cycloalkyl listed or shown above are not exhaustive and that other species within the scope of these defined terms may also be selected.

As described herein, the compounds disclosed herein may be optionally substituted with one or more substituents, or as exemplified by particular classes, subclasses, and species of the invention.

As used herein, the term "substituted" means that the specified group or moiety bears one or more suitable substituents. As used herein, the term "unsubstituted" means that the specified group bears no substituents. As used herein, the term "optionally substituted" means that the specified group is unsubstituted or substituted with the specified number of substituents. Where the term "substituted" is used to describe a structural system, substitution is meant to occur at any valency-allowed position in the system.

As used herein, the expression "one or more substituents" means one to the maximum possible number of substitutions that can occur at any valency-allowed position in the system. In a certain embodiment, one or more substituents refers to 1,2,3,4, or 5 substituents. In another embodiment, one or more substituents refers to 1,2 or 3 substituents.

It is assumed that an atom represented herein by an unsatisfied valence has a sufficient number of hydrogen atoms to satisfy the valence of the atom.

When any variable (e.g. alkyl, alkylene, heteroaryl, R)¹、R²Or R^a) When occurring at more than one position in any formula or description provided herein, the definition of a variable at each occurrence is independent of its definition at every other occurrence.

As used herein, a range of values is intended to include consecutive integers. For example, a range denoted "0 to 4" or "0-4" includes 0, 1,2,3, and 4, while a range denoted "10-20%" includes 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%. Similarly, numerical ranges are also intended to include consecutive fractional integers. For example, a range expressed as "1-2%" would include 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, and 2.0%.

When the multifunctional moiety is displayed, the point of attachment to the core is represented by a line or hyphen. For example, aryloxy-refers to a moiety in which an oxygen atom is the point of attachment to the core molecule and an aryl group is attached to the oxygen atom.

Additional definitions

As used herein, the term "subject" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian species: a human; non-human primates such as chimpanzees, as well as other apes and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the invention, the mammal is a human.

"patient" includes both humans and animals.

The term "inhibitor" refers to a molecule, such as a compound, drug, enzyme activator, or hormone, that blocks or otherwise interferes with a particular biological activity.

The term "modulator" refers to a molecule, such as a compound of the invention, that increases or decreases or otherwise affects the activity of a given protein, receptor, and/or ion channel.

The term "effective amount" or "therapeutically effective amount" refers to an amount of an agent sufficient to provide a desired biological result. The result may be a reduction and/or alleviation of the signs, symptoms, or causes of diseases and medical conditions, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound or composition comprising the compound required to provide a clinically relevant change in a disease state, symptom, or medical condition. One of ordinary skill in the art can use routine experimentation to determine an appropriate "effective" amount in any individual case. Thus, the expression "effective amount" generally refers to an amount of active substance that has the desired effect of treatment.

As used herein, the terms "treatment" or "treating" encompass both "prophylactic" and "curative" treatment. "prophylactic" treatment refers to an indication that a disease, symptom of a disease, or medical condition is delayed in progression, inhibits a symptom that may occur, or reduces the risk of progression or recurrence of a disease or symptom. "curative" treatment includes reducing the severity or inhibiting the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of the symptoms of an existing disease, preventing the onset of other symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting a disorder or disease, e.g., arresting the development of a disorder or disease, relieving a disorder or disease, causing regression of a disorder or disease, relieving a condition caused by a disorder or disease, or stopping the symptoms of a disorder or disease.

As used herein, the term "administering" a compound is understood to be referring to providing a compound of the invention, a pharmaceutical composition comprising a compound of the invention or a precursor of a compound of the invention to an individual in need thereof. It will be appreciated that one skilled in the non-limiting art can treat patients currently suffering from neurological and psychiatric disorders with an effective amount of a compound of the invention, or treat patients suffering from such disorders by prophylactic means.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such terms as relating to pharmaceutical compositions are intended to encompass a product comprising one or more active ingredients and one or more inert ingredients which constitute a carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from other types of reactions or interactions, for example, to cause dissociation of one or more of the ingredients. Thus, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

Description of the alternative chemistry

Any chemical formula given herein is intended to represent a compound having the structure depicted by the structural formula, as well as certain variants or forms. For example, a compound of any of the formulae given herein may have an asymmetric or chiral center and thus exist in different stereoisomeric forms. All stereoisomers (including optical isomers, enantiomers and diastereomers) and mixtures thereof of compounds of formula (la) are considered to fall within the scope of the formula. In addition, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. All such isomeric forms and mixtures thereof are considered herein as part of the present invention. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more tautomeric or atropisomeric forms, and mixtures thereof.

"stereoisomers" refers to compounds having the same chemical composition but differing with respect to the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.

"chiral" refers to a molecule that is non-superimposable with a mirror pair, while the term "achiral" refers to a molecule that can be superimposed on its mirror pair.

"enantiomer" refers to two stereoisomers of a compound that are mirror images of each other.

"diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectroscopic properties, or biological activities. Mixtures of diastereomers may be separated according to high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and conventions used herein generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "stereospecificity of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in an optically active form, i.e. they have the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule about its chiral center. The sign of the compound to rotate plane polarized light is represented by the prefixes d and l or (+) and (-), wherein (-) or l represents that the compound is left-handed. Compounds with (+) or d prefixes are dextrorotatory. A particular stereoisomer may be referred to as an enantiomer, and a mixture of such stereoisomers is referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur where there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can be racemic or enantiomerically enriched, e.g., in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% in the (R) -or (S) -configuration.

