HK1059078A - Novel n-(2-phenyl-3-aminopropyl)naphtamides - Google Patents

Description

Novel N- (2-phenyl-3-aminopropyl) naphthamides

Background

Mammalian neurokinins comprise a class of peptide neurotransmitters found in the peripheral and central nervous systems. The three major neurokinins are Substance P (SP), neurokinin a (nka) and neurokinin b (nkb).

At least NKA also exists in N-terminal expanded form. At least three receptor types are known for the three major neurokinins. Based on their relative selectivity for neurokinin agonists SP, NKA and NKB, these receptors are classified as neurokinin 1 (NK) respectively₁) Neurokinin 2 (NK)₂) And neurokinin 3 (NK)₃) A receptor.

It is now recognized that anxiety, stress and depression are associated disorders (File SE Pharmacol, Biochem)&Behavior 54/1: 3-12, 1996). Furthermore, these complex emotional states cannot be simply attributed to a deficiency of a single neurotransmitter, although a major role has been attributed to 5-HT (Graeff et al, Pharmacol, Biochem)&Behavior 54/1: 129-141, 1996). Substance P (SP) is a first neuropeptide identified in mammalian brain, and it is now well recognized that all three tachykinins can be found in the CNS (Iversen LL J. psychopharmacol 3/1: 1-6, 1989), particularly in stritonigel neurons, the hypothalamus and the forebrain borders (supra). NK have also been identified in the brain₁And NK₃Receptors (Beaujouan et al, Neurosci.18: 857-ketone 875, 1986). Related NK in brain₂The existence of receptors is also controversial, although recent evidence suggests that receptors are localized in at least compartments (Steinberg et al, Eur J Neurosci 10/7: 2337-451998).

Pharmacological evidence supports the accumulation of NK by various animal behavioral tests₁Or NK₂The role of the receptor in anxiety disorders (see, e.g., table 1). However, animal models of depression are now rarely used to determine the potential efficacy of NK receptor antagonists. SP stimulates the turnover of 5-HT, the other neurotransmitter involved in depression, in the nucleus pulposus, which is believed to be the region associated with the depressive phenomenon (Forchetti et al, J.neurohem.38: 1336-1341, 1982). SP induces a hemodynamic stress response when injected centrally into the nucleus responsible for controlling mood and stress, a peptide implicated in hypertension-induced stress (Ku et al, Peptides; 19/4: 677-82, 1998). Furthermore, an increase in both heart rate and mean arterial blood pressure induced under physical stress may be in rodentsBy central administration of NK₁Receptor antagonists to block (Culman et al, Pharmacol Exp Ther 280/1: 238-46, 1997). TABLE 1 neurokinin receptor antagonist Activity in behavioral tests for anxiety/Depression

Authors refer to Compounds (receptor class) Behavioral testing ResultsTeixeira et al, Eur J NK₁Agonists&Elevated positive maze agonist Pharmacol FK888 (NK)₁) (plus-maze) anxiety antagonist-5; 311(1): 7-14, 1996 SR⁴8968(NK₂) Anxiolytic File Pharm Bio CGP49823 (NK)₁) Population interaction anxiolytic 58 (3): 747-752, 1997.

Vassout et al CGP49823 (NK)₁) Population interaction anxiolytic neuropeps 26/S test with elevated positive inactivity

1: 38, 1994, maze forced swimming test antidepressant

(depression model) (only 30mg/kg bid) Stratten et al, GR¹00679(NK₂) Light-dark box anxiolytic eur.j.pharmacol.sr⁴8968(NK₂)250：R¹1-12，1993.

Walsh, etc. GR¹59987(NK₂) SR light-dark box anti-focusPsychopharmacogolog of anxiety⁴8968(NK₂) Anti-anxiety y 121 of marmoset human invaders: 186-191, 1995

Description of the invention

The present invention relates to diaminopropyl compounds; a method of using the compound in the treatment of a disease, the use of the compound in the manufacture of a medicament; and to pharmaceutical compositions containing said compounds. These compounds antagonize neurokinin 1 (NK)₁) Pharmacological effects of the receptor. These compounds are effective when antagonism is desired. The compounds are therefore of value in the treatment of those diseases in which substance P is involved, for example in the treatment of major depressive disorder (majordepressive disorder), major anxiety disorder, stress disorder, major depressive disorder with anxiety, eating disorders, bipolar disorders, substance use disorder (substention use disorder), schizophrenia, psychosis, movement disorders, cognitive disorders, depression and/or anxiety, mania or mild mania, aggressive behavior, obesity, emesis, rheumatoid arthritis, alzheimer's disease, cancer, edema, allergic rhinitis, inflammation, pain, gastrointestinal hypermotility, huntington's chorea, Chronic Obstructive Pulmonary Disease (COPD), hypertension, migraine, bladder hypermotility, or urticaria.

Accordingly, the present invention provides a compound of the formula

The compounds of the invention may have multiple chiral centers, for example in the-CH (Ph-X)¹，X²) -. The present invention includes antagonizing NK₁All isomers, diastereomers and mixtures thereof.

in-CH (Ph-X)¹，X²) The preferred configuration of (a) is as follows:

X¹and X²Independently hydrogen, methyl or halogen. More preferably, X¹And X²Independently is hydrogen or halogen, provided that X¹Or X²At least one of (a) and (b) is halogen. Most preferably, X¹And X²And is also chlorine. In a preferred aspect Ph-X¹，X²Is 3, 4-dichlorophenyl.

R¹Is H or CH₃。

R²Is H, halogen, -OR⁷Or C_1-4An alkyl group. In one embodiment, R²is-OR⁷Or C_1-4An alkyl group.

R³Is H, halogen, -OR⁷or-CN. In one embodiment, R³is-CN.

R⁴Is H, halogen, -OR⁷Or C_1-4An alkyl group. In one embodiment, R⁴Is H or C_1-4An alkyl group.

