阅读说明：本技术 用于治疗nk-1受体相关疾病的取代的4-苯基吡啶 (Substituted 4-phenylpyridines for the treatment of NK-1 receptor related diseases ) 是由 卢卡·法蒂尼 彼得·马尼尼 克劳迪奥·彼得拉 克劳迪奥·朱利亚诺 埃马努埃拉·洛瓦蒂 罗伯 于 2012-11-28 设计创作，主要内容包括：公开了用于预防和/或治疗由神经激肽(NK<Sub>1</Sub>)受体病理生理学介导的疾病的化合物、组合物和方法。所述化合物具有通式(I)：<Image he="560" wi="698" file="DDA0002559687360000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Disclosed are pharmaceutical compositions for the prevention and/or treatment of Neurokinin (NK) 1 ) Compounds, compositions and methods for treating diseases mediated by receptor pathophysiology. The compounds have the general formula (I):)

1. An oral pharmaceutical dosage form comprising compound GA1, or a pharmaceutically acceptable salt thereof, in an amount of from about 50mg to about 500mg, based on the weight of the netupitant component of the molecule,

2. the oral pharmaceutical dosage form of claim 1, wherein the compound GA1 or a pharmaceutically acceptable salt thereof has the formula:

3. the oral pharmaceutical dosage form of claim 1 or 2, comprising the compound GA1 or a pharmaceutically acceptable salt thereof in an amount of about 100mg to about 400mg, based on the weight of the netupitant component of the molecule.

4. The oral pharmaceutical dosage form of claim 1 or 2, comprising the compound GA1 or a pharmaceutically acceptable salt thereof in an amount of about 150mg to about 350mg, based on the weight of the netupitant component of the molecule.

5. An oral pharmaceutical dosage form according to claim 1 or 2, comprising said compound GA1 or a pharmaceutically acceptable salt thereof in an amount of about 300mg, based on the weight of the netupitant component of the molecule, of compound GA1 or a pharmaceutically acceptable salt thereof.

6. The oral pharmaceutical dosage form of claim 1 or 2, further comprising from about 0.1 to about 2.0mg of palonosetron or a pharmaceutically acceptable salt thereof.

7. An intravenous pharmaceutical dosage form comprising compound GA1, or a pharmaceutically acceptable salt thereof, in an amount of from about 10mg to about 200mg, based on the weight of the netupitant component of the molecule,

8. the intravenous pharmaceutical dosage form of claim 7, wherein the compound GA1 or a pharmaceutically acceptable salt thereof has the formula:

9. the intravenous pharmaceutical dosage form of claim 7 or 8, comprising the compound GA1 or a pharmaceutically acceptable salt thereof in an amount of about 50 to 150mg, based on the weight of the netupitant component of the molecule, of compound GA1 or a pharmaceutically acceptable salt thereof.

10. The intravenous pharmaceutical dosage form of claim 7 or 8, comprising the compound GA1 or a pharmaceutically acceptable salt thereof in an amount of about 75mg to 125mg, based on the weight of the netupitant component of the molecule.

11. The intravenous pharmaceutical dosage form of claim 7 or 8, comprising said compound GA1 or a pharmaceutically acceptable salt thereof in an amount of about 100mg, based on the weight of the netupitant component of the molecule, of compound GA1 or a pharmaceutically acceptable salt thereof.

12. The intravenous pharmaceutical dosage form of claim 7 or 8, further comprising from about 0.05 to about 2.0mg of palonosetron or a pharmaceutically acceptable salt thereof.

Technical Field

The present invention relates to novel 4-phenylpyridine compounds, and their medical use, in particular for the prevention and/or treatment of medical conditions modulated by neurokinin (NK1) receptors.

Background

Substance P is an 11 amino acid neuropeptide which, because of its position and function, has been reported to be involved in a variety of pathological conditions, including asthma, inflammatory pain psoriasis, migraine, and motorDyskinesia, cystitis, schizophrenia, emesis, and anxiety. Substance P is NK₁Agonists of receptors and by reaction with NK₁The interaction of the receptors causes intracellular signaling.

NK has been reported₁The receptors are involved in a variety of conditions and diseases, and a variety of NK1 antagonists have been developed for the purpose of treating or preventing such conditions and diseases. For example, Kramer et al (Science 281(5383), 1640-1645, 1988) report NK₁Receptor antagonists are used in clinical trials for the treatment of anxiety, depression, psychosis, schizophrenia and emesis. Gesztesi et al (Anesthesiology 93(4), 931-937, 2000) also report the use of NK in the treatment of emesis₁A receptor antagonist.

U.S. patent No.6,297,375 to Hoffmann-La Roche describes a class of 4-phenyl-pyridine compounds that are NK1 antagonists for the treatment of CNS disorders such as depression, anxiety or emesis. Among these 4-phenyl-pyridine compounds, netupitant from Helsinn Healthcare is a selective NK₁Receptor antagonists, current clinical research with palonosetron (a 5-HT)₃Receptor antagonists) for the treatment of chemotherapy-induced nausea and vomiting (CINV).

mono-N-oxide derivatives of 4-phenyl-pyridine compounds are described in U.S. patent No.6,747,026 to Hoffmann La Roche. These N-oxide derivatives are reported to be expected to overcome limitations on the parent compounds that would otherwise limit their clinical usefulness, such as solubility or pharmacokinetic limitations. However, in the' 026 patent, no physicochemical or biological data of the mono-N-oxide derivative was reported.

U.S. patent No.5,985,856 to kansas university describes water-soluble N-phosphoryloxymethyl derivatives of secondary and tertiary amines, and the use of such derivatives to improve the solubility profiles of loxapine and cinnarizine. The' 856 patent does not disclose how the N-phosphoryloxymethyl moiety affects other key features of the drug product, such as prodrug structure, synthesis cost, and selectivity of the phosphoryloxymethyl scheme.

In view of the foregoing, there is a need for a hair treatment compositionNovel derivatives of 4-phenyl-pyridine compounds, which are potent NK compounds, and methods for preparing the same₁A receptor antagonist having enhanced physicochemical and/or biological properties.

Disclosure of Invention

In view of the foregoing, the present inventors have developed a new class of 4-phenyl-pyridine derivatives, which are particularly suitable for antagonizing NK₁A receptor and having the following general formula (I):

and pharmaceutically acceptable salts or adducts thereof.

Compounds of formula (I), also referred to as 4-phenyl-pyridine derivatives, are particularly useful for the prevention and/or treatment of NK-related diseases in a subject₁A condition associated with the pathophysiology of the receptor. Thus, in another embodiment, the invention provides a method of treating NK₁A method of treating a receptor mediated disease, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof.