Depending on the choice of starting materials and procedures, the compounds may be present as one of the possible stereoisomers or as a mixture thereof (e.g. racemates and diastereomeric mixtures), depending on the number of asymmetric carbon atoms. Optically active (R) -and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis-or trans-configuration relative to another substituent of the same cycloalkyl framework.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers based on the physicochemical differences of the components, for example, by chromatography and/or fractional crystallization. Racemates of any resulting final product or intermediate can be resolved into the optical enantiomers by methods known to those skilled in the art, for example, by separating the diastereomeric salts thereof. The racemic product can also be resolved by chiral chromatography, for example High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. Preferred enantiomers may also be prepared by asymmetric synthesis. See, e.g., Jacques et al, eneriomers, Racemates and solutions (Enantiomers, Racemates and resolution) (Wiley Interscience, New York, 1981); principles of asymmetric Synthesis (second edition, Robert E. Gawley, Jeffrey Aub, Elsevier, Oxford, UK, 2012); eliel, e.l. stereoschemistry of Carbon Compounds (McGraw-Hill, NY, 1962); wilen, s.h. tables of Resolving Agents and optical resolution p.268(e.l. eliel, ed., univ. of note dam press, note dam, IN 1972); chiral Separation Techniques: A Practical Approach (Chiral Separation technique: Practical method) (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the mixture of enantiomers to a mixture of diastereomers by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher acid chloride, or by forming a mixture of diastereomeric salts), separating the diastereomers and converting (e.g., hydrolyzing or desalting) each diastereomer to the corresponding pure enantiomer. Enantiomers can also be separated by using a chiral HPLC column.

The compounds of the present invention may form pharmaceutically acceptable salts, which are also within the scope of the present invention. "pharmaceutically acceptable salt" refers to a salt of the free acid or base of a compound of formula a that is non-toxic, physiologically tolerable, compatible with the pharmaceutical composition in which it is formulated, and otherwise suitable for formulation and/or administration to a subject. Unless otherwise indicated, reference herein to a compound is to be understood as including reference to a pharmaceutically acceptable salt of the compound.

The compound salt includes an acidic salt formed with an inorganic acid and/or an organic acid, and a basic salt formed with an inorganic base and/or an organic base. Additionally, where a given compound contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), one skilled in the art will recognize that the compound may exist as a zwitterion ("inner salt"); such salts are included within the term "salt" as used herein. Salts of the compounds of the invention may be prepared, for example, by reacting the compound with an amount of the appropriate acid or base (e.g., an equivalent amount) in a medium such as one in which the salt precipitates or in an aqueous medium, followed by lyophilization.

Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate (gentisate), fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate (methanesulfonate) ("methanesulfonate (mesylate)"), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1, 1' -methylene-bis (2-hydroxy-3-naphthoate)). Pharmaceutically acceptable salts may involve inclusion of another molecule such as an acetate, succinate or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, pharmaceutically acceptable salts may have more than one charged atom in their structure. Examples where the plurality of charged atoms are part of a pharmaceutically acceptable salt may have a plurality of counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.

Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate (also known as tosylate), and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamine, t-butylamine, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, and dibutyl sulfate), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

Also, for example, by P.Stahl et al, Camile G. (eds.) Handbook of pharmaceutical salts, Properties, Selection and Use (Handbook of salts of drugs: Properties, Selection and Use.) (2002) Zurich: Wiley-VCH; berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; gould, International J.of pharmaceuticals (1986) 33201-217; anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and acids and bases generally considered suitable for forming pharmaceutically acceptable salts from pharmaceutical compounds are discussed in The Orange Book (Food & drug administration, MD, available from FDA). These disclosures are incorporated herein by reference.

In addition, any compound described herein is also intended to refer to any unsolvated form or hydrates, solvates, or polymorphs of such compounds, as well as mixtures thereof, even if such forms are not expressly listed. "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic bonding and covalent bonding (including hydrogen bonding). In some cases, such as when one or more solvent molecules are incorporated into the crystalline lattice of a crystalline solid, the solvate will be able to dissociate. "solvate" encompasses both solution phase and isolatable solvates. Suitable solvates include those formed with pharmaceutically acceptable solvents such as water, ethanol and the like. In some embodiments, the solvent is water and the solvate is a hydrate.

One or more compounds of the present invention may optionally be converted to solvates. Methods for preparing solvates are generally known. Thus, for example, m.caira et al, j.pharmaceutical sci.,93(3), 601-. Van binder et al, AAPS pharmcitech, 5(1), article 12 (2004); and a.l. bingham et al, chem.commu., 603-604(2001) describe the analogous preparation of solvates, hemisolvates, hydrates, etc. A typical, non-limiting method involves dissolving the compound of the invention in a suitable amount of solvent (organic solvent or water or mixtures thereof) at above ambient temperature and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example, infrared spectroscopy indicate the presence of solvent (or water) in the crystals as a solvate (or hydrate).