R⁵Is H, C_1-8Alkyl, -C (═ O) R⁹、-C(＝O)OR⁸、-C(＝O)N(R⁶)R⁸、-S(＝O)_nR⁹Cyanoguanidino or C_1-4An acylguanidino group.

R⁶Independently in each occurrence is H or C_1-6An alkyl group.

R⁷Independently in each case C_1-6An alkyl group.

R⁸Is H, substituted by 0, 1 or 2 groups selected from-OH and-NHR⁶C substituted by a substituent of_1-6Alkyl or C substituted by 1, 2, 3 or 4 halogen atoms_1-3An alkyl group.

R⁹Independently each occurrence is substituted by 0, 1 or 2 substituents selected from-OH and-NHR⁶C substituted by a substituent of_1-6Alkyl, or C substituted by 1, 2, 3 or 4 halogen atoms_1-3An alkyl group.

n is 0, 1 or 2.

Another aspect of the invention relates to compounds having the general formula:- - (Y- -O) - -in which R¹-R⁶And X¹And X²As described above-the use thereof for the preparation of a medicament for the treatment of a disease selected from: major depressive disorder, major anxiety disorder, stress disorder, major depressive disorder with anxiety, eating disorder, bipolar disorder, substance use disorder, schizophrenia, psychosis, movement disorder, cognitive disorder, depression and/or anxiety, mania or hypomania, aggressive behavior, obesity, emesis, rheumatoid arthritis, Alzheimer's disease, cancer, edema, allergic rhinitis, inflammation, pain, gastrointestinal hypermotility, Huntington's chorea, COPD, hypertension, migraine, overactive bladder or urticaria.

Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of an NK having the structure₁A pharmaceutical composition of an antagonist and a pharmaceutically acceptable carrier or diluent:- - (Y- -O) - -in which R¹-R⁶And X¹And X²As described above- -.

Yet another aspect of the invention relates to a method of treating: major depressive disorder, major anxiety disorder, stress disorder, major depressive disorder with anxiety, eating disorder, bipolar disorder, substance use disorder, schizophrenia, psychosis, movement disorder, cognitive disorder, depression and/or anxiety, mania or hypomania, aggressive behavior, obesity, emesis, rheumatoid arthritis, Alzheimer's disease, cancer, edema, allergic rhinitis, inflammation, pain, gastrointestinal hypermotility, Huntington's chorea, COPD, hypertension, migraine, overactive bladder or urticaria,

the method comprises administering an effective amount of an NK having the structure₁Antagonists- - (Y- -O) - -in which R¹-R⁶And X¹And X²As defined above.

Specific compounds of the invention are provided in the examples below.

Unless otherwise stated, C_y-zAlkyl refers to an alkyl chain containing a minimum total number of carbon atoms Y and a maximum total number of carbon atoms Z. These alkyl chains may be branched or straight, cyclic, acyclic or a combination of cyclic and acyclic. For example, the following substituents will be encompassed by the general description "C_4-7In the alkyl group ":pharmaceutically acceptable salts can be prepared from the corresponding acids in a conventional manner. Non-pharmaceutically acceptable salts may be used as intermediates and are a further aspect of the invention.

The term "oxo" refers to double-bonded oxygen (═ O).

Some of the compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases, and such salts are within the scope of the present invention. Examples of said acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclohexylsulfamate, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-isethionate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, picrate, pivalate, propionate, quinic acid, salicylate, stearate, succinate, sulfamate, sulfanate, sulfate, tartrate, tosylate (p-toluenesulfonate), and undecanoate salts. Basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, and the like. In addition, basic nitrogen-containing organisms may be quaternized with agents such as: lower alkyl halides such as methyl, ethyl, propyl and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl sulfate, diamyl sulfate; long chain halides such as decyl, dodecyl, myristyl and stearyl halides; aralkyl halides such as benzyl bromide and others. Non-toxic physiologically acceptable salts are preferred, others are also useful, for example in isolating or purifying the product.

The salts may be formed in conventional manner, for example by reaction of the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which may be removed by vacuum or freeze drying, or by ion exchange of an existing salt with another anion on a suitable ion exchange resin.

For use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment (including prophylactic treatment) of mammals, including humans, pharmaceutical compositions are generally formulated in accordance with standard pharmaceutical practice.

Thus in a further aspect the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may be administered in a standard manner in the disease state to be treated, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation. For these purposes, the compounds of the invention may be formulated in a manner known per se in the art, for example in the form of tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, jellies, nasal sprays, suppositories, finely divided preparations and aerosols or nebulisers for inhalation, and in the form of sterile aqueous or oily solutions or suspensions or sterile emulsions for parenteral use, including intravenous, intramuscular or infusion.

In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also contain, or be administered in combination (simultaneously or sequentially), with one or more pharmacological agents of value in the treatment of one or more of the disease states described herein.

The pharmaceutical compositions of the invention are generally administered to humans, for example, to achieve a daily dose of 0.01-25mg/kg body weight (and preferably 0.1-5mg/kg body weight). Such daily dosages may be administered as necessary in divided doses, the precise amounts and routes of administration of the compounds being dependent on the weight, age and sex of the patient to be treated and the particular disease state being treated according to principles well known in the art.

Typically, a unit dosage form will contain from about 1mg to about 500mg of a compound of the invention. For example tablets or capsules for oral administration will generally contain up to 250mg (and usually 5 to 100mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, for administration by inhalation, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in a daily dose of 5-100mg, which administration may take a single dose or divided into 2 to 4 administrations per daily dose. In another embodiment, for administration by intravenous or intramuscular injection or infusion, sterile solutions or suspensions containing up to 10% w/w (and usually 5% w/w) of a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used.

In a further aspect, therefore, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of therapeutic treatment of the human or animal body.

In yet another aspect the invention provides a method of treating wherein NK₁A method of treating a disease condition which is effectively antagonized by a receptor, which comprises administering to a warm-blooded animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of NK therein₁Use of a medicament for a disease condition for which a receptor is effective.

