阅读说明：本技术 用于预防和/或治疗动物中的疼痛的4-[5-[(rac)-1-[5-(3-氯苯基)-3-异噁唑基]乙氧基]-4-甲基-4H-1,2,4-三唑-3-基]吡啶 (4- [5- [ (rac) -1- [5- (3-chlorophenyl) -3-isoxazolyl ] ethoxy ] -4-methyl-4H-1, 2, 4-triazol-3-yl ] pyridine for the prevention and/or treatment of pain in an animal ) 是由 克拉斯·图林 于 2019-11-22 设计创作，主要内容包括：本发明涉及4-[5-[(rac)-1-[5-(3-氯苯基)-3-异噁唑基]乙氧基]-4-甲基-4H-1,2,4-三唑-3-基]吡啶(TT00),或其药学上可接受的盐、非对映异构体、对映异构体、同位素、前药或代谢物或其混合物,或包含所述TT00的药物组合物,用于预防和/或治疗动物诸如狗、猫或马中的疼痛,诸如慢性疼痛和/或周围疼痛和/或与关节炎诸如骨关节炎有关的疼痛,或用于预防和/或治疗动物诸如狗、猫或马中的所述疼痛与b)GERD或c)焦虑的组合。(The present invention relates to 4- [5- [ (rac) -1- [5- (3-chlorophenyl) -3-isoxazolyl ] ethoxy ] -4-methyl-4H-1, 2, 4-triazol-3-yl ] pyridine (TT00), or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, or a pharmaceutical composition comprising said TT00, for use in the prevention and/or treatment of pain, such as chronic pain and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, in an animal, such as a dog, cat or horse, or for use in the prevention and/or treatment of said pain in an animal, such as a dog, cat or horse, in combination with b) GERD or c) anxiety.)

1. Compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or mixtures thereof, for use in the prevention and/or treatment of pain in dogs, cats or horses.

2. Compounds TT00, TT001 and/or TT002 according to claim 1, wherein the animal is a dog.

3. Compounds TT00, TT001 and/or TT002 according to claim 1 or 2, wherein the pain is pain associated with arthritis.

4. Compounds TT00, TT001 and/or TT002 according to claim 3, wherein pain is associated with osteoarthritis.

5. Compounds TT00, TT001 and/or TT002 according to claims 1 to 4, wherein the pain is chronic and/or peripheral pain.

6. Compounds TT00, TT001 and/or TT002 according to claims 1 to 4, wherein the pain is chronic and peripheral pain associated with osteoarthritis.

7. Compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis such as osteoarthritis and b) gastroesophageal reflux disease (GERD), in a dog, cat or horse.

8. Compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite or mixture thereof, for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, and c) anxiety in dogs, cats or horses.

9. A pharmaceutical composition comprising compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or mixtures thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention and/or treatment of pain, such as chronic and/or peripheral pain, and/or pain associated with arthritis, such as osteoarthritis, in a dog, cat or horse.

10. A pharmaceutical composition comprising the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, and b) gastroesophageal reflux disease (GERD) in a dog, cat or horse.

11. A pharmaceutical composition comprising compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, and c) anxiety, in dogs, cats or horses.

12. A pharmaceutical composition comprising (i) a compound TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in the prevention and/or treatment of pain, such as chronic and/or peripheral pain, in a dog, cat or horse and/or pain associated with arthritis such as osteoarthritis.

13. A pharmaceutical composition comprising (i) a compound TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, and b) gastroesophageal reflux disease (GERD) in a dog, cat or horse.

14. A pharmaceutical composition comprising (i) a compound TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, and c) anxiety in a dog, cat or horse.

15. The pharmaceutical composition according to claims 12 to 14, wherein the additional therapeutic agent is an anesthetic, NSAID or opiate.

16. The pharmaceutical composition according to claims 12 to 14, wherein the additional therapeutic agent is an NSAID selected from the group comprising: butylpyrazoles, oxicams, propionic acid derivatives, fenamic acid and coxibs.

17. The pharmaceutical composition according to claims 12 to 14, wherein the additional therapeutic agent is an anesthetic selected from the group comprising: acepromazine, morphine or propofol.

18. The pharmaceutical composition according to claims 12 to 14, wherein the additional therapeutic agent is an opiate such as tramadol or tapentadol.

19. Compound TT00, TT001 and/or TT002 according to any one of claims 1 to 8, or a pharmaceutical composition according to any one of claims 9 to 18, wherein the compound is TT001, or a hydrochloride or sulfate salt thereof.