The invention also relates to pharmaceutically active metabolites of compounds of formula (a), and the use of such metabolites in the methods of the invention. "pharmaceutically active metabolite" refers to a pharmacologically active product of the metabolism of a compound of formula (A) or a salt thereof in the body. The active metabolites of the compounds can be determined using conventional techniques known or available in the art. See, e.g., Bertolini et al, j.med.chem.1997,40, 2011-2016; shan et al, J.pharm.Sci.1997,86(7), 765-; bagshawe, Drug Dev. Res.1995,34, 220-; bodor, adv. drug Res.1984,13, 255-331; bundgaard, Design of produgs (prodrug Design) (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (prodrug applications, Drug Design and Development) (Krogsgaard-Larse et al, eds., Harwood Academic Publishers, 1991).

Any formulae given herein are also intended to represent unlabeled as well as isotopically labeled forms of these compounds. Isotopically-labeled compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl and¹²⁵I. such isotopically-labeled compounds are useful in metabolic studies (e.g., using¹⁴C) Reaction kinetics study (e.g. using²H or³H) Detection or imaging techniques (such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including drug or substrate tissue distribution assays, or may be used for radiotherapy of a patient. In particular, it is possible to use, for example,¹⁸f or¹¹C-labeled compounds may be particularly useful for PET or SPECT studies. In addition, heavier isotopes such as deuterium (i.e. deuterium) are used²H) May offer certain therapeutic advantages due to greater metabolic stability, e.g. increased in vivoHalf-life or reduced dosage requirements. Isotopically labeled compounds of the present invention can generally be prepared by carrying out the procedures disclosed in the schemes below, or in the examples and preparations, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The terms "salt", "solvate", "polymorph" and the like as used in relation to the compounds described herein are intended to apply equally to the salt, solvate and polymorph forms of the enantiomers, stereoisomers, rotamers, tautomers, atropisomers and racemates of the compounds of the present invention.

Description of the Compounds of the invention

Provided herein are prodrugs of (S) -or (R) -ketamine (including isotopically labeled ketamine), compositions and uses thereof. More specifically, the compounds disclosed herein having the formulae (Ia) to (Vd) as prodrugs of (S) -or (R) -ketamine (including isotopically labeled ketamine) are useful as NMDA receptor antagonists for the treatment, prevention or alleviation of neurological and psychiatric disorders or diseases of the central nervous system associated with NMDA receptors, and the pharmaceutical compositions disclosed herein also have the function of preventing, treating or alleviating diseases associated with NMDA receptors.

In one embodiment of the present invention, there is provided a compound having the structure of formula (Ia) or (Ib), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

wherein R is-C (═ O) R¹、-C(＝O)OR²、-C(＝O)O(CHR³)OC(＝O)R⁴or-CD₃(ii) a And X is-CH₃or-CD₃；

Wherein R is²Is optionally substituted or unsubstituted alkyl, aryl, carbocyclyl or heterocyclyl containing one or more O; and X is-CH₃or-CD₃；

Wherein R is⁴Independently is a substituted or unsubstituted alkyl, aryl, azaaryl, carbocyclyl, or heterocyclyl containing one or more O or N, and R³Is H or substituted or unsubstituted alkyl; and X is-CH₃or-CD₃。

In another aspect, provided herein is a compound having the structure of formula (IIa) or (IIb), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

In one embodiment, R¹Is amino C_1-6Alkyl, -R^1aNHCOR^1b、-R^1aOCOR^1b、-R^1aCOOR^1b、Or C_3-6A heterocyclic group,

wherein R is¹Optionally substituted by C_1-6Alkyl, -OH or oxo (═ O),

wherein R is^1aAnd R^1bIndependently is H, C_1-6Alkyl or C_2-6Alkenyl radical and

R^1cis-OH, C_1-3Hydroxyalkyl, -OCOR^1bor-CH₂OCOR^1b。

In one implementationIn this case, the heterocyclic group containing one or more N or O is

In another aspect, provided herein is a compound selected from the group consisting of:

wherein X is-CH₃or-CD₃。

In another aspect, provided herein is a compound having a structure of formula (IIIa) or (IIIb), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

wherein R is²Is optionally substituted or unsubstituted alkyl, aryl, carbocyclyl or heterocyclyl containing one or more O; and X is-CH₃or-CD₃。

In one embodiment, R²Is C_1-6Alkyl radical, C_1-6Hydroxyalkyl, amino C_1-6Alkyl, -R^2aS(O)_n1R^2b、-R^2aCOOR^2b、C_3-6Aryl or C_3-6A heterocyclic group,

wherein R is²Optionally substituted by C_1-6Alkyl, -OH, C_1-6A hydroxyalkyl group,

or-R^2aCOOR^2bProvided that C is_1-6Alkyl substituted with

R^2aIs C_1-6Alkyl radical, wherein R^2aOptionally substituted by C_1-6Alkyl or-NH₂；

R^2bIs H or C_1-6An alkyl group; and is

n₁Are 0, 1, 2.

In another aspect, provided herein is a compound selected from the group consisting of:

wherein X is-CH₃or-CD₃。

In another aspect, provided herein is a compound having the structure of formula (IVa) or (IVb), or a stereoisomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

In one embodiment, R³Is H or C_1-6An alkyl group.