The compounds of formula (I) and pharmaceutically acceptable salts thereof may be prepared by the methods described and exemplified herein, by analogous methods, and by methods well known in the chemical arts. The starting materials for these processes may be prepared, if not commercially available, by a method selected from the chemical arts and using the same or similar techniques as the synthesis of known compounds.

It is well known in the art how to prepare optically active forms (e.g., by resolution of the racemate or by synthesis from optically active starting materials) and how to determine NK by standard assays known in the art and those described below₁The nature of the antagonist.

Some of the individual compounds falling within the scope of the present invention may have double bonds. The expression of double bonds in the present invention refers to both E and Z isomers including double bonds. In addition, certain materials within the scope of the present invention may contain one or more asymmetric centers. The present invention includes the use of any optically pure stereoisomer as well as any combination of stereoisomers.

In general, compounds with 2-substituted naphthamides may exist as mixtures of conformers (atropisomers); this is certainly due to The slowing of rotation around The naphthamide and/or aryl linkages ("The Chemistry of chiral Isomers"; Oki, M.; Springer Verlag, NY; 1993). Where the individual atropisomers have been separated and defined chemical and biological properties observed. The compounds of the present invention include mixtures of atropisomers and monomers of atropisomers.

The following biological test methods, data and examples serve to exemplify and further illustrate the invention.

The utility of the compounds of the present invention or pharmaceutically acceptable salts thereof (hereinafter collectively referred to as "compounds") can be demonstrated by standard testing and clinical studies, including those described in the following publications.SP receptor binding assay (assay A)

Use of expression of human NK in Mouse Erythroleukemia (MEL) cells₁Receptor assays may demonstrate that the compounds of the invention antagonize SP in NK₁The ability of the receptor to bind. According to the followingMethods for isolation and characterization of human NK₁The characteristics of the receptor: hopkins, et al "human lung NK₁Isolation and characterization of receptor cDNA "biochem. biophysis. res. comm., 1991, 180, 1110-; and expression of NK in Mouse Erythroleukemia (MEL) cells using an assay B similar to that described below₁A receptor.Neurokinin A (NKA) receptor binding assay (assay B)

Use of human NK expressing Mouse Erythroleukemia (MEL) cells₂The receptor can prove that the compound of the invention antagonizes NKA in NK₂The properties of the binding of the receptor are shown in: aharony, D.et al "isolation and pharmacological characterization of hamster neurokinin A receptor cDNA" molecular Pharmacology.1994, 45, 9-19.

Compound pair in NK₁And NK₂Selectivity of binding at a receptor can be demonstrated by measuring its binding at other receptors, e.g., on NK cells, using standard assays₃Deuterated derivatives of NKB are used in tissue samples where the receptor is selective. Generally, the tested compounds of the invention proved to have significant differences in test a and test B, while Ki's typically measured to be equal to or very less than 1 mM.Rabbit pulmonary artery：NK₁In vitro functional assay (assay C)

The antagonist agonist Ac- [ Arg⁶，Sar⁹，Met(O₂)¹¹]The performance of the role of substance P (6-11), ASMSP, in non-tissue can be demonstrated as follows.

Male New Zealand white rabbits were euthanized by intravenous injection of 60mg/kg pentobarbital (50mg/mL) into the ear vein. Pentobarbital intravenously entered as described above was heparinized at 0.0025mL/kg (1000 units/mL) for anticoagulation purposes. The chest is opened from the top of the rib cage towards the sternum and the heart, lungs, part of the trachea are removed. The pulmonary artery is separated from the rest of the tissue and bisected into a pair.

The segments were suspended between stainless steel stirrups so as not to remove any endothelium, and placed in a water jacket (37.0) containing a physiological saline solution of the following composition (mM)C) tissue bath: NaCl, 118.0; KC1, 4.7; CaCl₂，1.8；MgCl₂，0.54；NaH₂PO₄，1.0；NaHCO₃25.0; glucose, 11.0; indomethacin, 0.005 (inhibition of cyclooxygenase); and dl-propranolol, 0.001 (blocking P receptor); continuously charging 95% O₂-5％CO₂And (4) qi. The reaction was measured on a Grass wave-graph by a Grass FT-03 sensor.

The initial tension applied to each tissue was 2 grams, which was maintained over an equilibrium period of 1.0 hour. The tissue was rinsed with saline solution at 15 minute intervals. The following treatments were added at 30 and 45 minutes of rinsing: 1X 10^-6M Thioprhan (retardation E.C.3.4.24.11), 3X 10^-8M (S) -N- [2- (3, 4-dichlorophenyl) -4- [ 4-2-oxoperhydropyrimidin-1-yl) piperidinyl]Butyl radical]-N-methylbenzamide (blocking NK)₂Receptor), and a specified concentration of test compound. At the end of the 1.0 hour equilibration period, 3X 10 was added over a 1.0 hour period^-6M phenylephrine hydrochloride. At the end of 1.0 hours, dose relaxation curves for ASMSP were plotted. Each tissue was treated as an individual and considered complete when it failed to relax further at 2 consecutive doses. When the tissue is complete, add 1X 10^-3M papaverine reaches maximum relaxation.