20. Compounds TT00, TT001 and/or TT002 according to any one of claims 1 to 8, or pharmaceutical compositions according to any one of claims 9 to 19, wherein compounds TT00, TT001 and/or TT002 are administered to a dog, cat or horse at a dose of 0.1 to 5.0 mg/kg.

21. Compounds TT00, TT001 and/or TT002 according to any one of claims 1 to 8, or pharmaceutical compositions according to any one of claims 9 to 19, wherein compounds TT00, TT001 and/or TT002 are administered to the dog, cat or horse once daily at a dose of 0.1 to 1.0 mg/kg.

22. Compounds TT00, TT001 and/or TT002 according to any one of claims 1 to 8, or pharmaceutical compositions according to any one of claims 9 to 19, wherein compounds TT00, TT001 and/or TT002 are administered to a dog, cat or horse at a dose of 0.1 to 0.5mg/kg twice daily.

23. Compounds TT00, TT001 and/or TT002 according to any one of claims 1 to 8, or pharmaceutical compositions according to any one of claims 9 to 19, wherein compound TT001 is administered to a dog once daily at a dose of 0.1 to 1.0 mg/kg.

Technical Field

The present invention relates to 4- [5- [ (rac) -1- [5- (3-chlorophenyl) -3-isoxazolyl ] ethoxy ] -4-methyl-4H-1, 2, 4-triazol-3-yl ] pyridine (TT00), or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, or a pharmaceutical composition comprising said TT00, for use in the prevention and/or treatment of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, in an animal, such as a dog, cat or horse, or for use in the prevention and/or treatment of said pain in an animal, such as a dog, cat or horse, in combination with b) GERD or c) anxiety.

Background

Pain is a major area of interest in veterinary medicine. The most common pain relief in dogs is the use of non-steroidal anti-inflammatory drugs (NSAIDs). However, chronic NSAID treatment in the case of osteoarthritis can cause severe (mayor) side effects. Today, NSAIDs are used in 75% of animals in the European Union (EU) suffering from osteoarthritis.

Typical side effects of NSAIDs in dogs are vomiting, loss of appetite, depression and diarrhea. Serious side effects such as gastrointestinal ulcers, liver/renal failure, and even death have also been reported.

TT00, or 4- [5- [ (rac) -1- [5- (3-chlorophenyl) -3-isoxazolyl ] ethoxy ] -4-methyl-4H-1, 2, 4-triazol-3-yl ] pyridine

And

TT002, or 4- [5- [ (1S) -1- [5- (3-chlorophenyl) -3-isoxazolyl ] ethoxy ] -4-methyl-4H-1, 2, 4-triazol-3-yl ] pyridine

And

TT001, or 4- [5- [ (1R) -1- [5- (3-chlorophenyl) -3-isoxazolyl ] ethoxy ] -4-methyl-4H-1, 2, 4-triazol-3-yl ] pyridine, CAS number 934282-55-0,

molecular formula C₁₉H₁₆ClN₅O₂And a relative molecular mass of 381.8 (base).

These compounds are selective non-competitive antagonists of the metabotropic glutamate receptor subtype 5(mGluR5) and have been developed for the oral treatment of neuropathic chronic pain syndrome, anxiety and gastroesophageal reflux disease (GERD) in humans. The development for all indications was discontinued after clinical trials.

TT00 acts on mGluR5 receptors in the central nervous system, thereby alleviating central pain. Arthritis, such as osteoarthritis, causes pain in the peripheral nervous system.

In clinical development, dogs were used for toxicity studies, but no efficacy studies were performed for pain indications. The literature catalogue searches for no disclosure of any such molecule for treating pain or treating pain and anxiety or a combination of pain and GERD in dogs, cats or horses.

Although animal models in rodents can predict effects in humans, no study has been shown in which rodent models predict outcomes in dogs. Pain models for large animals are rare.

Comparison of species metabolites

There are many things that must be made clear before a molecule becomes a drug candidate. Two important steps that a molecule must pass through are species compatibility as assessed by metabolite profiling.

In the non-clinical part of drug development, studies are aimed at determining metabolite profiles and characterizing selected metabolites produced after incubation of molecules in rat and human hepatocytes. The results obtained were used to compare liver metabolism in humans with that of rodent models used in safety studies.

One method used is to collect rat and human hepatocytes and incubate them with the molecule. The metabolite profile in the supernatant will be recorded by liquid chromatography. The selected metabolites will be characterized by accurate mass spectrometry. There may be more than 10 different metabolites from liver metabolism.

The metabolite profiles between the two species should be similar. If this is not the case, the predictability of rodent models for humans is not significant and the molecule is likely not to be further developed.