In one embodiment, R⁴Is C_1-6Alkyl, amino C_1-6Alkyl radical, C_1-6Hydroxyalkyl, -R^4aNCOR^4b、-R^4aOCOR^4b、-R^4aS(O)_n2R^4b、C_1-6Heterocyclic group, C_1-5Azaaryl or

Wherein R is⁴Optionally substituted by C_1-6Alkyl, -NH₂Oxo (═ O), C_1-6A hydroxyalkyl group,

Provided that C is_1-6Alkyl substituted with

Wherein R is^4aIs C_1-6Alkyl radical, R^4bIs C_1-6Alkyl or C_1-6A haloalkyl group;

R^4cis benzyl, R^4dIs H, or R^4cAnd R^4dTogether with the carbon atom to which they are attached form C_5-6A heterocyclic group; and is

n₂Is 0, 1 or 2.

In one embodiment, C_1-6The heterocyclic radical is

In one embodiment, C_1-5The nitrogen heteroaryl group isWhereinOptionally substituted with one or more methyl groups or-NH₂Or a combination thereof.

In one embodiment of the process of the present invention,

is that

In another aspect, provided herein is a compound selected from the group consisting of:

wherein X is-CH₃or-CD₃。

unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds disclosed herein are within the scope of the present invention.

The compounds shown above in formulae (Ia) to (Vd) may exist in different tautomeric forms, and all such tautomers are contemplated within the scope of the present invention.

N-oxides of the compounds disclosed herein are also within the scope of the present invention. The N-oxides of the compounds disclosed herein may be prepared by oxidation of the corresponding nitrogen base using conventional oxidants such as hydrogen peroxide in the presence of an acid such as acetic acid at elevated temperatures or by reaction with a peracid such as peracetic acid in a suitable solvent such as DCM, ethyl acetate or methyl acetate or with 3-chloroperoxybenzoic acid in chloroform or DCM.

Further, when the compounds disclosed herein form hydrates or solvates, they are within the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates and solvates of the compounds disclosed herein are also within the scope of the invention.

The compounds of formulae (Ia) to (Vd) may be present in the form of salts. In some embodiments, the salt is a pharmaceutically acceptable salt. The pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent or in a mixture of both. Generally, where feasible, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Other lists of suitable salts may be found, for example, in "Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences)". 20 th edition, Mack Publishing Company, Easton, Pa., (1985) and in Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Handbook of Pharmaceutical Salts: Properties, Selection and Use) "(Wiley-VCH, Weinheim, Germany, 2002).

The compounds of the invention are basic and therefore pharmaceutically acceptable acid addition salts can generally be formed by processing the appropriate acid. Suitable acids include pharmaceutically acceptable inorganic and organic acids. Representative pharmaceutically acceptable acid addition salts include the hydrochloride, hydrobromide, nitrate, methyl nitrate, sulphate, bisulphate, sulphamate, phosphate, acetate, glycolate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, para-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, formate, stearate, ascorbate, palmitate, oleate, hydrogen sulphate, sulfamate, phosphate, glycolate, lactate, oxalate, succinate, tartrate, lactate, acetate, oxalate, succinate, tartrate, palmitate, oleate, tartrate, Pyruvate, pamoate, malonate, laurate, glutarate, glutamate, propionate dodecyl sulfate (estolate), methanesulfonate, ethylsulfate, 2-hydroxyethanesulfonate (2-hydroxynesylate), benzenesulfonate, sulfanilate, p-toluenesulfonate, naphthalene-2-sulfonate, and the like.

Any formula given herein is also intended to represent compounds in non-isotopically enriched forms as well as isotopically enriched forms. Isotopically enriched compounds have the structure represented by the general formula (i) of the present invention, but in fact one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example wherein a radioisotope is present, e.g.³H、¹⁴C and¹⁸f, or in which a non-radioactive isotope is present, e.g.²H and¹³C. such isotopically enriched compounds are useful in metabolic studies (using¹⁴C) Reaction kinetics study (e.g. using²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including drug or substrate tissue distribution assays, or may be used for radiotherapy of a patient. Rich in¹⁸Compounds of F are particularly desirable for PET or SPECT studies. Suitable isotopically-labeled reagents can generally be employed in place of the unlabeled reagents employed previously, by conventional techniques known to those skilled in the art, or by procedures analogous to those described in the accompanying examples and preparationsAnalogous methods are used to prepare isotopically enriched compounds of formula (I).

In another aspect, provided herein is a pharmaceutical composition comprising a compound of the invention.

In one embodiment, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.

In one embodiment, the neurological and psychiatric disorder or disease of the central nervous system is depression or pain.

At least one of (a).

In another aspect, provided herein is the use of the compound or pharmaceutical composition in the manufacture of a medicament for antagonizing NMDA receptors.

In another aspect, provided herein is the compound or pharmaceutical composition for use in antagonizing NMDA receptors.

In yet another aspect, the invention relates to a process for preparing compounds of formulae (Ia) to (Vd), and pharmaceutically acceptable salts thereof.