Percent inhibition was determined when the tested compounds produced a statistically significant (p < 0.05) reduction in total relaxation, which was calculated using the total relaxation of papaverine as 100%. The apparent dissociation constant (K) at each test concentration was calculated using a standard formula_B) The potency of the compounds was determined:

K_Bas an antagonist]V (dose ratio-1) wherein dose ratio is inverse log [ (antagonist-log compound-free molar EC)₅₀) - (-log molar EC of Compound used₅₀)]。K_BValues can be converted to negative logarithms and expressed as-log molar K_B(i.e., pK)_B). For this evaluation, full concentration-response curves of agonist in the presence and absence of compound were obtained using paired pulmonary artery rings. The potency of the agonist is determined at half of its own maximum relaxation in each curveIn (1). EC (EC)₅₀Values were converted to negative controls and expressed as-log molar EC₅₀。NK₂In vitro functional assay (assay D)

The compounds of the present invention antagonize agonist [ beta-ala 8]The role of NKA (4-10), BANK, in non-tissue can be confirmed as follows. Male New Zealand white rabbits were euthanized by intravenous injection of 60mg/kg pentobarbital (50mg/mL) into the ear vein. Pentobarbital intravenously entered as described above was heparinized at 0.0025mL/kg (1000 units/mL) for anticoagulation purposes. The chest was opened from the top of the rib cage towards the sternum and a small incision was made into the heart to allow insertion of polyethylene tubes (PE 260 and PE190, respectively) into the left and right pulmonary arteries. The pulmonary artery is isolated from the remaining tissue, followed by abrading the intimal surface to remove the endothelium, and bisecting the cut into pairs. The segments were suspended between stainless steel stirrups and placed in a water-jacketed (37.0 ℃) tissue bath containing a physiological saline solution of the following composition (mM): NaCl, 118.0; KC1, 4.7; CaCl₂，1.8；mgCl₂，0.54；NaH₂PO₄，1.0；NaHCO₃25.0; glucose, 11.0; indomethacin, 0.005 (inhibition of cyclooxygenase); and dl-propranolol, 0.001 (blocking P receptor); continuously charging 95% O₂-5％CO₂And (4) qi. The reaction was measured on a Grass wave-graph by a Grass FT-03 sensor.

The initial tension applied to each tissue was 2 grams, which was maintained over an equilibrium period of 1.0 hour. After a 45 minute equilibration period, a 60 minute 3X 10 dose was administered^-2M KCl to test the viability of the tissue. The tissue was then rinsed thoroughly for 30 minutes. The concentration of the test compound was then added over 30 minutes to complete the cumulative dose response curve for BANK. Each tissue was treated as an individual and considered complete when it failed to contract further at 2 consecutive doses. When the tissue is complete, add 1X 10^-3M BaCl₂Maximum shrinkage is reached.

Percent inhibition was determined when the tested compounds produced a statistically significant (p < 0.05) reduction in total contraction using BaCl₂The total shrinkage of (c) was calculated as 100%. Using standardsThe equation is calculated by calculating the apparent dissociation constant (K) at each test concentration_B) The potency of the compounds was determined:

K_Bas an antagonist]V (dose ratio-1) wherein dose ratio is inverse log [ (antagonist-log compound-free molar EC)₅₀) - (-log molar EC of Compound used₅₀)]。K_BValues can be converted to negative logarithms and expressed as-log molar K_B(i.e., pK)_B). For this evaluation, full concentration-response curves of agonist in the presence and absence of compound were obtained using paired pulmonary artery rings. Agonist potency is determined at half its own maximum relaxation in each curve. EC (EC)₅₀Values were converted to negative controls and expressed as-log molar EC₅₀。 NK₁And NK₂In vivo functional assay

Compounds as NK₁And/or NK₂The activity of antagonists of the receptor can also be demonstrated in vivo in test animals as follows: buckner et al "tachykinin NK for direct acting agonists and direct acting mimetics capsaicin, 5-hydroxytryptamine and 2-methyl-5-hydroxytryptamine induced bronchoconstriction in anesthetized guinea pigs₁And NK₂Differential blockade of receptor antagonistsJ.Pharm.Exp. The.1993.Vol 267(3). pp.l168-1175, the assay was performed as follows.

The compounds were tested in anesthetized guinea pigs that were pretreated intravenously with indomethacin (10mg/kg, 20 minutes), propranolol (0.5mg/kg, 15 minutes) and thiorphan (10mg/kg, 10 minutes).

Antagonists or vehicles were administered intravenously and orally 30 and 120 minutes before increasing the concentration of agonist, respectively. The agonist in these studies was ASMSP (Ac- [ Arg)⁶，Sar⁹，Met(O₂)¹¹SP (6-11)) and BANK (B-ala-8 NKA 4-10).

Intravenously administered ASMSP vs NK₁The receptor is selective and BANK is on NK₂The receptor is selective. The maximum response is defined as zero conductance (G)_L1/Rp). Calculating ED₅₀Value (G)_LDose of agonist obtained at 50% reduction to baseline) and conversion to negative control (-logED)₅₀). ED obtained in the Presence (P) and absence (A) of an antagonist₅₀The values can be used to calculate the dose ratio (P/A), an expression of potency. Data are expressed as mean ± SEM and significant differences were determined using ANOVA/Tukey-Kramer and student t-test, whereas p < 0.05 was considered statistically significant.

The compounds of the present invention have significant activity in the above assays and are believed to be effective in treating those in which NK is implicated₁And/or NK₂Diseases of the receptor, for example in the elimination and related disorders.

Examples

The invention is now illustrated by the following non-limiting examples, in which, unless otherwise stated:

(i) temperature means degrees Celsius (. degree. C.); unless otherwise stated, the operation is carried out at room temperature or at ambient temperature, i.e. within 18-25 ℃;

(ii) drying the organic solution with anhydrous magnesium sulfate; the evaporation of the solvent is carried out using a rotary evaporator under reduced pressure (600-4000 Pa; 4.5-30mmHg) and in a bath at a temperature of at most 60 ℃;

(iii) chromatography refers to flash chromatography on silica gel; thin Layer Chromatography (TLC) was performed on silica gel plates;

(iv) generally, the course of the reaction is monitored by TLC and the reaction time is by way of example only;

(v) melting point is not modified and (dec) means decomposition;

(vi) the final product had satisfactory proton Nuclear Magnetic Resonance (NMR) spectra;

(vii) when given, NMR data is in the form of delta values for the main identified protons expressed in parts per billion (ppm) relative to Tetramethylsilane (TMS) as an internal standard and data is in deuterated chloroform (CDCl) at 300MHz₃) Measured as a solvent; conventional abbreviations for signal peaks are used; reporting directly observed shifts for AB spectra; the coupling constant (J) is expressed in Hz; ar refers to a designated aromatic proton;

(viii) reduced pressure is expressed as absolute pressure in pascals (Pa); high pressure is expressed as gauge pressure in bar;

(ix) solvent ratio is expressed in terms of volume to volume (v/v); and

(x) Mass Spectrometry (MS) was performed with an automated system using Atmospheric Pressure Chemical Ionization (APCI). Typically, only spectra where maternal mass was observed were reported. The lowest macroion reports a molecule whose isotopic fragmentation produces multiple mass spectral peaks (e.g., when chlorine is present).