It is also well known that rodent models are very poorly predictable for humans for certain indications, such as inflammatory diseases. (PNAS |2 month 26 days, 2013| vol.110| No.9| 3507-.

The same is true for clinical pain. Unfortunately, the biology of rodents may not accurately predict the biology and pharmacology of clinical pain conditions in humans in many ways. (Blackburn-Munro 2004; Le Bars et al 2001, relational Panel Research: From Mouse to Man. Kruger L, Light AR, editors. boca Raton, FL: CRC Press/Taylor & Francis; 2010. vane 17Large Animal Models for Panel Therapeutic Development, Darrell A. Henze and Mark O. Urban).

Based on the difficulty of predicting drug metabolism and metabolite profiles between species and the difficulty of predicting human responses based on rodent models, one skilled in the art would be unable to predict the effectiveness and toxicity of a drug to one species based on data from another species unless specific studies were conducted to verify the activity of the compound in the relevant species.

Furthermore, there is no published data on TT001 and liver metabolism and metabolite profiles in rats and dogs, and certainly no published data for rats compared to cats and horses.

There are many examples of drugs that have different effects in different species.

Tramadol is widely used as an analgesic (pain killer) and is highly effective in humans, but not in dogs. (J Am Vet Med Assic.2018 Feb 15; 252(4):427-432.doi:10.2460/javma.252.4.427., Lack of effectiveness of tramadol hydrochloride for the treatment of pain and joint dysfuntions in dogs with hydrochloric acid, Budsberg SC, Torres BT, Kleine SA, Sandberg GS, Berjeski AK.)

It is also known that adverse effects of tramadol can cause dogs to lose concept (concept) and balance, giving the impression of "high". Also, drugs for humans are toxic to animals. Examples of such are phenolic drugs including acetaminophen and aspirin which should not be given to cats. (Shrestha B et al, Evolution of a major drug metabolism enzyme defect in the biomedical site and other defects: styrene timing and the roll of hypercardiovary, Life Sci.2006Nov 25; 79(26):2463-73.Epub 2006 Oct 5).

Coort MH, Feline drug metabolism and displacement, pharmaceutical evidence for properties and molecular mechanisms, Vet Clin North Am Small Anim practice.2013 Sep; 43(5) 1039-54. doi: 10.1016/j.cvsm.2013.05.002, pharmacokinetic evidence of drug elimination rate differences between cats, dogs and humans is shown in fig. 1. A comparison is shown between the elimination half-life values disclosed in cats, dogs and humans for representative drugs that are eliminated primarily by binding (glucuronidation, sulfation and glycination), oxidation (CYP enzymes) or excreted primarily as prototypes into the urine and/or bile. All values are expressed as ratios of human values. Complete pharmacokinetic data and references for acetylsalicylic acid, propofol, acetaminophen, carprofen, and piroxicam are given in table 1.

Some may be more or less lethal, especially for NSAIDs, while others work well. One difficulty with NSAIDs is that both lethal and good NSAIDs can be from the same chemical group/class. A good example of this is ibuprofen, which is a toxic substance for dogs and cats. Ibuprofen is a propionic acid derivative and belongs to the same chemical group as ketoprofen, vildaprofen (Vedaprofen) and carprofen (all of which can be administered to all animals).

Further examples are listed below.

Dog

NSAIDs (e.g., Advil, Aleve and Motrin)

Although these medications are safe for humans, even one or two pills can cause serious injury to pets. Dogs, cats, birds and other small mammals (ferrets, gerbils and hamsters) may develop severe gastric and intestinal ulcers as well as renal failure.

Acetaminophen (e.g. Tylenol)

Acetaminophen (e.g., Tylenol) is of course popular when pain medication is referred to. Although this medication is very safe, even for children, it is not so for pets, especially cats. A conventional strength paracetamol tablet may cause red blood cell damage in cats, thereby limiting their ability to carry oxygen. In dogs, acetaminophen can lead to liver failure and, at high doses, to red blood cell damage.

Antidepressants (e.g., Effexor, Cymbalta, Prozac, Lexapro)

Although these antidepressants are occasionally used in pets, overdosing can lead to serious neurological problems such as sedation, movement disorders, tremor and seizures (seizure). Some antidepressants also have an excitatory effect, resulting in dangerously high heart rates, blood pressure, and body temperature. Pets, especially cats, seem to prefer the flavor of Effexor and often eat whole pellets. Unfortunately, only one pill causes severe poisoning.