Also disclosed are methods for preventing and/or treating NK in a subject₁A pharmaceutical composition for treating a condition associated with the pathophysiology of a subject, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or adduct thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, the present invention is a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof,

wherein:

r is selected from hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR¹⁰¹、-NR¹⁰¹R¹⁰²、-NR¹⁰¹C(O)R¹⁰²、-C(O)R¹⁰¹、-C(O)OR¹⁰¹、-C(O)NR¹⁰¹R¹⁰²-alkyl NR¹⁰¹R¹⁰²、-S(O)₂R¹⁰²、-SR¹⁰¹、-S(O)₂NR¹⁰¹R¹⁰²Aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution;

R₁and R₂Independently selected from hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR¹⁰¹、-NR¹⁰¹R¹⁰²、-NR¹⁰¹C(O)R¹⁰²、-C(O)R¹⁰¹、-C(O)OR¹⁰¹、-C(O)NR¹⁰¹R¹⁰²-alkyl NR¹⁰¹R¹⁰²、-S(O)₂R¹⁰²、-SR¹⁰¹、-S(O)₂NR¹⁰¹R¹⁰²Aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution; or R₁Together with the atoms and/or other substituents on the same phenyl ring form a fused or non-fused monocyclic, bicyclic or tricyclic heterocycle or carbocycle, which rings are optionally substituted independently by one or more R¹⁰³Substituent group substitution; or R₂Together with the atoms and/or other substituents on the same phenyl ring form a fused or non-fused monocyclic, bicyclic or tricyclic heterocycle or carbocycle, which rings are optionally substituted independently by one or more R¹⁰³Substituent group substitution;

R₃and R₄Independently selected from hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR¹⁰¹、-NR¹⁰¹R¹⁰²、-NR¹⁰¹C(O)R¹⁰²、-C(O)R¹⁰¹、-C(O)OR¹⁰¹、-C(O)NR¹⁰¹R¹⁰²-alkyl NR¹⁰¹R¹⁰²、-S(O)₂R¹⁰²、-SR¹⁰¹、-S(O)₂NR¹⁰¹R¹⁰²Aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution; or R₃And R₄Atom attached theretoTogether form a fused or non-fused monocyclic, bicyclic or tricyclic heterocycle or carbocycle, which ring is optionally independently substituted with one or more R¹⁰³Substituent group substitution;

R₅and R₆Independently selected from hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR¹⁰¹、-NR¹⁰¹R¹⁰²、-NR¹⁰¹C(O)R¹⁰²、-C(O)R¹⁰¹、-C(O)OR¹⁰¹、-C(O)NR¹⁰¹R¹⁰²-alkyl NR¹⁰¹R¹⁰²、-S(O)₂R¹⁰²、-SR¹⁰¹、-S(O)₂NR¹⁰¹R¹⁰²Aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution;

x is selected from-C (O) NR¹⁰¹R¹⁰²-alkyl O, -alkyl NR¹⁰¹R¹⁰²、-NR¹⁰¹C (O) and-NR¹⁰¹Alkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution;

y is selected from-NR¹⁰¹R¹⁰²、-NR¹⁰¹Alkyl OH, -NR¹⁰¹S(O)₂Alkyl, -NR¹⁰¹S(O)₂Phenyl, -N ═ CH-NR¹⁰¹R¹⁰²Heterocycloalkyl and heterocycloalkylalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution;

z is a structural formula selected from the group consisting of:

wherein formula (Ia) refers to an oxide;

R¹⁰⁰、R^100”、R¹⁰¹、R¹⁰²and R¹⁰³Each independently selected fromHydrogen, cyano, -NO₂、-OR¹⁰⁴Oxide, hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C (O) R¹⁰⁴、-C(O)OR¹⁰⁴、-C(O)NR¹⁰⁴R¹⁰⁵、-NR¹⁰⁴R¹⁰⁵、-NR¹⁰⁴S(O)₂R¹⁰⁵、-NR¹⁰⁴C(O)R¹⁰⁵、-S(O)₂R¹⁰⁴、-SR¹⁰⁴and-S (O)₂NR¹⁰⁴R¹⁰⁵Each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution; or R¹⁰¹、R¹⁰²Together with the atoms to which they are attached form a fused or non-fused monocyclic, bicyclic or tricyclic heterocycle or carbocycle, said ring optionally being independently substituted with one or more R¹⁰³Substituent group substitution; or R¹⁰⁰、R¹⁰⁰"taken together with the atoms to which they are attached form a fused or non-fused monocyclic, bicyclic or tricyclic heterocycle or carbocycle, which ring is optionally independently substituted with one or more R¹⁰³Substituent group substitution;

R¹⁰⁴and R¹⁰⁵Each independently selected from hydrogen, cyano, -NO₂Hydroxyl, oxide, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3, 4 or 5;

p is 0 or 1; and

with the proviso that if a compound of formula (I) is present other than pyridine N-oxide (N)^-→O⁺) The total number of N-oxides of the compound of formula (I) is more than 1.

In another embodiment, the invention is the use of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or adduct thereof as defined above, in the manufacture of a medicament for the treatment of emesis, bladder dysfunction, depression or anxiety in a patient in need thereof.

In another embodiment, the invention is a method of treating emesis, bladder dysfunction, depression or anxiety in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of formula (I) as defined above.

In yet another embodiment, the invention is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt or adduct thereof.

In a further embodiment the invention is a compound of formula GA1,

or a pharmaceutically acceptable salt or adduct thereof.

Drawings

FIG. 1 shows the degradation behavior over time of various salts of 4- (5- (2- (3, 5-bis (trifluoromethyl) phenyl) -N, 2-dimethylpropionamido) -4- (o-tolyl) pyridin-2-yl) -1-methyl-1- ((phosphonooxy) methyl) piperazin-1-ium, reproducing the stability data for various salts of 4- (5- (2- (3, 5-bis (trifluoromethyl) phenyl) -N, 2-dimethylpropionamido) -4- (o-tolyl) pyridin-2-yl) -1-methyl-1- ((phosphonooxy) methyl) piperazin-1-ium.

Detailed Description

Before the present compounds, compositions, articles, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods or specific methods of treatment unless otherwise specified, or to specific reagents unless otherwise specified, as such, can naturally vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting.

Material

A. Compound (I)

Disclosed are compounds represented by formula (I) and pharmaceutically acceptable salts or adducts thereof:

wherein:

r is selected from hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, -OR¹⁰¹、-NR¹⁰¹R¹⁰²、-NR¹⁰¹C(O)R¹⁰²、-C(O)R¹⁰¹、-C(O)OR¹⁰¹、-C(O)NR¹⁰¹R¹⁰²-alkyl NR¹⁰¹R¹⁰²、-S(O)2R¹⁰²、-SR¹⁰¹、-S(O)₂NR¹⁰¹R¹⁰²Aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution;

R₁and R₂Independently selected from hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, -OR¹⁰¹、-NR¹⁰¹R¹⁰²、-NR¹⁰¹C(O)R¹⁰²、-C(O)R¹⁰¹、-C(O)OR¹⁰¹、-C(O)NR¹⁰¹R¹⁰²-alkyl NR¹⁰¹R¹⁰²、-S(O)₂R¹⁰²、-SR¹⁰¹、-S(O)₂NR¹⁰¹R¹⁰²Aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution; or R₁Together with the atoms and/or other substituents on the same phenyl ring form a fused or non-fused monocyclic, bicyclic or tricyclic heterocycle or carbocycle, which rings are optionally substituted independently by one or more R¹⁰³Substituent group substitution; or R₂Together with atoms on the same phenyl ring and/or other substituents form a fused or non-fused monocyclic, bicyclic or tricyclic heterocycle or carbocycleOptionally independently substituted by one or more R¹⁰³Substituent group substitution;

