4-[5-[(rac)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine for use in prevention and/or treatment of surmenage in a mammal

Abstract

The present invention relates to compounds 4-[5-[(rac)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4 H-1,2,4-triazol-3-yl]pyridine (TT00, TT001 and/or TT002), or a pharmaceutical composition comprising said TT00, TT001 and/or TT002, for use in prevention and/or treatment of surmenage, optionally in combination with one or more disorders selected from operative gastroesophageal reflux, anxiety, ulcer, renal and vascular disorders, wound healing and/or inappetence in a mammal, such as dogs, pigs, cats or horses.

Claims

1. One or more of compounds 4-[5-[(rac)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT00), 4-[5-[(1R)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT001) and 4-[5-[(1S)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (TT002), or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use in prevention and/or treatment of stress in combination with one or more disorders selected from the group comprising operative gastroesophageal reflux, anxiety, ulcer, renal and vascular disorders, wound healing and inappetence in a dog, cat, horse or pig.

2. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according to claim 1, wherein the dog, cat, horse or pig is under operational conditions.

3. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according to claim 1, wherein the dog, cat, horse or pig is treated with one or more muscle relaxing drugs.

4. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according to claim 2, wherein said compounds are administered prior to an operation.

5. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according to claim 2, wherein said compounds are administered after the operation.

6. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according to claim 1 in combination with prevention and/or treatment of ulcer, renal and/or vascular disorders.

7. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according to claim 1 in combination with prevention and/or treatment of wound healing and/or inappetence.

8. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according claim 1 in combination with prevention and/or treatment of operative gastroesophageal reflux.

9. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according claim 1 in combination with anxiety.

10. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according to claim 1 in combination with prevention and/or treatment of operative gastroesophageal reflux and anxiety.

11. A pharmaceutical composition, comprising one or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, in the association with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in prevention and/or treatment of stress in combination with one or more disorders selected from the group comprising operative gastroesophageal reflux, anxiety, ulcer, renal and vascular disorders, wound healing and inappetence.

12. The pharmaceutical composition according to claim 11, comprising (i) one or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate or isotope or mixture thereof, (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt or solvate thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent.

13. The pharmaceutical composition according to claim 11, comprising (i) one or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate or isotope or mixture thereof, and a pharmaceutically acceptable excipient, carrier or diluent (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, carrier or diluent.

14. The pharmaceutical composition according to claim 11, wherein the additional therapeutic agent is an NSAID selected from the group comprising butyl pyrrolidine, oxicams, propionic acid derivative, fenamic acid, coxibs and other non-steroidal anti-inflammatory.

15. The pharmaceutical composition according to claim 11, wherein the additional therapeutic agent is an opiate selected from the group comprising tramadol and tapentadol.

16. The pharmaceutical composition according to claim 11, wherein the additional therapeutic agent is an antirheumatic agent.

17. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according to any one of claims 1 to 10, or the pharmaceutical composition according to claims 11 to 16, wherein compounds TT00, TT001 and/or TT002 is administered to a dog, cat, horse or pig in a dose of 0.1 to 5.0 mg/kg.

18. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according to any one of claims 1 to 10, 17, or the pharmaceutical composition according to claims 11 to 17, wherein the compound is TT001, or a hydrochloride salt thereof.

19. One or more of compounds TT00, TT001 and TT002, or a pharmaceutically acceptable salt, solvate, isotope, or mixture thereof, for use according to any one of claim 1 for use in a dog.

Description

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS OF THE INVENTION

[0083] The definitions set forth in this application are intended to clarify terms used throughout this application. The term “herein” means the entire application.

[0084] As used herein, “recuperation” means recovery of or restoration to the normal state of health and function.

[0085] It is to be understood that the expression “ compounds TT00, TT001 and/or TT002” includes pharmaceutically acceptable salt, solvate, diastereomer, enantiomer, isotope, pro-drug or metabolite or mixture thereof, unless specified otherwise.

[0086] As used herein, “pharmaceutically acceptable salts” refer to forms of the disclosed compounds, wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues, such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid. Examples of salts are hydrochloride salts or sulphate salts, especially 4-[5-[(1R)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine hydrochloride or 4-[5-[(1R)-1-[5-(3-ChlorophenyI)-3-isoxazolyl]ethoxy]-4-methyl-4H-1,2,4-triazol-3-yl]pyridine sulphate.

[0087] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[0088] Compounds TT00, TT001 and/or TT002, especially TT001, may exist in particular geometric or stereoisomeric forms. The present invention considers all such compounds, including tautomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this invention.

[0089] As used herein, the phrase “or pharmaceutically acceptable salts” include hydrates and solvates thereof.