ADD/ADHD medications (e.g., Concerta, Adderall, Ritalin)

Drug therapy for the treatment of attention deficit disorder/attention deficit hyperactivity disorder contains potent agonists such as amphetamines and methylphenidate. Even a small intake of these medications by pets can cause life-threatening tremors, seizures, elevated body temperatures, and heart problems.

Dinitrogen benzeneClasses and sleep aids (e.g., Xanax, Klonopin, Ambien, Lunesta)

These medications are intended to reduce anxiety and help people sleep better. However, in pets, they may have opposite effects. About half of dogs taking sleep aids become agitated rather than sedated. In addition, these drugs may cause the pet to be severely sleepy, disoriented in movement (including "drunk" walking), and slowed in breathing. In cats, certain forms of benzodiazepinesThe group causes liver failure.

Beta-blockers (e.g. tenon, Toprol, Coreg)

Beta-blockers are used to treat hypertension, but ingestion of these drugs in small amounts in pets can cause severe poisoning. Overdosing can cause life-threatening drops in blood pressure and very slow heart rates.

Cat (cat)

The cat toxic drug includes acetaminophen (Tylenol), aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve, Anaprox), antidepressant, ADD/ADHD medication, and hypnotic (benzodiazepine)Paraids, Xanax, Ambien), beta-blockers, thyroxins, and cholesterol drug therapy (Lipitor).

There is an unmet need for the treatment of pain, particularly peripheral pain in animals such as dogs, cats and horses, particularly pain associated with arthritis such as osteoarthritis. There is a need for treatments with reduced side effects, such as gastrointestinal and renal toxicity.

WO2007/040982 discloses the use of TT00, TT001 and/or TT002 in humans for the treatment of neurological, psychiatric or pain disorders. IC50 binding data in mGluR receptors are shown as well as studies on the effects of TT00, TT001 or TT002 on TLESR in healthy dogs in relation to food consumption. No study results are disclosed. No clinical data at all exists, in particular no clinical data relating to pain treatment after administration of TT00, TT001 and/or TT 002.

Rohof et al, animal, Pharmacol, ther.22012, vol 35, pp 1231-1242, disclose a clinical study using TT001 to measure its effect on TLESR in healthy volunteers in relation to food intake. The results in figures 2 and 4 show that a high dose of only 13mg (about 0.19mg/kg) had some effect 2 to 3 hours after food consumption, but had no significant effect on reflux before food consumption, nor 1-2 hours after food consumption. Some serious side effects associated with high doses of 13mg are mentioned. No clinical data relating to pain treatment after administration of TT00, TT001 and/or TT002 are disclosed.

Combination Drug Therapy (CDT)

There are several studies focused on the use of CDT for pain management.

Mao et al, j.pain, 2011, vol 12, pp 157-. Most therapies use opiates in combination with another analgesic. mGluR5 is not mentioned at all for use in combination therapy, such as pain treatment, or in the treatment of pain associated with arthritis (such as osteoarthritis).

In the review by Mao j et al, CDT data are available for use in humans, but there is no information whatsoever about treatment in animals. In table 1, different combinations are listed and evaluated according to positive or negative results. It should be noted that for osteoarthritis, the oral combination of tramadol and NSAIDs showed positive and better pain relief in humans for the additional drug (add-on drug), but there were studies using the same CDT in dogs, where no additional clinical effect of the combination was reported.

In table 1 from Mao et al it is also mentioned that oral combinations of tramadol and acetaminophen show positive and better pain relief in humans with additional drugs. If such CDT is given to a cat, toxicity may kill it.

See also Meuner N et al, random three of periodic trap for cancer pain management, Vet Rec.2019 Oct 5; 185(13) doi 10.1136/vr.105009.Epub 2019 Jul 18, and Tanaka N et al, cDNA cloning and characterization of weline CYP1A1 and CYP1A2, Life Sci.2006Nov 25; 79(26) 2463-73.Epub 2006 Oct 5.

There may be a general misunderstanding that merely combining different drugs together produces additional effects. In table 1 from Mao et al, a combination of one quarter gave no positive results. There are even situations where the combination reduces the overall effectiveness of the pain treatment.

It is obvious to those skilled in the art that clinical results from different species are not automatically transformed into other species. Thus, one skilled in the art should and will suggest an independent assessment of the efficacy and toxicity of each species. This is obviously also the position of the pharmaceutical product administration in most countries.

The need to treat pain using a safe, effective and efficacious combination of drugs has not been met.

Summary of the invention

The present invention relates to compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or mixtures thereof, for use in the prevention and/or treatment of pain in dogs, cats or horses. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In another aspect, the compound is the hydrochloride salt of TT 001. In a further aspect, the compound is a sulfate salt of TT 001. In one aspect, the animal is a dog.