R₃and R₄Independently selected from hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, -OR¹⁰¹、-NR¹⁰¹R¹⁰²、-NR¹⁰¹C(O)R¹⁰²、-C(O)R¹⁰¹、-C(O)OR¹⁰¹、-C(O)NR¹⁰¹R¹⁰²-alkyl NR¹⁰¹R¹⁰²、-S(O)₂R¹⁰²、-SR¹⁰¹、-S(O)₂NR¹⁰¹R¹⁰²Aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution; or R₃And R₄Together with the atoms to which they are attached form a fused or non-fused monocyclic, bicyclic or tricyclic heterocycle or carbocycle, said ring optionally being independently substituted with one or more R¹⁰³Substituent group substitution;

R₅and R₆Independently selected from hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, -OR¹⁰¹、-NR¹⁰¹R¹⁰²、-NR¹⁰¹C(O)R¹⁰²、-C(O)R¹⁰¹、-C(O)OR¹⁰¹、-C(O)NR¹⁰¹R¹⁰²-alkyl NR¹⁰¹R¹⁰²、-S(O)₂R¹⁰²、-SR¹⁰¹、-S(O)₂NR¹⁰¹R¹⁰²Aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution;

x is selected from-C (O) NR¹⁰¹R¹⁰²-alkyl O, -alkyl NR¹⁰¹R¹⁰²、-NR¹⁰¹C (O) and-NR¹⁰¹Alkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution;

y is selected from-NR¹⁰¹R¹⁰²、-NR¹⁰¹Alkyl OH, -NR¹⁰¹S(O)₂Alkyl, -NR¹⁰¹S(O)₂Phenyl, -N ═ CH-NR¹⁰¹R¹⁰²Heterocycloalkyl and heterocycloalkylalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution;

z is a structural formula selected from the group consisting of:

wherein formula (Ia) refers to an oxide;

R¹⁰⁰、R^100”、R¹⁰¹、R¹⁰²and R¹⁰³Each independently selected from hydrogen, cyano, -NO₂、-OR¹⁰⁴Oxide, hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C (O) R¹⁰⁴、-C(O)OR¹⁰⁴、-C(O)NR¹⁰⁴R¹⁰⁵、-NR¹⁰⁴R¹⁰⁵、-NR¹⁰⁴S(O)₂R¹⁰⁵、-NR¹⁰⁴C(O)R¹⁰⁵、-S(O)₂R¹⁰⁴、-SR¹⁰⁴and-S (O)₂NR¹⁰⁴R¹⁰⁵Each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution; or R101, R102 together with the atoms to which they are attached form a fused or non-fused monocyclic, bicyclic or tricyclic heterocycle or carbocycle ring, which ring is optionally substituted independently by one or more R¹⁰³Substituent group substitution; or R¹⁰⁰、R^100”Together with the atoms to which they are attached form a fused or non-fused monocyclic, bicyclic or tricyclic heterocycle or carbocycle, said ring optionally being independently substituted with one or more R¹⁰³Substituent group substitution;

R¹⁰⁴and R¹⁰⁵Each independently selected from hydrogen, cyano, -NO₂Hydroxyl, oxide, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

m is 0 to 4; n is 0 to 5; p is 0 to 1; with the proviso that if a compound of formula (I) is present other than pyridine N-oxide (N)^-→O⁺) The total number of N-oxides of the compound of formula (I) is more than 1. In another embodiment, the present invention excludes all N-oxide forms.

In certain forms, the compound as presently disclosed is a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, wherein R, R₁、R₂、R₃、R₄、R₅And R₆Each independently selected from hydrogen, hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, cyano, -OR¹⁰¹And CF₃。

In certain other forms, the compound as presently disclosed is a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, wherein X is-NR¹⁰¹C (O). In certain other forms, the compound as presently disclosed is a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, wherein Y is heterocycloalkyl or heterocycloalkylalkyl. In still certain other forms, the compound as presently disclosed is a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, wherein the compound of formula (I) has the structure of formula (II):

wherein Q and R' are each independently selected from C, O, S and N, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution; r7 is selected from hydrogen, alkoxy, alkoxyalkyl, -OR¹⁰¹Hydroxyl, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl and halogen, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution; s is 0 to 4; and all other variables are as defined for formula (I).

In still certain other forms, the compound as presently disclosed is a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, wherein the compound of formula (I) has the structure of formula (III):

wherein R is₈Selected from the group consisting of hydrogen, alkyl, alkenyl and cycloalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution; r₉Is alkyl or cycloalkyl, each optionally substituted with one or more independent R¹⁰³Substituent group substitution; and all other groups are as defined for formula (I) and formula (II).

In certain other forms, the compound as presently disclosed is a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, wherein the compound of formula (I) has the structure of formula (IV):

wherein p is independently 0 or 1; all other groups are as defined for formula (I), formula (II) and formula (III).

In still another form, the compound as presently disclosed is a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, wherein the compound of formula (I) has the structure of formula (V):

wherein p is independently 0 or 1; and all other groups are as defined for formula (I), formula (II), formula (III) and formula (IV).

In certain other forms, the compound as presently disclosed is a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, wherein the compound of formula (I) has the structure of formula (VI):

wherein R is₂₀₀And R₃₀₀Each independently selected from hydrogen, alkyl and cycloalkyl, each optionally independently substituted with one or more independent R¹⁰³Substituent group substitution; or R₂₀₀And R₃₀₀Each independently isAn organic or inorganic cation; p is independently 0 or 1; and all other groups are defined according to formula (I), formula (II), formula (III), formula (IV) and formula (V).

In certain forms, the compound as presently disclosed is a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, wherein the compound of formula (I) is a compound selected from the group consisting of:

one particularly preferred compound is the chloride hydrochloride HCl salt of GA1, having the chemical structure shown below, which was found to be extremely resistant to uncoupling of oxo-phosphorylmethyl groups (decoupling) and active partial inversion (turnover) to their parent state.

Salts and adducts

The disclosed compositions and compounds can be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, salts of the compounds may be advantageous due to one or more physical properties of the salt, such as enhanced storage stability at different temperatures and humidities, or the desired solubility in water or oil. In some cases, salts of the compounds may also serve as aids in the isolation, purification, and/or resolution of the compounds.

When the salt is intended for administration to a patient (as opposed to, for example, being used in an in vitro environment), the salt is preferably pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt made by mixing a compound, such as the disclosed compound, with an acid or a base, the anion of which is generally considered suitable for human consumption, and the cation of which is. Pharmaceutically acceptable salts are particularly useful as the product of the process of the invention because of their greater aqueous solubility relative to the parent compound. For pharmaceutical use, salts of the disclosed compounds are non-toxic "pharmaceutically acceptable salts". Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the disclosed compounds, which salts are typically prepared by reacting the free base with a suitable organic or inorganic acid.

Suitable pharmaceutically acceptable acid addition salts of the disclosed compounds include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, nitric acid, carbonic acid, sulfonic acid, and sulfuric acid, and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothiocarboxylic acid (isothionic), lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid, and trifluoroacetic acid, when possible. Suitable organic acids generally include, for example, organic acids of the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid types.

Specific examples of suitable organic acids include, but are not limited to, acetic acid, trifluoroacetic acid, formic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, digluconate (digluconate), lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid (sulfamilate), cyclohexylsulfamic acid, alginic acid (algenic acid), beta-hydroxybutyric acid, galactaric acid, galacturonic acid, adipic acid, alginic acid, butyric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, dodecylsulfuric acid, glycerheptonic acid, Glycerophosphoric acid, heptanoic acid, hexanoic acid, nicotinic acid, 2-naphthalenesulfonic acid (2-naphthalsulfonate), oxalic acid, palmitic acid (palmoate), pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, thiocyanic acid, toluenesulfonic acid and undecanoic acid.