[0090] As used herein, “operation” means a comatose and none-comatose operation, whereby the mammal is unconscious or conscious. The operation may be surgery. As used herein, “under operational condition(s)” means performing an operation on a mammal and includes a period before the operation until a period after the operation, whereby the period before the operation may be 1 to 4 days and the period after the operation may be 1 to 21 days. The term thus includes the whole period in which a mammal experiences stress due to the performance of an operation on the mammal.

[0091] As used herein “surmenage ” or “stress” or “situation in which the mammal experiences stress” refers to a clinical condition of the mammal, wherein a clinician would diagnose one or more stress symptoms present in the mammal.

[0092] As used herein, “TLESR” means transient lower esophageal sphincter relaxation. During relaxation of the lower esophageal sphincter, fluid from the stomach can pass into the esophagus. This event is referred to as “reflux”.

[0093] As used herein, “wound healing” means poor or reduced wound healing, i.e. a healing of a wound in a mammal that takes more time compared to the norm.

[0094] As used herein, “mammal” may include any mammal. For some disorders or combination of disorders, “mammal” may even include human. In some aspects, “mammal” means dogs, pigs, cats or horses, rabbits, guinea pig, rat, birds, mice and cows. In other aspects, “mammal” means dogs, pigs, cats or horses.

[0095] Compounds TT00, TT001 and/or TT002, especially TT001, as defined herein may be isotopically labelled (or “radio-labelled”). In that instance, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Examples of suitable isotopes that may be incorporated include .sup.2H (also written as “D” for deuterium), .sup.3H (also written as “T” for tritium), .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O, .sup.18O, .sup.18F, .sup.35S, .sup.36Cl, .sup.82Br, .sup.75Br, .sup.76Br, .sup.77Br, .sup.123I, .sup.124I, .sup.125I and .sup.131I. The radionuclide that is used will depend on the specific application of that radio-labelled derivative. For example, for in vitro receptor labelling and competition assays, compounds that incorporate .sup.3H or .sup.14C are often useful. For radio-imaging applications .sup.11C or .sup.18F are often useful. In some embodiments, the radionuclide is .sup.3H. In some embodiments, the radionuclide is .sup.14C. In some embodiments, the radionuclide is .sup.11C. And in some embodiments, the radionuclide is .sup.18F. The present invention includes any isotope for use in diagnosis on mammals, such as dogs, pigs, cats or horses.

[0096] Compounds TT00, TT001 and/or TT002, especially TT001, may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.

[0097] The optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species, age, sex, size and weight, diet, and general physical condition of the particular mammal; other medication the mammal may be taking; the route of administration; the formulation; and various other factors known to physicians and others skilled in the art.

[0098] The quantity of the compounds TT00, TT001 and/or TT002, especially TT001, to be administered will vary for the mammal being treated and will vary from about 0.01 ng/kg of body weight to 10 mg/kg of body weight per day, or 0.1 ng/kg to 1 mg/kg. For instance, dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art. Thus, the skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in compositions to be administered in methods mentioned herein.

[0099] Compounds TT00, TT001 and/or TT002 can be prepared as a free base or a pharmaceutically acceptable salt or solvate thereof by the processes described in U.S. Pat. No. 7,476,684B2 or WO2007/040982A1, which are hereby included by reference.

[0100] For preparing pharmaceutical compositions from the compounds TT00, TT001 and/or TT002, especially TT001, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form compositions include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.

[0101] Liquid form compositions include ointments, creams, gels, aqueous liquids, which may be formulated inside a transdermal patch.

[0102] A process for preparation of a capsule may comprise the following steps; [0103] a) Mixing compound TT00, TT001 or TT002, especially TT001 together with additives, such as calcium hydrogen, phosphate and hydroxy propyl cellulose and stir for a period, [0104] b) Adding further additives, such as mannitol and croscarmellose sodium, [0105] c) Adding water and granulating the mixture, [0106] d) Drying the obtained granulate, [0107] e) Milling the dried granulate, [0108] f) Adding further additives, such as sodium stearyl fumarate, [0109] g) Mixing the obtained mixture, [0110] h) Filling of the mixture in capsules or pressing the mixture into tablets.