The characteristics and central working mechanisms of compounds TT00, TT001 and/or TT002 make them very different pain relieving candidates compared to NSAIDs mainly used today.

Compounds TT00, TT001 and/or TT002 have few side effects in dogs, cats and horses at the planned doses. They do not lose efficacy over a prolonged period of application. Although compounds TT00, TT001 and/or TT002 are known to affect the central nervous system, they show a positive effect in the treatment of peripheral pain such as pain associated with arthritis (such as osteoarthritis). This pain may be chronic. TT00, TT001 and/or TT002 are considered effective without any serious side effects when used for a long period of time, such as months or years. TT00, TT001 and/or TT002 are believed to have a reduced potential for side effects, particularly when treated for longer periods of time, compared to current conventional analgesics for animals, such as NSAIDS. The compounds of the invention are believed to have reduced gastrointestinal and renal toxicity in dogs, cats and horses, particularly as compared to NSAIDs.

In one aspect, the pain is chronic pain. In another aspect, the pain is peripheral pain. In a further aspect, the pain is chronic and peripheral pain. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis.

The invention also relates to compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, and b) gastroesophageal reflux disease (GERD), in a dog, cat or horse.

In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse. Since the compounds act on the central nervous system, they are useful for the simultaneous treatment and/or prevention of pain and GERD.

The invention also relates to compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, and c) anxiety in dogs, cats or horses. In one aspect, the animal is a horse. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the animal is a cat or dog. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. Since the compounds act on the central nervous system, they are useful for the simultaneous treatment and/or prevention of pain and anxiety. This is important before and during veterinary treatment of the animal, such as injection or surgery.

The present invention relates to a method of treating, preventing or reducing the risk of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, or a combination of a) said pain with b) GERD or c) anxiety, which method comprises administering to a dog, cat or horse in need thereof a therapeutically effective amount of compound TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite or mixture thereof. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof.

The invention further relates to a pharmaceutical composition comprising compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof, or a mixture thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof.

The invention also relates to a process for the preparation of a pharmaceutical composition as defined above, which comprises admixing the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof.

One aspect relates to a pharmaceutical composition comprising compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention and/or treatment of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis such as osteoarthritis, in a dog, cat or horse. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse.

One aspect relates to a pharmaceutical composition comprising the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, and b) gastroesophageal reflux disease (GERD) in a dog, cat or horse. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis.

One aspect relates to a pharmaceutical composition comprising compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, and c) anxiety, in a dog, cat or horse. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis.

The invention also relates to the use of compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, in the manufacture of a medicament for the treatment of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis such as osteoarthritis, in a dog, cat or horse, or a) a combination of said pain with b) GERD or c) anxiety. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse.

Compounds TT00, TT001 and/or TT002 may be administered at a dose of 0.1 to 5.0mg/kg, or 0.1 to 2.0mg/kg, or 0.1 to 1.0mg/kg per day. One aspect relates to a dosage regimen wherein compounds TT00, TT001 and/or TT002 are administered to the animal once daily or twice daily at a dose of 0.1 to 5.0 mg/kg. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the dose is for prophylaxis and/or treatment in a dog.

In one aspect, the dosage regimen is the administration of compounds TT00, TT001 and/or TT002 once daily at a dose of 0.1 to 1.0 mg/kg. In one aspect, the dosage regimen is the administration of compounds TT00, TT001 and/or TT002 twice daily at a dose of 0.1 to 0.5 mg/kg. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof.

As mentioned above, there is no disclosure of the use of mGluR5 antagonists for the treatment of pain in dogs, cats and horses. Even in the TLESR study, no mention was made of the effect of the compounds on pain relief. Clinical studies in humans have been discontinued.

The prevention and/or treatment of pathologically relevant pain as defined herein may be applied as a sole prevention and/or therapy or may involve, in addition to TT00, TT001 and/or TT002, a combined treatment with conventional therapies of value in the prevention and/or treatment of one or more of the disease conditions mentioned herein. Such conventional therapies may include one or more of the following classes of agents: NSAIDs, anesthetic, and opiate. It is believed that TT00, TT001 and/or TT002 in combination with other analgesics may have a synergistic effect on pain relief in animals as well as an additional effect through dual treatment of different disease conditions.