Pharmaceutical compositions and formulations and administration of the compounds of the invention

In one aspect, provided herein is a pharmaceutical composition comprising a compound of formula (Ia) to (Vd), or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. Optionally, the pharmaceutical composition further comprises at least a pharmaceutically acceptable carrier, adjuvant or excipient, and optionally other therapeutic and/or prophylactic ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c. et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (Ansel Dosage Forms and Drug Delivery Systems) (2004) Lippincott, Williams & Wilkins, philiadelphia; gennaro A.R. et al, Remington, The Science and Practice of Pharmacy (Remington: pharmaceutical Science and Practice) (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition or vehicle involved in imparting a form or consistency to a pharmaceutical composition. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition so as to avoid interactions that would substantially reduce the efficacy of the compounds of the invention and would produce a pharmaceutically unacceptable composition when administered to a patient. In addition, each excipient must, of course, be of sufficiently high purity to be pharmaceutically acceptable.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable excipients may be selected for the particular function they can serve in the composition. For example, certain pharmaceutically acceptable excipients may be selected because of their ability to facilitate the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected because of their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected because they have the ability to facilitate carrying or transport of the compounds of the invention from one organ or portion of the body to another organ or portion of the body once administered to a patient. Certain pharmaceutically acceptable excipients may be selected for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants and buffers. One skilled in the art will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how many excipients are present in the formulation and what other ingredients are present in the formulation.

The skilled person has the knowledge and skill in the art to enable them to select an appropriate amount of a suitable pharmaceutically acceptable excipient for use in the present invention. In addition, a person skilled in the art will have access to a number of sources describing pharmaceutically acceptable excipients and which can be used to select suitable pharmaceutically acceptable excipients. Examples include the Remington Pharmaceutical sciences (MackPublioning Company), the handbook of Pharmaceutical additives (Gower Publishing Limited) and the handbook of Pharmaceutical excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

Various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington, The Science and Practice of Pharmacy, 21 st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology (Encyclopedia of Pharmaceutical Technology), eds.J.Swarbrick and J.C.Boylan,1988-1999, Marcel Dekker, New York (The contents of each of which are incorporated herein by reference). Except insofar as any conventional carrier medium is incompatible with the compounds of the present invention, e.g., by causing any undesired biological effect or otherwise interacting in a deleterious manner with any other component or components of the pharmaceutically acceptable composition, its use is contemplated within the scope of the present invention.

The compounds of the present invention will typically be formulated in a dosage form suitable for administration to a patient by the desired route of administration. For example, dosage forms include those suitable for: (1) oral administration, such as tablets, capsules, caplets (caplets), pills, troches (troches), powders, syrups, elixirs, suspensions, solutions, emulsions, sachets (sachets), and cachets (cachets); (2) parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical applications such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy, or where appropriate as pharmaceutically acceptable derivatives or prodrugs thereof. According to the present invention, a pharmaceutically acceptable derivative or prodrug includes, but is not limited to, a pharmaceutically acceptable prodrug, salt, ester, salt of such an ester, or any other adduct or derivative that, upon administration to a patient in need thereof, is capable of providing, directly or indirectly, a compound as described elsewhere herein, or a metabolite or residue thereof.

In one embodiment, the compounds disclosed herein can be prepared in oral dosage forms. In one embodiment, the compounds disclosed herein can be prepared in an inhalation dosage form. In one embodiment, the compounds disclosed herein can be prepared in dosage forms for nasal administration. In one embodiment, the compounds disclosed herein can be prepared in transdermal dosage forms. In one embodiment, the compounds disclosed herein may be prepared in a dosage form for topical administration.

The pharmaceutical compositions provided herein can be provided as compressed tablets, molded tablets (tablets), chewable lozenges, fast dissolving tablets, multilayer compressed or enteric coated tablets, sugar coated tablets, or film coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to gastric acid but dissolves or disintegrates in the small intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial for masking unpleasant tastes or odors and protecting the tablets from oxidation. Film coated tablets are compressed tablets covered with a thin layer or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general characteristics as sugar coatings. Multilayer compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets as well as press-coated or dry-coated tablets.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical compositions provided herein can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two parts, one sliding over the other, thereby completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methylparaben and propylparaben, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. patent nos. 4,328,245, 4,409,239, and 4,410,545. The capsules may also be coated as known to those skilled in the art to alter or maintain the dissolution of the active ingredient.

The pharmaceutical compositions provided herein can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system in which one liquid is dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcohol solution may include pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g., acetaldehyde diethyl acetal; and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, to be conveniently measured for administration.

Provided herein are pharmaceutical compositions that can be prepared in a dosage form suitable for administration to a patient by inhalation, for example, as a dry powder, aerosol, suspension, or solution composition. In one embodiment, the present invention relates to a dosage form suitable for administration to a patient by inhalation in dry powder form. At one endIn one embodiment, the present invention relates to a dosage form suitable for administration to a patient by inhalation as a dry powder. Dry powder compositions for delivery to the lung by inhalation typically comprise a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as a finely divided powder and one or more pharmaceutically acceptable excipients as finely divided powders. Pharmaceutically acceptable excipients that are particularly suitable for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. Finely divided powders may be prepared by, for example, micronization and milling. Typically, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns₅₀Values (e.g., as measured using laser diffraction).