Terms and abbreviations: the solvent mixture composition is expressed as a volume percentage or volume ratio. In the case of very complex NMR spectra, only the identification signal is reported. atm ═ atmospheric pressure, Boc ═ tert-butoxycarbonyl, Cbz ═ benzyloxycarbonyl, DCM ═ dichloromethane, DIPEA ═ diisopropylethylamine, DMF ═ N, N-dimethylformamide, DMSO ═ dimethyl sulfoxide, Et₂O-diethyl ether, EtOAc-ethyl acetate, equiv, h-h, HPLC-high performance liquid chromatography, min-min, NMR-nuclear magnetic resonance, psi-lb/sq-in, TFA-trifluoroacetic acid, THF-tetrahydrofuran.

Standard reductive amination refers to a typical process in which a solution of amine (1-1.2equiv.), aldehyde (1-1.2equiv.), and acetic acid (2equiv.) is stirred in methanol for 5-60 minutes, after which NaBH is added₃CN (1.7 equiv.). The reaction was optionally concentrated after 1-16 h, dissolved in DCM and washed with saturated sodium bicarbonate and then purified by chromatography.

Standard Swern oxidation refers to oxidation according to manucuso, AJ; huang, SL; swern, D; chem.; 1978, 2840 to the corresponding aldehyde.

The standard method for the formation of acid chlorides is typical, where a solution of a substituted carboxylic acid in DCM is stirred with 1-1.2equiv oxalyl chloride and catalytic amount of DMF for 1-12h, concentrated under reduced pressure, and used without effective purification.

Standard acylation refers to the typical process, in which the acid chloride (1-1.2equiv.) is brought into a stirred solution of the amine (1-1.2equiv.) and triethylamine (2equiv.) in DCM. After 1-16 h the reaction was selectively concentrated, dissolved in DCM and washed with saturated sodium bicarbonate and subsequently purified by chromatography.

Care was taken when the final compound was converted to citrate, mixing the free base with citric acid (1.0equiv.) in methanol, concentrating under reduced pressure and drying under vacuum (25-70 ℃). When indicated by slave Et₂When the compound is isolated by filtration, the citrate salt of the compound is dissolved in Et₂Stirring in O for 12-18 hours, taking out by filtration, and using Et₂Washed with O and dried under vacuum at 25-70 ℃.

Care was taken to convert HCl to Et as the final compound was converted to the hydrochloride salt₂The solution in O was added to a solution of the pure free base in DCM or methanol while stirring. The resulting precipitate was collected by filtration and dried under vacuum.

Some compounds with 2-substituted naphthalene carboxamides exist as mixtures of conformers (atropisomers); this is certainly caused by slowing down the rotation around the amide and/or aryl bonds. Such compounds typically show multiple peaks in HPLC chromatograms and highly complex NMR spectra. In some cases, each component of the atropisomeric mixture should be purified by reverse phase HPLC and its properties evaluated independently.

Analytical HPLC conditions were as follows: a Hewlett Packard HP1100 system using Luna C18(2) 4.6X 75mm, 3 micron column (Phenomenex; Torrance, Calif.) with the following gradient: 0-0.5 min; 20% solvent B, followed by a ramping up to 85% solvent B over 15 minutes with a fixed flow rate of 2 mL/min (solvent A: water with 0.1% TFA; solvent B: methanol with 0.1% TFA), using UV detection at 255 nm.

Mass spectrometry data; (APCI) m/z. did not account for multiple peaks resulting from isotope separations; data corresponding to the main isotopic abundance signal of the protonated molecular ion cluster are given (unless otherwise indicated).

EXAMPLE 1N- [2- (S) - (3, 4-dichlorophenyl) -3-trifluoroacetylaminopropyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide

N- [2- (S) - (3, 4-dichlorophenyl) -3-carboxypropyl ] salt using oxalyl chloride under standard defined conditions]-N-methyl-3-cyano-2-methoxy-1-naphthamide (0.278g, 0.58mmol) was converted to the corresponding acid chloride. The acid chloride, NaN, were reacted at 0 ℃ in a process based on Pfister, J.R, and Wyman, W.E., Synthesis, 1983, 38₃(0.049g, 0.76mmol) and (Bu)₄NBr (30mg) was stirred in a mixture of water (2mL) and DCM (4mL) for 2 h. The organic layer was dried and mixed with TFA (0.068mL, 0.88mmol) and heated at reflux overnight. The solution was saturated NaHCO₃Washing, drying, concentration and purification by chromatography (0-10% MeOH in DCM) gave the product as a white foam (0.206g).¹H NMR(300MHz，DMSO-d₆)δ9.51(m)，9.32(m)，8.69-8.63(m)，8.07-6.41(m)，4.48-4.43(m)，4.05-2.27(m)；MS APCI，m/z＝538(M⁺)；HPLC 12.50，12.78，13.49。

The desired N- [2- (S) - (3, 4-dichlorophenyl) -3-carboxypropyl ] -N-methyl-3-cyano-2-methoxy-1-naphthamide was prepared as follows. (a) 3-hydroxy-4-iodo-2-naphthoic acid