In one aspect, the NSAIDs are selected from the group comprising or consisting of: pyrazolidine class, which is 1, 2-diphenylpyrazolidine-3, 5-dione with a butyl group in the 4-position. It has effects as a non-narcotic analgesic, a non-steroidal anti-inflammatory drug, an antirheumatic, a peripheral nervous system drug, a metabolite and an EC 1.1.1.184[ carbonyl reductase (NADPH) ] inhibitor. In another aspect, the NSAIDs are selected from the group comprising or consisting of: butylpyrazoles, oxicams (oxicams), propionic acid derivatives, fenamic acid, coxibs (coxibs) and other nonsteroidal anti-inflammatory drugs and anti-rheumatic agents. In a further aspect, the NSAIDs are selected from the group comprising or consisting of: oxicams, propionic acid derivatives and coxibs.

The opiates may be selected from the group comprising or consisting of: tramadol or tapentadol (tapentadol).

Such combination therapy may be achieved by the simultaneous, sequential or separate administration of the individual components of the therapy. Such combinations utilize compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or mixtures thereof, for the prevention and/or treatment of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis such as osteoarthritis, in dogs, cats or horses.

In one aspect, the present invention relates to a pharmaceutical composition comprising (i) a compound TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in the prevention and/or treatment of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, in a dog, cat or horse. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse.

In one aspect, the present invention relates to a pharmaceutical composition comprising (i) a compound TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in the prevention and/or treatment of pain associated with arthritis, such as osteoarthritis, in a dog, cat or horse. In one aspect, the pain is chronic pain associated with arthritis, such as osteoarthritis. In one aspect, the present invention relates to a pharmaceutical composition comprising (i) the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, and b) gastroesophageal reflux disease (GERD), in a dog, cat or horse. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse.

Anesthetics, such as acepromazine, have muscle relaxant properties that affect the Lower Esophageal Sphincter (LES), causing more reflux episodes during anesthesia. Co-treatment of the anesthetic with TT00, TT001, and/or TT002 can ameliorate a condition in the animal that is at least associated with veterinary treatment (such as surgery).

In one aspect, the present invention relates to a pharmaceutical composition comprising (i) a compound TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) an additional therapeutic agent or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in the prevention and/or treatment of a) pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, and c) anxiety in a dog, cat or horse. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse. While TT00, TT001, and/or TT002 are believed to treat pain and anxiety, it may be advantageous to combine TT00, TT001, and/or TT002 with additional drugs to improve the condition of the animal. Furthermore, as mentioned above, in combination with an anesthetic, TT00, TT001, and/or TT002 can improve the condition of the animal before, during, and after veterinary treatment (such as surgery). Compounds TT00, TT001 and/or TT002 are considered to have a positive effect on GERD. It is even possible to use compounds TT00, TT001 and/or TT002 in combination with NSAIDs for treatment because it has been shown to affect GERD, which may be a serious side effect of NSAIDs. Since TT00, TT001 and/or TT002 act from the central nervous system and NSAIDs act from the periphery, the combination of the two may have a synergistic effect on pain relief in animals, especially dogs. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof.

In one aspect, the additional therapeutic agent is an NSAID, such as butylpyrazole, oxicams, propionic acid derivatives, fenamic acid, or coxibs. In a further aspect, the NSAIDs are selected from the group comprising or consisting of: oxicams, propionic acid derivatives and coxibs. In one aspect, the additional therapeutic agent is any other non-steroidal anti-inflammatory drug. In a further aspect, the NSAIDs are anti-rheumatic agents. In one aspect, the additional therapeutic agent is an opiate such as tramadol or tapentadol. In one aspect, the additional therapeutic agent is an anesthetic, such as acepromazine, morphine, or propofol.

In another embodiment, the present invention relates to a pharmaceutical composition comprising (i) the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) at least one additional therapeutic agent selected from the group comprising or consisting of: (ii) narcotics, NSAIDs and opiates, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in the prevention and/or treatment of pain, such as chronic pain and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, in dogs, cats or horses, or in the prevention and/or treatment of a) said pain in combination with b) GERD or c) anxiety in dogs, cats or horses. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse.

In another embodiment, the present invention relates to a pharmaceutical composition comprising (i) compound TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) at least one additional therapeutic agent which is an NSAID selected from the group comprising or consisting of: (ii) oxicams, propionic acid derivatives and coxibs, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in the prevention and/or treatment of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, or in the prevention and/or treatment of a) a combination of said pain with b) GERD or with c) anxiety. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse.

In another embodiment, the present invention relates to a pharmaceutical composition comprising (i) the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) at least one additional therapeutic agent which is a further non-steroidal anti-inflammatory drug or an anti-rheumatic agent, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in the prevention and/or treatment of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, or the prevention and/or treatment of a) said pain in combination with b) GERD or with c) anxiety. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse.