Pharmaceutical compositions suitable for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. Ointments, creams and gels may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. Thus, such a base may for example comprise water and/or an oil such as liquid paraffin or a vegetable oil such as peanut oil or castor oil, or a solvent such as polyethylene glycol. Thickening and gelling agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol (carboxyvinyl) and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.

The compounds disclosed herein may also be coupled to soluble polymers as targeted drug carriers. Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamylphenol, or polyethyleneoxide polylysine (which are substituted with palmitoyl groups). Furthermore, these compounds may also be coupled to a class of biodegradable polymers suitable for achieving controlled release of the drug, such as polylactic acid, poly-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms of solutions or suspensions suitable for formulation in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in The art of Pharmacy (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including but not limited to aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial or preservative agents (to prevent microbial growth), stabilizing agents, solubility enhancing agents, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

The pharmaceutical compositions provided herein may be formulated as immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release forms.

The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. Multi-dose parenteral formulations must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. As is known and practiced in the art, all parenteral formulations must be sterile.

The pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not impair the desired therapeutic effect or with substances that supplement the desired effect.

In one embodiment, the methods of treatment disclosed herein comprise administering to a patient in need of treatment a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention. Various embodiments disclosed herein include treating the above-described conditions or diseases by administering to a patient in need of treatment a safe and effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention.

In one embodiment, a compound of the invention or a pharmaceutical composition thereof may be administered by any suitable route of administration (including systemic and topical administration). Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Parenteral administration refers to routes of administration other than enteral or transdermal, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular and subcutaneous injection or infusion. Topical administration includes application to the skin as well as intraocular, otic (otic), intravaginal, inhalation, and intranasal administration. In one embodiment, a compound of the invention or a pharmaceutical composition thereof may be administered orally. In one embodiment, the compounds of the present invention or pharmaceutical compositions thereof may be administered by inhalation. In another embodiment, a compound of the invention or a pharmaceutical composition thereof may be administered intranasally.

In one embodiment, a compound of the invention or a pharmaceutical composition thereof may be administered once or according to a dosing regimen in which multiple doses are administered at different time intervals over a given period of time. For example, multiple doses may be administered once, twice, three times, or four times daily. In one embodiment, the dose is administered once daily. In another embodiment, the dose is administered twice daily. Multiple doses may be administered until the desired therapeutic effect is achieved or maintained indefinitely. Suitable dosing regimens for the compounds of the invention or pharmaceutical compositions thereof depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, the appropriate dosing regimen (including the duration of administration of such regimen) of the compounds of the present invention or pharmaceutical compositions thereof will depend upon the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and similar factors within the knowledge and expertise of the skilled artisan. Such skilled persons will further appreciate that appropriate dosage regimens may need to be adjusted in view of individual patient response to the dosage regimen or as individual patient needs change over time.

The compounds of the present invention may be administered simultaneously with, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately, by the same or different route of administration, or together with other agents in the same pharmaceutical composition.

The compounds provided herein may be used with sedatives, hypnotics, anxiolytics (anxiolytics), antipsychotics, anxiolytics (antimanic agents), cyclic pyrrolidones, imidazopyridines, pyrazolopyrimidines, weakly-immobilizers (minorraquilibrium), melatonin agonists and antagonists, melatoninergic agents (melatoninergic agents), benzodiazepinesBarbiturates, 5HT-2 antagonists, and the like. For example: adizolam (adinazolan), amobarbital (allobarbital), alomiprone (alonimid), alprazolam (alprazolam), amitriptyline (amitriptyline), amobarbital (amobarbital), amoxapine (amoxapine), phenetazepam (bentazepam), taicetidine (tacitin), brotizolam (brotizolam), bupropion (bupropion), buspirone (buspirone), butarbital (butarbital), butatalbarbital (butalbital), carparbital (butital), carpourea (carpuride), carboxaldehyde (carbocloraldehyde), chloral betaine (chloral betaine), chloral hydrate (chloral)drate), croudine (chlorodyne), clomipramine (clomipramine), clonazepam (clonazepam), domperidone (domperidone), methotrexate

(methamidodizsections), clozapine (clozapine), cyclopropam (cycloprazepam), desipramine (desipramine), dexcloramo, diazepam (diazepam), chloraldosalamide (chloralkamine), dipropionic acid (divalproic acid), diphenhydramine (diphenhydramine), doxepin (doxepin), estazolam (estazolam), ethhlorovoranol (ethochlorvynol), etomidate (etomidate), fenoban (fenobam), flunitrazepam (flunitrazepam), fluazepam (fluzapam), fluvoxamine (fluflufluxetine), fluflufazine (fluzamide), meprobrazine (fluquinate), meprobamate (fluquinamide), meprobrazine (fluquinacrine), meprobrazine (meprobamate), meprobrazone (meprobrazine), meprobrazine (meprobamate), meprobrazine (meprobamate), meprobamate (meprobamate), nisodiamide (nisobamate), nitro-diazepam (nitrazepam), nortriptyline (nortriptyline), noroxazepam (oxazepam), paraldehyde (paraaldehyde), paroxetine (paraoxetine), pentobarbital (pentobarbital), perlapine (perlapine), perphenazine (perphenazine), phenelzine (phenoxazine), phenobarbital (phenobarbital), pramipeam (Prazepam), promethazine (promethazine), isopropenylphenol (isopropyphenol), protriptyline (protrylene), quazepam (quasipam), relzepam (recazepam), rolipramipem (rolipramipem), rolipratropium (rolipraz), secobarbital (secotrazebra), sertraline (sertraline), sultone (sulbactopram), thidone (thidone, thiuram), benzodiazepine (thidone (thiuram), benzodiazepine (propione (thiuram), thiurazone (benzodiazepine (propine), thiurazone (propine), thiurazone (s (thiurazone), thiurazone (propione (s (benzodiazepine), thiurazone (thiurazone), thiurazone (propione (thiurazone), thiurazone (propione