Furthermore, where the disclosed compounds carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, for example, copper, calcium or magnesium salts; and salts with suitable organic ligands, for example, quaternary ammonium salts. In certain forms, the base salts are formed from bases which form non-toxic salts and include aluminum, arginine, dibenzylethylenediamine (benzathine), choline, diethylamine, diethanolamine, glycinate, lysine, meglumine, ethanolamine, tromethamine salts and zinc salts.

Organic salts may be prepared from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Basic nitrogen-containing groups may be quaternized with agents such as: lower alkyl (C)₁-C₆) Halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and the like. In certain forms, hemisalts of acids and bases, for example, hemisulfate and hemicalcium salts, may also be formed. The disclosed compounds can exist in both unsolvated and solvated forms. As used herein, a "solvate" is a non-aqueous solution or dispersion that presents a non-covalent or readily dispersible combination, or mode of dispersion and dispersed phase, between the solvent and solute.

The disclosed compositions and compounds can be used in the form of adducts derived by forming lewis pairs, covalently linked adducts (e.g., between an N atom and a carbonyl-containing reactant, between a hydrate and an ethanolate), host-guest adducts comprising molecular species not bound to or associated with a medical compound.

Depending on the particular compound, adducts of the compounds may be advantageous due to physical properties of one or more adducts of the salts, such as enhanced storage stability at different temperatures and humidities, or desired solubility in water or oil. In some cases, adducts of compounds may also serve as aids in the isolation, purification and/or resolution of the compounds. When the adduct is intended for administration to a patient (as opposed to, for example, being used in an in vitro environment), the adduct is preferably pharmaceutically acceptable. The term "pharmaceutically acceptable adduct" refers to an adduct made by mixing a compound such as the disclosed compound with a gas, water, a solvent, a lewis base, a carbonyl-containing molecule, or a guest molecule (which is generally considered suitable for human consumption). The pharmaceutically acceptable addition species are particularly useful as products of the disclosed methods because of their greater water solubility relative to the parent compound. For use in medicine, the adducts of the disclosed compounds are non-toxic "pharmaceutically acceptable adducts". Adducts encompassed within the term "pharmaceutically acceptable adducts" refer to non-toxic adducts of the disclosed compounds, which are typically prepared by reacting a compound of the present invention with a suitable organic or inorganic addition species.

Suitable pharmaceutically acceptable adducts of the disclosed compounds include those derived from lewis bases such as boric acid, aluminum hydroxide, organic sulfoxides, organic sulfones, organic sulfonium salts, H, when possible₃PO₃Siloxane and other lewis bases.

Suitable pharmaceutically acceptable adducts of the disclosed compounds also include those derived from covalent bonds between the oxygen, nitrogen, or sulfur atoms of the compounds and carbon dioxide, lower alkyl aldehydes or ketones, vanillin, amino acids, or nucleic acids, when possible.

Suitable pharmaceutically acceptable adducts of the disclosed compounds also include those derived from the inclusion of unbound gases such as molecular oxygen (dioxygen), molecular nitrogen, carbon dioxide, nitrous oxide, diethyl ether, or other gases, when possible, contained within the crystalline or amorphous phase of the compound rather than bound thereto.

Suitable pharmaceutically acceptable adducts of the disclosed compounds also include those derived from the compound molecule in combination with water, a pharmaceutically acceptable lower alkyl alcohol, or another pharmaceutically acceptable solvent which is associated with the compound in molecular ratio, when possible.

In one embodiment, the adduct is optionally a clathrate.

General synthetic schemes

The compounds of formula (I) (and other disclosed compounds), or pharmaceutically acceptable salts or adducts thereof, can be prepared by the methods as exemplified in the examples described in the "examples" section, together with synthetic methods known in the art of organic chemistry or methods of modification and derivatization well known to those of ordinary skill in the art. The starting materials used herein are commercially available or may be prepared by conventional Methods known in the art, such as those disclosed in standard reference books such as the company of organic Synthesis Methods, Vol.I-VI (published by Wiley-Interscience). Preferred methods include, but are not limited to, those described below. During any of the synthetic sequences described below, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule of interest. This can be achieved using conventional protecting groups, such as those described in: greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, and P.G.M.Wuts and T.W.Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 2006. Isolation and purification of the product is accomplished by standard methods known to the chemist of ordinary skill.

The invention further provides suitable prodrugs for the preparation of 4-phenyl-pyridine derivatives. In one embodiment, the present invention provides a single step, acid-free synthesis method of functionalized tertiary amines by reaction with chloromethyl dialkyl phosphates to produce (phosphonooxy) methyl prodrugs as phosphatase substrates. In contrast, the prior art requires multiple synthetic steps for comparable reactions, including the need to use proton scavengers during the initial reaction and strong acids to deprotect the phosphate groups in another step. In another embodiment, the present invention provides a process for the preparation of chloromethyl dialkyl phosphates having suitable purity and economy, since the quality of the phosphate compositions from commercial sources is too low to provide acceptable yields for the reactions according to the present invention. In another embodiment, the present invention provides a method of stabilizing the (phosphonooxy) methyl prodrugs according to the invention by combining two equivalents of hydrochloric acid, since whereas the prior art prefers to use a (phosphonooxy) methyl dibasic salt substituent for the quaternary ammonium salt in the prodrug, the present invention finds that such salts are unstable during storage and alter the drug based thereon.

Definition of terms

The term "alkyl" refers to a straight or branched chain saturated hydrocarbon substituent (i.e., a substituent obtained by removing hydrogen from a hydrocarbon) containing one to twenty carbon atoms; in one embodiment, from one to twelve carbon atoms; in another embodiment, one to ten carbon atoms; in another embodiment, one to six carbon atoms; and in another embodiment, from one to four carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, isopentyl, hexyl and the like.

The term "alkenyl" refers to a straight or branched chain hydrocarbyl substituent comprising one or more double bonds and 2 to 20 carbon atoms; in another embodiment, from 2 to 12 carbon atoms; in another embodiment, from 2 to 6 carbon atoms; and, in another embodiment, from 2 to 4 carbon atoms. Examples of alkenyl groups include ethenyl (also known as vinyl), allyl, propenyl (including 1-propenyl and 2-propenyl), and butenyl (including 1-butenyl, 2-butenyl, and 3-butenyl). The term "alkenyl" encompasses substituents having "cis" and "trans" directions, alternatively, "E" and "Z" directions.

The term "benzyl" refers to a methyl group substituted with a phenyl group.

The term "carbocyclic ring" refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 carbon ring atoms (a "ring atom" being an atom bonded together to form a ring). Carbocycles typically contain 3 to 10 carbon ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. A "carbocyclic ring system" may optionally be 2 or 3 rings fused together, such as naphthyl, tetrahydronaphthyl (also known as "tetralinyl"), indenyl, isoindolyl, indanyl, bicyclodecyl, anthracenyl, phenanthrenyl, benzonaphthylmethine (also known as "phenalenyl"), fluorenyl, and decahydronaphthyl.