A mixture of NaOH (2.12g) in methanol (100mL) was stirred until the solution was homogeneous. Sodium iodide (3.98g) and 3-hydroxy-2-naphthoic acid (5.00g) were added and stirred for 30 minutes. The resulting suspension was cooled to 0 ℃ and an aqueous solution of 5.25% (w/v) sodium hypochlorite was added dropwise and stirring was continued for 1 hour. Saturated sodium thiosulfate (25mL) was added and after 5 minutes the solution was acidified to pH2 by addition of 6N HCl, resulting in a yellow precipitate, which was filtered and washed with water (50 mL). The precipitate was transferred to a round bottom flask, dissolved in methanol (70mL) and toluene (100mL), concentrated, redissolved in methanol (70mL) andtoluene (100mL) and concentration gave the product as a yellow solid (6.26 g). MS M/z 313(M-1).¹H NMR(DMSO-d₆): δ 12.41 (width, 1H), 8.63(s, 1H), 8.05-7.97(m, 2H), 7.70(m, 1H), 7.42(m, 1H). (b) 3-methoxy-4-iodo-2-naphthoic acid methyl ester

A solution of 3-hydroxy-4-iodo-2-naphthoic acid (8.0g), dimethyl sulfate (8.03g), potassium carbonate powder (8.80g), and dry acetone (150mL) was heated under reflux for 18 hours. The solution was cooled to room temperature, triethylamine (15mL) was added, and stirring was continued for 30 minutes. The solution was filtered through a pad of celite and washed with dry acetone (50 mL). The filtrate was concentrated to a yellow oil, diluted with EtOAc and washed successively with 1N HCl (100mL), saturated aqueous sodium bicarbonate (100mL) and brine (100 mL). The organic layer was dried (sodium sulfate), filtered, concentrated, and purified by chromatography (0-10% EtOAc in hexanes) to give the product as a yellow oil (5.53 g).¹H NMR(DMSO-d₆) δ 8.47(s, 1H), 8.09(m, 2H), 7.74(m, 1H), 7.61(m, 1H), 3.94(s, 3H), 3.87(s, 3H). (c) 1-iodo-3-cyano-2-methoxynaphthalene

Based on Wood, JL; khatri, NA; weinreb, SM; tetrahedron Lett; 51, 4907(1979) methyl 3-methoxy-4-iodo-2-naphthoate (5.0g) was suspended in xylene (100mL), cooled to 0 deg.C, a solution of dimethylammoniumate (about 37mmol) was added and the solution was heated at reflux for 2.5 hours. The solution was then cooled to 0 ℃ and acidified to pH2 by addition of 1N HC1 and extracted with EtOAc (3X 100 mL). The combined EtOAc extracts were washed with saturated aqueous sodium bicarbonate (150mL) and brine (150mL), dried (sodium sulfate), filtered, concentrated, and purified by chromatography (1: 1 EtOAc: DCM, followed by 10-20% EtOAc in DCM) to give the product as a white solid (3.29g).¹HNMR(DMSO-d₆): δ 8.69(s, 1H), 8.24-8.04(m, 2H), 7.91-7.81(m, 1H), 7.76-7.65(m, 1H), 3.99(s, 3H); MS M/z 311(M + H). (d) 3-cyano-2-methoxy-1-naphthoic acid methyl ester

To a solution of 1-iodo-3-cyano-2-methoxynaphthalene (0.250g), Pd (OAc)₂(0.018g), triethylamine (0.081g) and methanol(20mL) of the suspension was sparged with carbon monoxide for 25 minutes, after which it was stirred at 70 ℃ under carbon monoxide (1atm) for 18 hours. The solution was cooled, filtered, rinsed with methanol (20mL) and DCM (20mL), concentrated, pre-adsorbed on silica gel (1g) and purified by chromatography (0-10% EtOAc in hexane) to give the product as a white solid (0.113g).¹HNMR(DMSO-d₆)：δ8.78(s，1H)，8.12-8.09(m，1H)，7.84-7.78(m，2H)，7.70-7.63(m，1H)，4.02-4.01(m，6H)；IR(cm^-1): 2228, 1724, 1296, 1236, 1208, 1017. (e) 3-cyano-2-methoxy-1-naphthoic acid

A solution of methyl 3-cyano-2-methoxy-1-naphthoate (0.113g) and LiOH HzO (0.0196g) in THF (3mL), water (1mL) and methanol (1mL) was stirred at room temperature overnight. The solution was diluted with saturated sodium bicarbonate and Et₂And (4) extracting. The aqueous layer was acidified to pH2 by addition of 1N HCl and Et₂And (4) extracting. The organic layer was washed with water (30mL) and brine (40mL), dried (sodium sulfate), filtered, and concentrated to a white solid¹H NMR(DMSO-d₆): δ 14.06 (width, 1H), 8.08-8.02(m, 1H), 7.83-7.76(m, 2H), 7.69-7.63(m, 1H), 4.02(s, 3H); MS m/z: 226 (M-1). (f) N- [2- (S) - (3, 4-dichlorophenyl) -4-hydroxybutyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide

Mixing N- [2- (S) - (3, 4-dichlorophenyl) -4-hydroxybutyl]A solution of-N-methylamine (Miller, SC; WO9512577) in DCM was mixed with a 10% aqueous solution of sodium bicarbonate. The mixture was cooled to 0 ℃ and a solution of 3-cyano-2-methoxy-1-naphthoyl chloride in DCM was added dropwise over 30 minutes. After stirring overnight at room temperature, the organic layer was concentrated and purified by column chromatography to give N- [2- (S) - (3, 4-dichlorophenyl) -4-hydroxybutyl ] -N- [2- (S) - (3, 4-dichlorophenyl) -4-hydroxy-butyl ] -N-tert-butyl-phenyl]-N-methyl-3-cyano-2-methoxy-I-naphthamide.¹HNMR(300MHz，DMSO-d₆)δ8.67-8.58(m)，8.07-8.00(m)，7.72-7.65(m)，7.64-7.43(m)，7.42-7.34(m)，7.02-7.01(m)，6.98-6.87(d)，6.77-6.74(d)，6.31-6.28(d)，4.55-4.52(t)，4.354.34(t)，4.03-3.92(m)，3.78-3.72(m)，3.68(s)，3.45-3.37(m)，3.29-2.89(m)，2.73(s)，2.592.49(m)，1.91-1.78(m)，1.58-1.46(m)；MS APCI，m/z＝457(M⁺). (g) N- [2- (S) - (3, 4-dichloro) benzenePhenyl) -3-carboxypropyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide

A solution of pyridinium dichromate (4.5g) was added to N- [2- (S) - (3, 4-dichlorophenyl) -4 hydroxybutyl) -4 according to Corey, EJ and Schmidt, g, Tetr]A solution of-N-methyl-3-cyano-2-methoxy-1-naphthamide (1.5g) in DMF (20mL) was stirred for 4 hours. After filtration, dilution with ethyl acetate and extraction of the filtrate with water, the product was purified by flash chromatography (80%).¹H NMR(300MHz，DMSO-d₆)δ12.28(s)，8.66-8.62(m)，8.09-7.95(m)，7.78-7.76(m)，7.72-7.56(m)，7.52-7.45(m)，7.40-7.30(m)，7.11-7.10(d)，7.04(s)，7.01(s)，6.87-6.84(d)，4.53-4.45(t)，3.94(s)，3.92(s)，3.68(s)，3.44-3.27(m)，3.11(s)，3.02(s)，2.76-2.73(m)，2.62(s)，2.55-2.38(m)；MS APCI，m/z＝471(M⁺)。Example 2N- [2- (S) - (3, 4-dichlorophenyl) -3-aminopropyl]-N-methyl-3-cyano-2-methoxy-1-naphthamide

A solution of the starting material from example 1 (1.00g, 1.85mmol) and 1N NaOH (3.7mL, 3.7mmol) was stirred in MeOH (5mL) for 2h, then extracted into EtOAc. The organic layer was dried, concentrated and purified by chromatography (0-10% MeOH in DCM) to give the product as a pale yellow foam (0.569g) and converted to citrate.¹H NMR(300MHz，DMSO-d₆)δ8.70-8.63(m)，8.09-6.80(m)，6.54-6.51(d，J＝8.4Hz)，4.39-4.31(m)，4.07-2.27(m)；MS APCI，m/z＝442(M⁺)；HPLC 8.77，9.24，10.24，10.38。Example 3N- [2- (S) - (3, 4-dichlorophenyl) -3-N ', N' -dimethylaminopropyl radical]-N-methyl-3-cyano-2-methoxy-1-naphthamide

A solution of the starting material from example 2 (0.100g, 0.22mmol), 37% formaldehyde in water (2mL) and 99% formic acid (0.069mL, 1.80mmol) was dissolvedThe solution was heated to reflux for 18 hours. To the cooled mixture was added 1M HCl (1mL) and 1M NaOH adjusted to pH 11, followed by extraction with EtOAc, washing with brine, drying, concentration and purification by chromatography (0-6% MeOH in DCM containing 0.1% concentrated NH)₄OH) to give the product as a white foam (97mg) which was converted to citrate.¹H NMR(300MHz，DMSO-d₆)δ 8.69-8.63(m)，8.12-6.86(m)，6.33-6.30(d，J＝8.4Hz)，4.50-4.42(m)，4.05-1.96(m)；MS APCI，m/z＝470(M⁺)；HPLC 8.63，9.00，10.05，10.28。Example 4N- [2- (S) - (3, 4-dichlorophenyl) -3- (N' -cyanoguanidino) propyl)]-N-methyl-3-cyano-2-methoxy-1-naphthamide

1N HCl (0.339mL, 0.339mmol), 1-butanol (0.70mL) and NaN (CN)₂(0.034g, 0.389mmol) was stirred for 5 minutes, followed by addition of the starting material from example 2 (0.150g, 0.339 mmol). The solution was heated at reflux for 2h, stirred at rt overnight, concentrated, and purified by chromatography (0-4% MeOH in DCM) to give the product as a yellow solid (0.088g).¹H NMR(300MHz，DMSO-d₆)δ8.65-8.61(m)，8.08-6.46(m)，4.44-2.27(m)；MS(MALDI-TOF)，m/z＝509(M⁺)；HPLC 11.33，11.45，12.15，12.26。Examples R MS ^a HPLC ^b Salt forms ^c Synthesis of5-NHC (═ O) -51412.51, 12.81, 13.39C ethyl chloroformate^d

OCH₂CH₃6 -NHS(＝O)₂CH₃52010.98, 11.38, 12.16C methanesulfonyl chloride^d7 -NHC(O) N-51311.42, 11.78, 12.68C dimethylaminomethyl

(CH₃)₂Acyl chloride^d8 -N(CH₃) C (O) 55213.12, 13.35, 13.92C methyl iodide^e

CF₃9 -NHCH₃4568.73, 9.18, 10.18, 10.32A sodium hydroxide^{f a}Mass spectrometry data; (APCI) multiplet due to the m/z. isotope column was not taken into account; indicating the signal corresponding to the main isotopic abundance of the protonated molecular ion cluster (unless otherwise indicated).^bSee general experimental section for HPLC conditions, retention time in minutes; "nd" means not determined.^cSalt form: a, citrate; b, iodide; c; not suitable, D, fumarate; e, trifluoroacetic acid salt.^dThe acylating agent (acid chloride, chloroformate or sulfonyl chloride) was reacted with the starting material of example 2 using standard acylation conditions. In the case where the acylating agent is an aluminum formate or sulfonyl chloride, these agents replace the acid chloride in the general process.^eUsing typical conditions, a solution of the starting material of example 1 was stirred overnight in DMF with NaH (1 equiv.) and iodomethane (2equiv.), recovered by extraction, and purified by chromatography (50-100% DCM in hexane).^fThe feed of example 8 was reacted with methanolated NaOH according to the method described in example 2.Example 10N- [2- (S) - (3, 4-dichlorophenyl) -3-aminopropyl]-3-cyano-2-ethyl-1-naphthamide citrate (1: 1)