In another embodiment, the present invention relates to a pharmaceutical composition comprising (i) the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) at least one additional therapeutic agent which is an opiate selected from the group comprising or consisting of: tramadol and tapentadol, and (iii) a pharmaceutically acceptable excipient, carrier or diluent for use in the prevention and/or treatment of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, or the prevention and/or treatment of a) a combination of said pain with b) GERD or with c) anxiety. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse.

In another embodiment, the present invention relates to a pharmaceutical composition comprising (i) the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) at least one additional therapeutic agent which is an anesthetic selected from the group comprising or consisting of: (ii) acepromazine, morphine or propofol, and (iii) a pharmaceutically acceptable excipient, carrier or diluent, for use in the prevention and/or treatment of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis such as osteoarthritis, or the prevention and/or treatment of a) a combination of said pain with b) GERD or with c) anxiety. In one aspect, the pain is pain associated with arthritis, such as osteoarthritis. In another aspect, the pain is chronic and peripheral pain associated with osteoarthritis. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof. In one aspect, the animal is a dog. In another aspect, the animal is a cat or a horse.

Such combination products utilize compounds TT00, TT001 and/or TT002 within the dosage ranges described herein, as well as other additional therapeutic agents within approved dosage ranges and/or within the dosages described in their published references.

A pharmaceutical composition comprising compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or mixtures thereof, optionally together with one or more additional therapeutic agents as defined above, may be administered topically or orally. In one aspect, the pharmaceutical composition is administered topically. In another aspect, the pharmaceutical composition is administered intramuscularly. In a further aspect, the pharmaceutical composition is administered intravenously.

Detailed Description

The definitions set forth herein are intended to clarify terms used throughout this application. The term "herein" refers to the entire application.

It will be understood that, unless otherwise indicated, the expression "compounds TT00, TT001 and/or TT 002" includes pharmaceutically acceptable salts, diastereomers, enantiomers, isotopes, prodrugs or metabolites thereof, etc., or mixtures thereof.

As used herein, "pharmaceutically acceptable salts" refer to forms of the disclosed compounds in which 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); basic or organic salts of acidic residues (such as carboxylic acids); and the like. Pharmaceutically acceptable salts include, for example, the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed 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 the hydrochloride or sulfate 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-chlorophenyl) -3-isoxazolyl ] ethoxy ] -4-methyl-4H-1, 2, 4-triazol-3-yl ] pyridine sulfate.

As used herein, the phrase "or pharmaceutically acceptable salt" includes hydrates and solvates thereof.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, 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; typically, a non-aqueous medium is used, such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.

Compounds TT00, TT001 and/or TT002, especially TT001, may exist in specific geometric or stereoisomeric forms. The present invention contemplates that all such compounds, including tautomers, R-and S-enantiomers, diastereomers, (D) -isomers, (L) -isomers, racemic mixtures thereof, and other mixtures thereof, are encompassed within the scope of the present invention.

As used herein, "tautomer" refers to other structural isomers that exist in equilibrium due to the migration of hydrogen atoms. For example, keto-enol tautomerism occurs when the resulting compound has the properties of a ketone and an unsaturated alcohol.

Compounds TT00, TT001 and/or TT002, especially TT001, and salts described in this specification may be isotopically labeled (or "radiolabeled"). In that case, 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 can be incorporated include²H (also written as "D" for deuterium),³h (also written as "T" for tritium),¹¹C,¹³C,¹⁴C,¹³N,¹⁵N,¹⁵O,¹⁷O,¹⁸O,¹⁸F,³⁵S,³⁶Cl,⁸²Br,⁷⁵Br,⁷⁶Br,⁷⁷Br,¹²³I,¹²⁴I,¹²⁵i and¹³¹I. the radionuclide used will depend on the particular application of the radiolabeled derivative. For example, for in vitro receptor labeling and competition assays, incorporation³H or¹⁴Compounds of C are generally useful. For the application of radiological imaging,¹¹c or¹⁸F is generally useful. In some embodiments, the radionuclide is³H. In some embodiments, the radionuclide is¹⁴C. In some embodiments, the radionuclide is¹¹C. And in some embodimentsIn the case, the radionuclide is¹⁸F. The invention includes any isotope of TT00, TT001 and/or TT002 for diagnosis in an animal such as a dog, cat or horse.

Compounds TT00, TT001 and/or TT002, especially TT001, may be administered as follows: oral, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingual, intramuscular, subcutaneous, topical, intranasal, intraperitoneal, intrathoracic, intravenous, epidural, intrathecal, intracerebroventricular, and by injection into the joints. The compounds may be administered topically.