The term "heterocyclic ring" refers to a ring containing from 3 to 14 ring atoms (a "ring atom" being an atom bonded together to form a ring), wherein at least one ring atom is a heteroatom, i.e., oxygen, nitrogen, or sulfur, and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur.

The term "cycloalkyl" refers to a saturated carbocyclic substituent having from 3 to 14 carbon atoms. In one embodiment, the cycloalkyl substituents have from 3 to 10 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "cycloalkyl" also includes fused to C₆-C₁₀A substituent of an aromatic ring or a 5-to 10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyl group as a substituent is bonded to a carbon atom of the cycloalkyl group. When such a fused cycloalkyl group is substituted with one or more substituents, the one or more substituents are each bonded to a carbon atom of the cycloalkyl group, unless otherwise specified. Condensed C₆-C₁₀The aromatic ring or 5-10 membered heteroaromatic ring may optionally be substituted by halogen, C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl or ═ O substitution.

The term "cycloalkenyl" refers to partially unsaturated carbocyclic substituents having from 3 to 14 carbon atoms, typically from 3 to 10 carbon atoms. Examples of cycloalkenyl groups include cyclobutenyl, cyclopentenyl, and cyclohexenyl.

Cycloalkyl or cycloalkenyl groups can be monocyclic, which typically contains 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. Alternatively, 2 or 3 rings may be fused together, such as bicyclic decyl and decahydronaphthyl.

The term "aryl" refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may have six to eighteen carbon atoms. As an example, an aryl substituent may have six to fourteen carbon atoms. The term "aryl" may refer to substituents such as phenyl, naphthyl and anthracenyl. The term "aryl" also includes substituents such as phenyl, naphthyl and anthracenyl, which are substituted with C_4-10Carbocyclic ring (such as C)₅Or C₆Carbocyclic rings) or with a 4-10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bonded to an aromatic carbon of the aryl group. When such a fused aryl group is substituted with one or more substituents, each of the one or more substituents is bonded to an aromatic carbon of the fused aryl group, unless otherwise specified. Said condensed C_4-10The carbocyclic or 4-10-membered heterocyclic ring may optionally be substituted by halogen, C_1-6Alkyl radical, C_3-10Cycloalkyl or ═ O substitution. Thus, examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl (also known as "tetralinyl"), indenyl, isoindolyl, indanyl, anthracyl, phenanthryl, benzonaphthylidene (also known as "phenalenyl"), and fluorenyl groups.

In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, etc.) is prefixed by the "C_x-C_y- "indicates where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms. Thus, for example, "C₁-C₆Alkyl "refers to an alkyl substituent containing 1 to 6 carbon atoms. As a further example, C₃-C₆Cycloalkyl means a saturated cycloalkyl group having 3 to 6 carbon ring atoms.

In certain instances, the number of carbon atoms in a cyclic substituent (e.g., heteroaryl or heterocycloalkyl) that includes one or more heteroatoms is indicated by the prefix "X-Y-member," where X is the minimum number of carbon atoms to form the cyclic portion of the substituent and Y is the maximum number of atoms. Thus, for example, a 5-8 membered heterocycloalkyl group refers to a heterocycloalkyl group containing from 5 to 8 atoms, which includes one or more heteroatoms in the cyclic portion of the heterocycloalkyl group.

The term "hydrogen" refers to a hydrogen substituent and may be described as — H.

The term "hydroxy" refers to-OH. The prefix "hydroxy", when used in combination with another term, indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds having a carbon attached to one or more hydroxyl substituents include, for example, alcohols, enols, and phenols.

The term "hydroxyalkyl" refers to an alkyl group substituted with at least one hydroxy substituent. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.

The term "nitro" means-NO₂。

The term "cyano" (also referred to as "nitrile") -CN.

The term "carbonyl" refers to-C (O) -.

The term "amino" refers to the group-NH₂。

The term "alkylamino" refers to an amino group wherein at least one alkyl chain is bonded to the amino nitrogen in place of a hydrogen atom. Examples of alkylamino substituents include monoalkylamino, such as methylamino (exemplified by the formula NH (CH)₃) And dialkylamino groups such as dimethylamino groups.

The term "aminocarbonyl" refers to-C (O) -NH₂。

The term "halogen" refers to fluorine (which may be represented by-F), chlorine (which may be represented by-Cl), bromine (which may be represented by-Br), or iodine (which may be represented by-I). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is fluorine.

The prefix "halogen" refers to a prefix attached substituent substituted with one or more independently selected halogen substituents. For example, haloalkyl refers to an alkyl group substituted with at least one halo substituent. The term "oxo" refers to ═ O.

The term "oxy" refers to an ether substituent, which may be described as-O-.

The term "alkoxy" refers to an oxygen-attached alkyl group, which may also be represented as-O-R, where R represents an alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy.

The term "alkylthio group"refers to S-alkyl. For example, "methylthio" is-S-CH₃. Other examples of alkylthio groups include ethylthio, propylthio, butylthio, and hexylthio.

The term "alkylcarbonyl" refers to-c (o) -alkyl. Examples of the alkylcarbonyl group include methylcarbonyl group, propylcarbonyl group, butylcarbonyl group, pentylcarbonyl group, and hexylcarbonyl group.

The term "aminoalkylcarbonyl" refers to the group-C (O) -alkyl-NH₂。

The term "alkoxycarbonyl" refers to-C (O) -O-alkyl. Examples of alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl. In another embodiment, when the carbon atom of the carbonyl group is attached to the carbon atom of the second alkyl group, the resulting functional group is an ester.

The terms "thio" and "thio (thia)" refer to a divalent sulfur atom, and such substituents may be described as-S-. For example, thioethers are represented as "alkyl-thio-alkyl" or another alkyl-S-alkyl.

The term "thiol" refers to a mercapto substituent and may be described as-SH.

The term "thione" refers to S.

The term "sulfonyl" refers to-S (O)₂-. Thus, for example, "alkyl-sulfonyl-alkyl" refers to alkyl-S (O)₂-an alkyl group. Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl and propylsulfonyl.

The term "aminosulfonyl" refers to-S (O)₂-NH₂。

The term "sulfinyl" or "sulfoxido" refers to-S (O) -. Thus, for example, "alkylsulfinylalkyl" or "alkylsulfenylalkyl" refers to alkyl-S (O) -alkyl. Exemplary alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl, and hexylsulfinyl.

The term "heterocycloalkyl" refers to a saturated or partially saturated ring structure containing a total of 3 to 14 ring atoms. At least one ring atom is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from carbon, oxygen, nitrogen, and sulfur. Heterocycloalkyl optionally can include 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom (e.g., nitrogen, oxygen, or sulfur) as a ring atom. In a group having a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent that is bonded to the group can be at least one heteroatom, or it can be a ring carbon atom, where the ring carbon atom can be in the same ring as the at least one heteroatom or where the ring carbon atom can be in a different ring from the at least one heteroatom. Similarly, if, in turn, the heterocycloalkyl substituent is substituted with a group or substituent, the group or substituent may be bonded to at least one heteroatom, or it may be bonded to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.