(a) To N- [2- (S) - (3, 4-dichlorophenyl) -3-carboxypropyl]-3-cyano-2-ethyl-1-naphthamide (0.51mmol) and triethylamine (1.1 equiv.) in acetonitrile (10mL)Diphenylphosphorylazide (1.4 equiv.) was added to the stirred solution of (1). After 3 hours at room temperature, the solution was heated (20 minutes at 65 ℃), allowed to cool again, and 10% HC1(1mL) in water was added. After stirring overnight, the mixture was concentrated, treated with saturated aqueous sodium bicarbonate, and extracted with EtOAc. The EtOAc extract was concentrated and the residue was purified by flash chromatography. Purified free base (22%) was converted to citrate and filtered from Et₂And (4) separating in O. MS APCI, M/z 426 (M)⁺) (free base); HPLC^a 15.0.^aThe analytical HPLC conditions used were as follows: a Hewlett Packard HP 1050 system using Zorbax RX-C8, 4.6X 250mm, 5 micron column, 30 ℃ with the following gradient: 0-0.5 min; 10% solvent B followed by a linear ramp up to 100% solvent B at 30 minutes with a fixed flow rate of 1.2 mL/min (solvent A: water with 0.1% TFA; solvent B: acetonitrile with 0.1% TFA); UV detection at 215 and 260 nm; the retention time is in minutes. (b) N- [2- (S) - (3, 4-dichlorophenyl) -3-carboxypropyl]-3-cyano-2-ethyl-1-naphthamide

N- [2- (S) - (3, 4-dichlorophenyl) -4-hydroxybutyl ] in acetone (10mL) over a period of several minutes]-3-cyano-2-ethyl-1-naphthamide (2.5mmol) in water was added to a chilled solution of Jones' reagent (2mL) in acetone (20mL) [ see "Reagents for organic Synthesis" (Fieser)&Fieser), Vol.1, Pg 142 and incorporated herein by reference]. After 2.5 h, the brown mixture was treated with isopropanol (4mL), stirred for 15 min, then treated with water and extracted with EtOAc. The EtOAc extract was concentrated to give the desired product (theoretical) as a tan. MS APCI, M/z 455 (M)⁺). (c) N- [2- (S) - (3, 4-dichlorophenyl) -4-hydroxybutyl]-3-cyano-2-ethyl-1-naphthamidePrepared from amino-alcohols by acylation in example 1(f) with an acid chloride.

Claims (8)

1. A compound having the formula or a pharmaceutically acceptable salt thereofWherein:

R¹is H or CH₃；

R²Is H, halogen, -OR⁷Or C_1-4An alkyl group;

R³is H, halogen, -OR⁷or-CN;

R⁴is H, halogen, -OR⁷Or C_1-4An alkyl group;

R⁵is H, C_1-8Alkyl, -C (═ O) R⁹、-C(＝O)OR⁸、-C(＝O)N(R⁶)R⁸、-S(＝O)_nR⁹Cyanoguanidino or C_1-4An acylguanidino group;

R⁶independently in each occurrence is H or C_1-6An alkyl group;

R⁷independently in each case C_1-6An alkyl group;

R⁸is H, substituted by 0, 1 or 2 groups selected from-OH and-NHR⁶C substituted by a substituent of_1-6Alkyl or C substituted by 1, 2, 3 or 4 halogen atoms_1-3An alkyl group;

R⁹independently each occurrence is substituted by 0, 1 or 2 substituents selected from-OH and-NHR⁶C substituted by a substituent of_1-6Alkyl or C substituted by 1, 2, 3 or 4 halogen atoms_1-3An alkyl group;

n is 0, 1 or 2; and

X¹and X²Independently is H, -CH³Or a halogen.

2. The compound of claim 1, wherein X¹And X²Is H or halogen, and X¹And X²At least one of (a) and (b) is halogen.

3. The compound of claim 1 or 2, wherein R²is-OR⁷Or C_1-4An alkyl group.

4. A compound according to any one of claims 1, 2 or 3, wherein R³is-CN.

5. A compound according to any one of claims 1, 2 or 3, wherein R⁴Is H or C_1-4An alkyl group.

6. A method for treating major depressive disorder, major anxiety disorder, stress disorder, major depressive disorder with anxiety, eating disorder,A method of bipolar disorder, substance use disorder, schizophrenia, psychosis, dyskinesia, cognitive disorder, depression and/or anxiety, mania or hypomania, aggressive behavior, obesity, emesis, rheumatoid arthritis, alzheimer's disease, cancer, edema, allergic rhinitis, inflammation, pain, gastrointestinal hypermotility, huntington's chorea, COPD, hypertension, migraine, cysthypermotility or urticaria comprising administering an effective amount of an NK as claimed in any one of claims 1 to 5₁An antagonist.

7. Use of a compound according to any one of claims 1-5 for the manufacture of a medicament for the treatment of a disease selected from major depressive disorder, major anxiety disorder, stress disorder, major depressive disorder with anxiety, eating disorders, bipolar disease, substance use disorder, schizophrenia, psychosis, movement disorders, cognitive disorders, depression and/or anxiety, mania or hypomania, aggressive behavior, obesity, emesis, rheumatoid arthritis, alzheimer's disease, cancer, edema, allergic rhinitis, inflammation, pain, gastrointestinal hypermotility, huntington's chorea, COPD, hypertension, migraine, bladder hypermotility, or urticaria.

8. A pharmaceutical composition comprising:

a therapeutically effective amount of the NK of any one of claims 1 to 5₁An antagonist; and

a pharmaceutically acceptable carrier or diluent.