[0111] Pharmaceutical Composition

[0112] Ointment

[0113] TT001 Weight: 0.1-100 milligrams

[0114] propylene carbonate weight: 50 milligrams

[0115] paraffin, hard weight: 30 milligrams

[0116] beeswax white weight: 35 milligrams

[0117] paraffin, liquid weight: 110 milligrams

[0118] paraffin, white soft weight: 774.7 milligrams

[0119] Cream

[0120] TT001 Weight: 0.1-100 milligrams

[0121] propylene glycol weight: 100 milligrams

[0122] isopropyl myristate weight: 50 milligrams

[0123] cetostearyl alcohol weight: 52.5 milligrams

[0124] citric acid, monohydrate (e330) weight: 0.5 milligrams

[0125] disodium phosphate, anhydrous weight: 0.6 milligrams

[0126] water weight: a sufficient amount is added to achieve the target weight of 30 or 100 grams

[0127] paraffin, liquid weight: 400 milligrams

[0128] macrogol cetostearyl ether weight: 7.5 milligrams

[0129] disodium phosphate dodecahydrate (e339) weight: 1.5 milligrams

[0130] imidurea Weight: 2 milligrams

[0131] Formulation Method for the Preparation of TT001 for I.V. Dosing, 0.1 to 10 mg/ml

[0132] The formulation method is applicable at concentrations in formulation between 0.1 and 10 mg/mL corresponding to 0.262 and 26.2 μmol/mL

[0133] TT001 M.W.: 381.8 g/mol

[0134] The dissolution of TT001 is moderate, allow a couple of hours for complete dissolution.

[0135] Vehicle

[0136] Preparation of 40% w/v HPβCD solution in water for injection

[0137] Excipients Hydroxypropyl-β-cyclodextrin, Kleptose, Roquette (HPβCD) 400 mg (40% w/v)

[0138] Water for injection to 1 mL (1.13 g)

[0139] Appearance Clear

[0140] Density 1.13 g/cm3

[0141] Formulation

[0142] Preparation of TT001 I.V. formulations between 0.1 and 10 mg/ml

[0143] TT001 parent form 0.1-10 mg

[0144] Vehicle (40% w/v HPβCD solution in water for injection) to 1 mL (1.13 g)

[0145] Appearance Clear

[0146] Density 1.13 g/cm3

[0147] Comments

[0148] The dissolution of TT001 is moderate, allow a couple of hours for complete dissolution.

[0149] Ointment

[0150] Active corresponding to TT001 Weight: 0.1 to 50 milligrams

[0151] propylene carbonate weight: 50 milligrams

[0152] paraffin, hard weight: 30 milligrams

[0153] beeswax white weight: 35 milligrams

[0154] paraffin, liquid weight: 110 milligrams

[0155] paraffin, white soft weight: 774.7 milligrams

[0156] Cream

[0157] TT001 Weight: 0.1-100 milligrams

[0158] propylene glycol weight: 100 milligrams

[0159] isopropyl myristate weight: 50 milligrams

[0160] cetostearyl alcohol weight: 52.5 milligrams

[0161] citric acid, monohydrate (e330) weight: 0.5 milligrams

[0162] disodium phosphate, anhydrous weight: 0.6 milligrams

[0163] water weight: a sufficient amount is added to achieve the target weight of 30 or 100 grams

[0164] paraffin, liquid weight: 400 milligrams

[0165] macrogol cetostearyl ether weight: 7.5 milligrams

[0166] disodium phosphate dodecahydrate (e339) weight: 1.5 milligrams

[0167] imidurea weight: 2 milligrams

[0168] Capsule

TABLE-US-00001 TABLE 1 Components and quantities for TT001 Capsules 2 mg and 8 mg Components 2 mg 8 mg Function Standard TT001    2 mg    8 mg Drug Substance AstraZeneca Calcium hydrogen  70.5 mg  68.5 mg Filler Ph Euror USP phosphate dehydrate/ Dibasic Calcium Phosphate Dihydrate Hydroxypropylcellulose/   12 mg   12 mg Binder Ph Eur or NF  Hydroxypropyl Cellulose Mannitol 141.1 mg 137.1 mg Filler Ph Euror USP Croscarmellose sodium  9.6 mg  9.6 mg Disintegrant Ph Eur or NF  Sodium stearyl fumarate  4.8 mg  4.8 mg Lubricant Ph Eur or NF  Water, purified/ q.s. q.s. Granulation Ph Euror USP Purified water.sup.a liquid Capsules 1 capsule 1 capsule Capsule JP

EXAMPLE 1

[0169] In cat or dog undergoing elective castration or ovariohysterectomy TT001 has a positive effect on duration of the recovery period.

[0170] To study recovery after neutering, cage demeanour scoring using a simple descriptive scale was used. The dogs were premedicated with acepromazine and pethidine, intermuscular (i.m.) in a first group, or in a second group TT001 was also added as pre-medication.

[0171] Twenty to forty minutes after pre-medication, the sedation was scored with the SDS (simple descriptive scale). The dogs were induced with propofol. Anesthesia was maintained with isoflurane in oxygen. Intraoperative analgesia was provided with morphine, prior to surgery. At the end of the surgery, group 1 received meloxicam, while group 2 received no additional treatment.

[0172] At the end of the procedure and recovery SDS was scored.