Examples of heterocycloalkyl groups include, but are not limited to, azetidine, 1, 3-diazatidine, pyrrolidine, 2-pyrroline, 3-pyrroline, 2-imidazoline, imidazolidine, 2-pyrazoline, pyrazolidine, piperidine, 1, 2-azacyclohexane, 1, 3-diazacyclohexane, 1, 4-diazacyclohexane, octahydroazocin, oxetane, tetrahydrofuran, tetrahydropyran, 1, 2-dioxane, 1, 3-dioxane, 1, 4-dioxane, 1, 3-dioxolane, thiocyclobutane, thiocyclopentane, 1, 3-dithiolane, thiocyclohexane, 1, 4-dithiane, 1, 3-oxathiaane, morpholine, 1, 4-thiaxane, 1, 3, 5-trithiane, and thiomorpholine.

The term "heterocycloalkyl" also includes alkyl groups with C_6-10An aromatic ring or a substituent fused with a 5-to 10-membered heteroaromatic ring, wherein a group having such a fused heterocycloalkyl group as a substituent is bonded to a heteroatom of the heterocycloalkyl group or a carbon atom of the heterocycloalkyl group. When such a fused heterocycloalkyl group is substituted with one or more substituents, each of the one or more substituents is bonded to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocycloalkyl group, unless otherwise specified. Condensed C₆-C₁₀Aromatic ringOr 5-10 membered heteroaromatic ring may optionally be substituted by halogen, C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl or ═ O substitution.

The term "heteroaryl" refers to an aromatic ring structure comprising 5 to 14 ring atoms, wherein at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), the remaining ring atoms being independently selected from carbon, oxygen, nitrogen, and sulfur. Heteroaryl groups can be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazinyl (pyrazyl), pyrimidinyl and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1, 2, 3-, 1, 2, 4-, 1, 2, 5-, or 1, 3, 4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothienyl, isobenzothienyl, benzisoxazolyl, benzoxazolyl, purinyl and anthrenyl; and 6/6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1, 4-benzoxazinyl. The term "heteroaryl" also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring.

Examples of monocyclic heteroaryl and heterocycloalkyl groups include, but are not limited to, furyl, dihydrofuryl, tetrahydrofuranyl, thiophenyl (also referred to as "thienyl"), dihydrothienyl, tetrahydrothienyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiol, oxathiol, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiadiazolyl, thiazolyl, oxadiazolyl (including oxadiazolyl, 1, 2, 4-oxadiazolyl (also referred to as "azoximyl"), 1, 2, 5-oxadiazolyl (also referred to as "furazanyl"), or 1, 3, 4-oxadiazolyl), oxatriazolyl (including 1, 2, 3, 4-or 1, 2, 3, 5-oxatriazolyl), dioxazolyl (dioxazolyl) (including 1, 2, 3-dioxazolyl, 1, 2, 4-dioxazolyl, 1, 3, 2-dioxazolyl, or 1, 3, 4-dioxazolyl), thiazolyl (oxathiazolyl), oxathiyl, oxathianyl, pyranyl (including 1, 2-pyranyl or 1, 4-pyranyl), dihydropyranyl, pyridinyl (also referred to as "azine"), piperidinyl, diazinyl (including pyridazinyl (also referred to as "1, 2-diazinyl"), pyrimidinyl (also referred to as "1, 3-diazinyl" or "pyrimidinyl"), or pyrazinyl (also referred to as "1, 4-diazinyl"), piperazinyl, triazinyl (including s-triazinyl (also referred to as "1, 3, 5-triazinyl "), as-triazinyl (also referred to as" 1, 2, 4-triazinyl "), and v-triazinyl (also referred to as" 1, 2, 3-triazinyl ")), oxazinyl (including 1, 2, 3-oxazinyl, 1, 3, 2-oxazinyl, 1, 3, 6-oxazinyl (also referred to as" pentoxazolyl "), 1, 2, 6-oxazinyl, or 1, 4-oxazinyl), isoxazolyl (including o-isoxazolyl or p-isoxazolyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1, 2, 5-oxathiazinyl or 1, 2, 6-oxathiazinyl), oxadiazinyl (including 1, 4, 2-oxadiazinyl or 1, 3, 5, 2-oxadiazinyl), morpholinyl, azaazepinyl, oxadiazinyl, and v-triazinyl (also referred to as" 1, 2, 4-triazinyl ")), and v-triazinyl (also referred to as" 1, 2, 3-triazinyl ")) Oxazepinyl, thiazepinyl, and diazepinyl.

Examples of 2-fused ring heteroaryl groups include indolizinyl, 4-indolizine, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridyl (including pyrido [3, 4-b ] -pyridyl, pyrido [3, 2-b ] -pyridyl, or pyrido [4, 3-b ] -pyridyl), and pteridinyl, indolyl, isoindolyl, pseudoindolyl, isoindolyl, azonaphthyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothienyl, benzoxazolyl, indoxazinyl, anthrenyl, benzodioxolyl (benzodioxolyl), benzodioxanyl, benzooxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, quinoxalyl, benzodioxolyl, benzofuranyl, benzothiophenyl, isobenzothiadiazolyl, and the like, Benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl.

Examples of 3-fused ring heteroaryl or heterocycloalkyl include 5, 6-dihydro-4H-imidazo [4, 5, 1-ij]Quinoline, 4, 5-dihydroimidazo [4, 5, 1-hi]Indole, 4,5, 6, 7-tetrahydroimidazo [4, 5 ]，1-jk][1]Benzazepine and dibenzofuranyl. The term "heteroaryl" also includes substituents such as pyridyl and quinolyl fused to a C4-10 carbocyclic ring (such as a C5 or C6 carbocyclic ring), or fused to a 4-10-membered heterocyclic ring wherein the group having such fused heteroaryl as a substituent is bonded to the aromatic carbon of the heteroaryl or a heteroatom of the heteroaryl. When such a fused heteroaryl group is substituted with one or more substituents, each of the one or more substituents is bonded to the aromatic carbon of the heteroaryl group or to the heteroatom of the heteroaryl group, unless otherwise specified. Condensed C₄-C₁₀Carbocyclic or 4-10 membered heterocyclic ring optionally substituted by halogen, C₁-C₆Alkyl radical, C₃-C₁₀Cycloalkyl or ═ O substitution.

The term "ethylene" refers to the group-CH₂-CH₂-. The term "ethylene" refers to the group-CH ═ CH-. The term "propene" means the radical-CH₂-CH₂-CH₂-. The term "butene" refers to the group-CH₂-CH₂-CH₂-CH₂-. The term "methyleneoxy" refers to the group-CH₂-O-. The term "methylenesulfoxy" refers to the group-CH₂-S-. The term "methyleneamino" refers to the group-CH₂-N (H) -. The term "vinyloxy" refers to the group-CH₂-CH₂-O-. The term "ethylenesulfoxy" refers to the group-CH₂-CH₂-S-. The term "vinylamino" refers to the group-CH₂-CH₂-N(H)-。

A substituent is "substitutable" if it includes at least one carbon, sulfur, oxygen, or nitrogen atom bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen and cyano do not fall within this definition. If a substituent is described as "substituted," then a non-hydrogen substituent is present at the position of the hydrogen substituent on a carbon, oxygen, sulfur, or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is at the position of a hydrogen substituent on the alkyl substituent.

If a substituent is described as "optionally substituted," that substituent may be (1) unsubstituted, or (2) substituted. When a substituent consists of multiple moieties, it is meant to serve as a point of attachment for the final moiety to the rest of the molecule, unless otherwise specified. For example, in the substituent A-B-C, the moiety C is attached to the rest of the molecule. If a substituent is described as "independently selected from" a group, then each substituent is selected independently of the other. Thus, each substituent may be the same or different from the other substituents.