(triazole benzodiazepine), trapipeam (trepepam), trimethoxyphenylacetamide (tricetamide), trichloroethyl phosphate (trichloroethylphosphate), trifluoperazine (trifluoperazine), trimetazidine (trimetazine), trimetazidine (trimipramine), udazepam (uldazepam), venlafaxine (venlafaxine), zaleplon (zaleplon), zolazepam (zolazepam), zolpidem (zolpidem), salts and compositions thereof, and the like. Alternatively, physical methods such as light therapy or electrical stimulation may be used during administration of the compounds disclosed herein.

Alternatively, the compounds of the present invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound that, upon administration to a patient, ultimately releases the compound of the invention in vivo. Administration of the compounds of the invention as prodrugs may enable the skilled person to perform one or more of the following: (a) altering the onset of action of the compound in vivo; (b) altering the duration of action of the compound in vivo; (c) altering the transport or distribution of the compound in vivo; (d) altering the solubility of the compound in vivo; and (e) overcoming side effects or other difficulties encountered with said compounds. Typical functional derivatives useful in the preparation of prodrugs include modifications of the compounds which are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

Use of compounds and pharmaceutical compositions

The compounds or pharmaceutical compositions disclosed herein are useful as NMDA receptor antagonists for the treatment or prevention of neurological and psychiatric disorders or diseases in which NMDA receptors are involved, and may be useful in the preparation of medicaments that antagonize NMDA receptors.

All diseases related to the NMDA receptor can be selected from all types of neurological and psychiatric disorders or diseases.

In one embodiment, the NMDA receptor-related disorder includes depression, anxiety, seasonal affective disorder, mania, bipolar disorder, obsessive-compulsive disorder, insomnia and fatigue due to jet lag, schizophrenia, seizure, panic attack, melancholia, alcohol addiction, drug addiction, alcoholism, drug abuse, withdrawal symptoms from drug addiction, insomnia, psychosis, epilepsy, sleep disorders (somnipathiy), sleep disorders, sleep apnea syndrome, compulsive eating disorders, fibromyalgia, stress, obesity, Parkinson's disease, cognitive disorders, memory disorders, premenstrual tension syndrome, migraine, memory loss, Alzheimer's disease, or a disorder related to normal or aging.

It will be appreciated that any of the above symptoms or diseases are promoted or accelerated under certain environmental conditions such as stress or fear (where stress may arise from social sources such as social stress or physical sources such as physical stress, including stress produced by fear), and that the compounds disclosed herein are particularly useful in the treatment of symptoms and diseases modulated by such environments.

In addition to being useful for human therapy, the compounds of the present invention and compositions thereof may also be useful for veterinary therapy of animals, such as companion animals, exotic animals, and mammals from farm animals. In other embodiments, the animals disclosed herein include horses, dogs, and cats. As used herein, the compounds disclosed herein include pharmaceutically acceptable derivatives thereof.

Preferred embodiments of the invention

General synthetic procedure

The following examples are provided so that the invention may be more fully understood. However, it should be understood that these embodiments merely provide methods for practicing the invention and that the invention is not limited to these embodiments.

In general, the compounds disclosed herein can be prepared by the methods described herein, wherein the substituents are as defined above for formula (Ia) or formula (Ib), unless otherwise specified. The following non-limiting schemes and examples are presented to further illustrate the invention.

One skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare many of the other compounds disclosed herein, and that alternative methods for preparing the compounds disclosed herein are considered to be within the scope of the present disclosure. One skilled in the art will recognize that the starting materials can be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated in the examples below. In some cases, it may be desirable to protect certain reactive functional groups to achieve some of the above transformations. In general, such a need for protecting groups and the conditions required to attach and remove such groups will be apparent to those skilled in the art of organic synthesis. The synthesis of non-exemplified compounds according to the invention can be successfully carried out, for example, by modifications apparent to those skilled in the art, for example, by appropriate protection of interfering groups, by the use of other suitable reagents known in the art (in addition to those described) and/or by routine modification of reaction conditions. Alternatively, known reaction conditions or reactions disclosed in the present invention will be considered to have applicability for the preparation of other compounds disclosed herein.

In the examples described below, all temperatures are in degrees celsius unless otherwise indicated. Unless otherwise indicated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arcos Chemical Company, AlfaAesar Chemical Company, and J & K Chemical Company and used without further purification.

Preparation of the Compounds

The compounds of the present invention, including salts, esters, hydrates or solvates thereof, may be prepared using any of a number of known organic synthesis techniques and may be synthesized according to any of a number of possible synthetic routes.