[0173] Group 2 showed the following;

[0174] Time to extubation became shorter,

[0175] Time to lifting the head after surgery became shorter,

[0176] Time to raising from the bed after surgery became shorter,

[0177] Time to start of spontaneous/voluntary urination after surgery became shorter,

[0178] Less nausea,

[0179] Time to starting to eat after surgery became shorter, and

[0180] Lower cortisol values than with commonly used anesthesia protocol.

EXAMPLE 2

[0181] In cat or dog undergoing elective castration or ovariohysterectomy TT001 has a positive effect on duration for the recovery period.

[0182] To study recovery after neutering, cage demeanour scoring using a simple descriptive scale was used. The dogs were premedicated with acepromazine and pethidine, i.m. in a first group, and meloxicam orally or in a second group TT001 was also added as pre-medication.

[0183] Twenty to forty minutes after pre-medication the sedation was scored with the SDS (simple descriptive scale). The dogs were induced with propofol. Anesthesia was maintained with isoflurane in oxygen. Intraoperative analgesia was provided with morphine, prior to surgery. At the end of the surgery, group 1 continued to receive meloxicam, while group 2 continued to receive TT001 as well as meloxicam. No additional treatment was administered.

[0184] At the end of the procedure and recovery SDS was scored.

[0185] Group 2 showed the following;

[0186] Time to extubation became shorter than for group 1,

[0187] Time to lifting the head after surgery became shorter than for group 1,

[0188] Time to raising from the bedding after surgery became shorter than for group 1,

[0189] Time to start of spontaneous/voluntary urination after surgery became shorter than for group 1,

[0190] Less nausea than for group 1,

[0191] Time to starting to eat after surgery became shorter than for group 1,

[0192] Lower cortisol values than in group 1, and

[0193] Less time in intensive care/PACU unit than for group 1.

[0194] In this study, TT001 displayed no effect on LES pressure. There was also no significant effect on swallows observed with TT001 in this study, however, there was a numerical trend towards a decrease in swallows for the higher dosages, which can be reconciled with a CNS mediated effect.

EXAMPLE 3

Forced Swim Test

[0195] TT001 has been used in the Forced Swim Test. _For protocol see Can A., et al., The Mouse Forced Swim Test, J Vis Exp. 2012; (59): 3638.

[0196] The results in table 1 show that the test animals are still for a significantly shorter period than placebo group.

TABLE-US-00002 TABLE 1 Effects of TT001 on mouse FST behavior Treatment Immobility (μmol/kg) duration (sec) Vehicle 112.5 ± 14.10  TT001 (3)  51.15 ± 7.788 .sup.a TT001 (10)  47.45 ± 11.45 .sup.a TT001 (30)  44.83 ± 4.693 .sup.a .sup.a p < 0.01 is associated with one way ANOVA comparing TT001 vs vehicle.

[0197] This test shows that TT001 reduces stress. Besides, none of the test animals had signs of gastric ulcer even any changes in mucosa.

EXAMPLE 4

Learned Helplessness Studies

[0198] Nomura S. et al., Studies on animal model of depression: review and perspective, Review, Yakubutsu Seishin Kodo, 1989 December; 9(4):349-58.

[0199] TT001 was used in learned helplessness studies in rats. The results are shown in table 2.

TABLE-US-00003 TABLE 2 Escape Failures Following Each Treatment level Total Treatment Day 3 Day 4 Day 3 + Compound Dose Mean SEM Mean SEM Day 4 Vehicle 0 23.2  7.8 11.1  6.20 34.25 TT001 1.8 μmol/kg 6.9 2.5 2.2 1.27   9.1 .sup.a .sup.a p < 0.05 by t-test vs. vehicle group.

[0200] The results show that TT001 lowered the stress and that stomach ulcers did not appear. Thus, TT001 has a specific therapeutic effect on stress and gastric ulcer.

EXAMPLE 5

Stress and Lab-Work—Ulcer

[0201] Toxicological studies for TT001 in dogs, were performed on dogs using 2, 6, 7 or 31 mg/kg, for a maximum of 52 weeks. The dogs were fed with gavage throughout this period and blood samples were taken throughout the period.

[0202] Balcome at al Contemporary Topics 2004 by the American Association for Laboratory Animal Science. Vol 43. No. 6/November 2004, showed that gavage and regular blood sampling create a lot of stress in the animals and an increase in cortisol values is normal under these circumstances. In addition, the animals are separated and live in small areas which further increase the stress.

[0203] After 52 weeks, none of the animals showed signs of gastric ulcer despite the fact that the environment and handling during the 52 weeks was causing stress. The results show that TT001 is a substance that relieves stress and thus the risk of stomach ulcers.