Pharmaceutical composition

Further provided is a pharmaceutical composition for the prophylaxis and/or treatment of a subject comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or adduct thereof, and one or more pharmaceutically acceptable excipients.

A "pharmaceutically acceptable" excipient is one that is not biologically or otherwise undesirable, i.e., the substance can be administered to a subject without causing any undesirable effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier may be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as is well known to those skilled in the art. The carrier may be a solid, a liquid, or both. The disclosed compounds may be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such a route and in a dose effective for the intended treatment or prevention. The active compounds and compositions may be administered, for example, orally, rectally, parenterally, ocularly, by inhalation, or topically. In particular, administration can be epidermal (epicutaneous), inhalation, enema, conjunctival, eye drop, ear drop, alveolar, nasal, intranasal, vaginal, intravaginal, vaginal, ocular, intraocular, ocular, enteral, oral, intraoral, oral, enteral, rectal, intrarectal, enteral, injection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular, intracerebroventricular, intracardial, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, intracavernosal, intraspinal, intraocular, intracranial, transdermal, transmucosal, nasal, inhalation, intracisternal, dural (epidural), intravitreal, and the like.

Suitable supports and their preparation are described in Remington: the Science and Practice of pharmacy (19th ed.) ed.A.R.Gennaro, Mack Publishing Company, Easton, PA, 1995. Oral administration of solid dosage forms, for example, is provided in the form of discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one disclosed compound or composition. In certain forms, oral administration may be in powder or granular form. In certain forms, the oral dosage form is a sublingual dosage form, such as, for example, a lozenge. In such solid dosage forms, the compound of formula I is typically combined with one or more excipients. Such capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents or may be prepared with an enteric coating.

In certain forms, oral administration may be in the form of a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions may also include adjuvants, such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweetening agents), and/or perfuming agents.

In certain forms, the disclosed compositions may include parenteral dosage forms. "parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable formulations (e.g., sterile injectable aqueous or oleaginous suspensions) may be prepared according to known techniques using suitable dispersing, wetting and/or suspending agents. Generally, a suitable amount of a pharmaceutically acceptable carrier is used in the formulation to render the formulation isotonic. Examples of pharmaceutically acceptable carriers include, but are not limited to, saline, ringer's solution, and dextrose solution. Other acceptable excipients include, but are not limited to, thickeners, diluents, buffers, preservatives, surfactants, and the like.

Other carrier materials and modes of administration known in the pharmaceutical art may also be used. The disclosed medicaments can be prepared by well-known pharmaceutical techniques (e.g., effective formulation and administration procedures)The composition is prepared by mixing the above raw materials. The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard texts. For example, the formulation of drugs is discussed in the following documents: hoover, John e., Remington's Pharmaceutical Sciences, Mack publishing co, Easton, Pennsylvania, 1975; liberman, et al, eds, Pharmaceutical document Forms, Marcel Decker, New York, n.y., 1980; and Kibbe, et al, Handbook of pharmaceutical Excipients (3)^rdEd.)，American Pharmaceutical Association，Washington，1999。

The disclosed compounds can be used to treat various disorders or disease states, either alone or in combination with other therapeutic agents. Administering two or more compounds "in combination" refers to administering the two compounds close enough in time that the presence of one compound alters the biological effect of the other compound. The two or more compounds may be administered simultaneously, concurrently or sequentially.

Disclosed are pharmaceutical compositions comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof; and a pharmaceutically acceptable carrier or excipient. These compositions may further comprise additional agents. These compositions are useful for modulating the activity of neurokinin (NK1) receptors, thereby ameliorating NK₁Prevention and treatment of receptor-related diseases such as nausea and vomiting, bladder dysfunction, depression or anxiety.

In certain forms, there is disclosed a pharmaceutical composition for the prophylaxis and/or treatment of a subject comprising a therapeutically effective amount of a compound according to formula (I) and one or more pharmaceutically acceptable excipients. In certain other forms, pharmaceutical compositions are disclosed that further include one or more therapeutic agents or pharmaceutically acceptable salts thereof. In certain forms, the therapeutic agent is 5-HT₃An antagonist, an NK1 antagonist, or dexamethasone. In certain other forms, the 5-HT₃The antagonist is ondansetron, palonosetron, granisetron or tropisetron, or a pharmaceutically acceptable salt thereof.

Method of producing a composite material

All methods of the invention can be practiced using the compounds of the invention alone or in combination with other agents.

Treatment of

The above compounds and compositions are useful for inhibiting, reducing, preventing and/or treating diseases whose pathophysiology is modulated by neurokinin (NK1) receptors. Thus, in certain forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of treating a receptor mediated disease comprising administering to a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or adduct thereof, as disclosed above.

Suitable subjects may include mammalian subjects. Mammals include, but are not limited to, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, and the like, and includes mammals in the uterus. In some forms, the human is the subject. The human subject may be of either sex and at any stage of development.

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of a receptor modulated disease, wherein the disease is nausea and vomiting, bladder dysfunction, depression or anxiety.

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of a receptor-modulated disease, wherein the nausea and vomiting is chemotherapy-induced nausea and vomiting (CINV), radiotherapy-induced nausea and vomiting (RINV), or post-operative nausea and vomiting (PONV).

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of receptor modulated diseases in which the nausea and vomiting are induced by moderate or high emetogenic (emetogenic) chemotherapy. In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of a receptor modulated disease state, wherein the nausea and vomiting are acute and/or delayed phases of CINV.

Acute emesis refers to the first twenty-four hour period following a vomiting-inducing event. Delayed emesis refers to the second, third, fourth, and fifth twenty-four hour periods following emesis-inducing events. When treatment is considered to be effective during the delay period, it is understood to mean that the efficacy of the treatment is statistically significant throughout the delay period, regardless of whether the treatment is effective during any particular twenty-four hour period of the delay period. It should also be understood that the method may be defined based on its efficacy during any one of the twenty-four hour periods of the delay period. Thus, unless otherwise specified, any method of treating nausea and/or vomiting during a delay period as described herein can also be practiced for treating nausea and/or vomiting for a second, third, fourth, or fifth twenty-four hour period or a combination thereof after the induction time of emesis.

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of a receptor-modulated disease in which the acute and/or delayed phase of CINV is induced by moderate or high emetogenic chemotherapy. "high emetic chemotherapy" refers to chemotherapy with high emetic potential, including those based on carmustine, cisplatin, cyclophosphamide ≥ 1500mg/m²Chemotherapy of dacarbazine, dactinomycin, mechlorethamine and streptozotocin. "moderate emesis-inducing chemotherapy" refers to chemotherapy with moderate emesis-inducing potential, including those based on carboplatin and cyclophosphamide < 1500mg/m²Cytarabine > 1mg/m²Chemotherapy with daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, and oxaliplatin.

In a preferred embodiment, the method of the invention is effective in the treatment of acute and delayed emesis induced by moderate and high emesis-inducing chemotherapy by administering a single dose of a netupitant derivative prior to chemotherapy, optionally in combination with other active ingredients.