The reaction for preparing the compound of the present invention may be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reaction is carried out, for example, may be at temperatures ranging from the freezing temperature of the solvent to the boiling temperature of the solvent. The given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, one skilled in the art can select a suitable solvent for the particular reaction step.

The reaction may be monitored according to any suitable method known in the art. For example, it can be determined by spectroscopic methods such as nuclear magnetic resonance spectroscopy (e.g.¹H or¹³C) Infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as High Performance Liquid Chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or Thin Layer Chromatography (TLC). Compounds can be purified by one skilled in the art by a variety of methods including High Performance Liquid Chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound specificity method optimization)" Karl F.Blom, BrianGlass, Richard Sparks, Andrew P.Combs J.Combi.Chem.2004,6(6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica chromatography.

The compounds of the invention may be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereon as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. Specifically, the compounds of the present invention of formulae (Ia) to (Vd) can be synthesized by following the procedures outlined in the exemplary general synthetic schemes listed below, and the abbreviations for the reactants or the abbreviations for the chemical groups of the reactants included in these synthetic schemes are defined in the examples.

In general, the synthesis of compounds having formula (IIa) or (IIb) can be carried out according to the following synthetic methods, but is not limited to these described methods. The following exemplifies formula (IIa).

Scheme 1

R¹Can be

Scheme 2

R¹Can be

Scheme 3

R¹Can be

Scheme 4

R¹Can be

Scheme 5

R¹Can be

In general, the synthesis of compounds having formula (IIIa) or (IIIb) can be performed according to the following synthetic methods, but is not limited to these described methods. The following illustrates formula (IIIa).

Scheme 6

R²Can be

Scheme 7

R²Can be

Scheme 8

R²Can be

In general, the synthesis of compounds having formula (IVa) or (IVb) can be carried out according to the following synthetic methods, but is not limited to these described methods. The following illustrates formula (IVa).

Scheme 9

Can be

Scheme 10

Scheme 11

Can be

In general, the synthesis of the compounds having formulae (Va) to (Vd) can be performed according to the following synthetic methods, but is not limited to these described methods. The following examples illustrate formula (Va) or formula (Vb).

Scheme 12

Preparation and characterization of exemplary Compounds

The compounds encompassed by the present disclosure may be prepared via different schemes. Detailed preparation procedures of 108 exemplary compounds via various schemes are described below, and characterization results are also listed.

All reagents were purchased from commercial suppliers without further purification unless otherwise indicated. Solvent drying was carried out using standard methods as necessary. The plates used for Thin Layer Chromatography (TLC) were e.merck silica gel 60F254(0.24nm thick) pre-coated on an aluminum plate and then visualized under UV light (365nm and 254nm) or by staining with 5% ethanolic dodecamolybdophosphate solution followed by heating. Column chromatography was performed using silica gel (200-400 mesh) from the supplier.¹HNMR spectra were recorded at room temperature on a BRUKER AVANCE III HD 500MHz NMR spectrometer and BRUKER AVANCE III HD 600 MHz. Solvent signal as¹Reference for HNMR (CDCl)₃，7.26ppm；CD₃OD，3.31ppm；DMSO-d₆2.50 ppm; acetone-d₆，2.05ppm；D₂O, 4.79 ppm). The following abbreviations are used to explain diversity: s is singlet, d is doublet, t is triplet, q is quartet, br.s is broad singlet, dd is doublet, td is triplet, dt is doublet, dq is doublet, m is multiplet. Other abbreviations used in the experimental details are as follows: ar ═ aryl, Ac ═ acyl, Boc ═ tert-butoxycarbonyl, Bn ═ benzyl, DCM ═ dichloromethane, DCE ═ dichloroethane, DMF ═ N, N' -dimethylformamide, NMP ═ N-methyl-2-pyrrolidone, DIBAL-H ═ diisobutylaluminum hydride, DIPEA ═ diisopropylethylamine, DMAP ═ 4- (dimethylamino) pyridine, DMSO ═ dimethyl sulfoxide, HATU ═ 1- [ bis (dimethylamino) methylene chloride, j]-1H-1,2, 3-triazole [4,5-b]Pyridinium 3-oxide hexafluorophosphate, HOBT ═ 1-hydroxybenzotriazole, EA ═ ethyl acetate, Et ═ ethyl, Me ═ methyl, Hz ═ hertz, HPLC ═ high performance liquid chromatography, J ═ coupling constant (in NMR), min ═ min, h ═ h, NMR ═ nuclear magnetic resonance, NBS ═ N-Bromosuccinimide, NCS ═ N-chlorosuccinimide, prep ═ preparative, PE ═ petroleum ether, s-Bu ═ sec-butyl, t-Bu ═ tert-butyl, iPr ═ isopropyl, TBAF ═ tetrabutylammonium fluoride, tert ═ tert, TFA ═ trifluoroacetic acid, THF ═ tetrahydrofuran, MTBE ═ methyl tert-butyl ether, TLC ═ thin layer chromatography.

Examples

It should be noted that the embodiments of the present invention described in detail below are exemplary and are only for the purpose of explaining the present invention, and should not be construed as limiting the present invention. Embodiments without specific techniques or conditions may be implemented according to the techniques or conditions recorded in the literature of the art or according to product specifications. No manufacturer's reagents or instruments are available for routine purchase. One skilled in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as evidenced by the following examples.

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