A particularly preferred regimen for the treatment of emesis, particularly chemotherapy-induced emesis, comprises a netupitant derivative of the invention, 5-HT₃An antagonist such as palonosetron or a pharmaceutically acceptable salt thereof, and a corticosteroid such as dexamethasone. A suitable fixed regimen for the treatment of acute and delayed CINV comprises a single administration of the netupitant derivative on the first day (preferably before chemotherapy) and a single administration of the netupitant derivative on the first day (preferably before chemotherapy)Administration of 5-HT₃An antagonist. Corticosteroids are optionally added to the combination on the first day, and the same on days 2, 3 and 4, immediately following the administration of the highly emetogenic chemotherapy. A preferred intravenous dose of palonosetron HCl is 0.25mg based on the weight of the free base. The preferred dexamethasone dose is 12 mg. For the highly emetogenic chemotherapy, 8mg was administered orally on day 1, followed by oral administration on days 2, 3, and 4.

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of a receptor modulated disease, wherein the bladder dysfunction is selected from the group consisting of urinary urgency, urinary frequency, pollakiuria, nocturia, low lag time, suboptimal volume threshold, and neurogenic bladder, or a combination thereof.

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of receptor-modulated diseases wherein the compound, or a pharmaceutically acceptable salt or adduct thereof, is administered by one or more routes selected from the group consisting of: rectal, buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drop, parenteral and topical administration.

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of receptor-modulated diseases wherein said administration is accomplished by intravenous administration of said compound, or a pharmaceutically acceptable salt or adduct thereof, in liquid form.

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of receptor modulated diseases, in particular by a derivative of netupitant, wherein said administration is accomplished by oral administration of said compound or a pharmaceutically acceptable salt or adduct thereof. In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of receptor modulated diseases wherein the oral dosage of the netupitant derivative is from about 50mg to about 500mg, from about 100mg to about 400mg, from about 150mg to about 350mg, or about 300mg, based on the weight of the netupitant component of the molecule.

In certain other forms, prevention and/or treatment of pathophysiology is disclosedReceptor of NK₁A method of receptor-modulated diseases, particularly by a netupitant derivative, wherein the compound, or a pharmaceutically acceptable salt or adduct thereof, is administered intravenously in a dose of from about 10mg to about 200mg, from about 50mg to about 150mg, from about 75mg to about 125mg, or about 100mg, based on the weight of the netupitant component of the molecule.

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of receptor-modulated diseases, particularly by a netupitant derivative, wherein the compound or a pharmaceutically acceptable salt or adduct thereof is formulated with a concentration of about 1 to about 20mg/mL, about 5 to about 15mg/mL, about 7 to about 2mg/mL, or about 10mg/mL, based on the weight of the netupitant component of the molecule.

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of a receptor-modulated disease, wherein the compound or pharmaceutically acceptable salt or adduct thereof is administered as a single daily dose, as a single dose in a multiple daily course of treatment (e.g., a five day treatment regimen for delayed emesis), or as multiple daily doses. In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of a receptor modulated disease wherein the multiple doses are between 2 and 4 doses per day.

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of treating a receptor modulated disease, further comprising administering one or more therapeutic agents or a pharmaceutically acceptable salt thereof. In certain other forms, the therapeutic agent is 5-HT₃An antagonist, an NK1 antagonist, or dexamethasone. In certain other forms, the 5-HT₃The antagonist is ondansetron, palonosetron, granisetron or tropisetron, or a pharmaceutically acceptable salt thereof. In still some other forms, the 5-HT₃The antagonist is palonosetron or a pharmaceutically acceptable salt thereof. In certain other forms, the oral dose of palonosetron or a pharmaceutically acceptable salt thereof is from about 0.1mg to about 2.0mg, from about 0.25mg to about 1.0mg, from about 0.5mg to about 0.75mg, or about 0.5 mg. In certain other forms, the intravenous dose of palonosetron or a pharmaceutically acceptable salt thereof is from about 0.05mg to about 2.0mg, from about 0.075mg to about 1.5mg, about 0.1mg to about 1.0mg, about 0.25mg to about 0.75mg, or about 0.25 mg. In certain other forms, the palonosetron or a pharmaceutically acceptable salt thereof is formulated to have a concentration of about 0.25mg/5 mL.

In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of receptor modulated diseases further comprising administering one or more therapeutic agents or pharmaceutically acceptable salts thereof, wherein the therapeutic agent is an NK₁An antagonist which is 2- (3, 5-bis (trifluoromethyl) phenyl) -N, 2-dimethyl-N- (6- (4-methylpiperazin-1-yl) -4- (o-tolyl) pyridin-3-yl) propionamide (netupitant). In one embodiment, the netupitant is administered in combination with GA8 in a ratio of GA8 to netupitant of greater than 1: 200 or 1: 100.

in certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of a receptor modulated disease, wherein the subject is a human. In certain other forms, the prevention and/or treatment of pathophysiology susceptible NK is disclosed₁A method of treating a receptor modulated disease, wherein the subject has been identified as in need of treatment for the disease or administration.

One of ordinary skill in the art of treating such diseases will be able to determine, without undue experimentation and depending on personal knowledge and the content of this application, a therapeutically effective amount of a compound of formula I for a given disease. In certain other forms, methods of preventing and/or treating a subject are disclosed that further include one or more therapeutic agents.

Definitions of further terms

1. One, one (A, an, the)

As used in the specification and the appended claims, the singular forms a, an and the include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes not only a single carrier, but also mixtures of two or more such carriers, and the like. 2. Abbreviations

Abbreviations well known to those of ordinary skill in the art may be used (e.g., "h" or "hr" for hours, "g" or "gm" for grams, "mL" for milliliters, and "rt" for room temperature, "nm" for nanometers, "M" for moles, etc.).

3. About

The term "about" when used to modify numerical values describing the amounts, concentrations, volumes, process temperatures, processing times, yields, flow rates, pressures, etc., of ingredients of compositions employed in embodiments of the present invention, and ranges thereof, refers to quantitative changes that may occur: for example, by typical measuring and handling procedures for preparing compounds, compositions, concentrates or use formulations; through inadvertent errors in these processes; by differences in the preparation, source or purity of the starting materials or ingredients used to carry out the method; and the like. The term "about" also encompasses quantitative differences due to aging of a composition or formulation having a particular initial concentration or mixture, quantitative differences due to mixing or processing of a composition or formulation having a particular initial concentration or mixture. Equivalents of these amounts are included in the claims, whether modified by "about".

4. Comprises that

Throughout the description and claims of this specification, the term "comprise" and variations of the term such as "comprises" and "comprising" mean "including but not limited to", and are not intended to exclude, for example, other additives, components, integers or steps.

5. Publication (S)

Throughout this application, various publications are referenced. To more fully and independently describe the state of the art to which this invention pertains, the contents of these publications are deemed to be incorporated herein by reference, individually, specifically and in their entirety, for the material(s) discussed in the sentence in which the reference is made.

6. Object

As used throughout, "subject" refers to an individual. Thus, a "subject" may include, for example, a domesticated animal such as a cat, dog, etc., a livestock (e.g., a cow, a horse, a pig, a sheep, a goat, etc.), an experimental animal (e.g., a mouse, a rabbit, a rat, a guinea pig, etc.); mammals, non-human mammals, primates, non-human primates, rodents, birds, reptiles, amphibians, fish, and any other animal. The subject may be a mammal, such as a primate or a human. The subject may also be a non-human.

Examples

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, temperature is in degrees Celsius or ambient temperature, and pressure is at or near atmospheric.