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

Dosages can be readily determined by those skilled in the art in light of this disclosure and knowledge in the art. Thus, the skilled person can easily determine the amount of compound and optional additives, vehicles and/or carriers to be administered in the composition and in the method of the invention.

The amount of compounds TT00, TT001 and/or TT002, especially TT001, to be administered varies with the dog, cat or horse receiving treatment and will vary from about 0.01ng/kg body weight to 10mg/kg body weight per day. Compounds TT00, TT001 and/or TT002 may be administered at a dose of 0.1 to 5.0mg/kg, or 0.1 to 2.0mg/kg, or 0.1 to 1.0mg/kg per day. One aspect relates to a dosage regimen wherein compounds TT00, TT001 and/or TT002 are administered to a dog, cat or horse once or twice daily at a dose of 0.1 to 5.0 mg/kg. In one aspect, the compound is TT001, or a hydrochloride or sulfate salt thereof.

In one aspect, the dosage regimen is to administer compounds TT00, TT001 and/or TT002 to the dog, cat or horse once daily at a dose of 0.1 to 1.0mg/kg or twice daily at a dose of 0.1 to 0.5 mg/kg.

For the preparation of pharmaceutical compositions from compounds TT00, TT001 and/or TT002, especially TT001, the inert, pharmaceutically acceptable carrier may be 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 may also be an encapsulating material.

Liquid form compositions include ointments, creams, gels, aqueous liquids, which may be formulated within transdermal patches.

The process for preparing the capsule may comprise the following steps;

a) mixing compounds TT00, TT001 or TT002, especially TT001, with additives such as calcium hydrogen carbonate (calcium hydroxide), phosphate and hydroxypropyl cellulose, stirring for a certain period of time,

b) further additives, such as mannitol and croscarmellose sodium,

c) water is added and the mixture is granulated,

d) the obtained granules were dried and the dried granules were,

e) the dried granules are ground and the dried granules are,

f) further additives, such as sodium stearyl fumarate,

g) mixing the resulting mixture, and

h) encapsulating the mixture, or compressing the mixture into a tablet.

The pharmaceutical composition may be used for the prevention and/or treatment of any disease condition or combination of conditions mentioned herein.

Combination therapy

The prevention and/or treatment of pathologically relevant pain as defined herein may be applied together with conventional therapies of value in the prevention and/or treatment of one or more of the disease conditions mentioned herein. Such conventional therapies may include one or more of the following classes of additional therapeutic agents: NSAIDs, anesthetic, and opiate.

Examples of NSAIDs may be NSAIDs selected from the group comprising or consisting of: pyrazolidine class, which is 1, 2-diphenylpyrazolidine-3, 5-dione with a butyl group in the 4-position. It has effects as a non-narcotic analgesic, a non-steroidal anti-inflammatory drug, an antirheumatic, a peripheral nervous system drug, a metabolite and an EC 1.1.1.184[ carbonyl reductase (NADPH) ] inhibitor. In another aspect, the NSAIDs are selected from the group comprising or consisting of: butylpyrazoles, oxicams, propionic acid derivatives, fenamic acid and coxibs. NSAIDs may be selected from the group consisting of: oxicams, propionic acid derivatives and coxibs.

NSAIDs may include butylpyrazoles, oxicams, propionic acid derivatives, or coxibs. The additional therapeutic agent may be any other non-steroidal anti-inflammatory agent or anti-rheumatic agent.

Examples of opiates may include tramadol and tapentadol.

Such combination therapy may be achieved by the simultaneous, sequential or separate administration of individual components for the prevention and/or treatment of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, in a dog, cat or horse.

The combination may comprise or consist of a pharmaceutical composition comprising (i) the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or mixtures thereof, (ii) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable excipient, carrier or diluent.

The combination may also comprise or consist of a pharmaceutical composition comprising (i) the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, (ii) at least one additional therapeutic agent selected from the group consisting of: (ii) an anesthetic, an NSAID, and an opiate, and (iii) a pharmaceutically acceptable excipient, carrier, or diluent.

The definition of said combination includes a pharmaceutical composition comprising (i) the compounds TT00, TT001 and/or TT002, or a pharmaceutically acceptable salt, diastereomer, enantiomer, isotope, prodrug or metabolite thereof or a mixture thereof, and a pharmaceutically acceptable excipient, carrier or diluent, and (ii) at least one additional therapeutic agent selected from the group consisting of: narcotics, NSAIDs and opiates, and pharmaceutically acceptable excipients, carriers or diluents.

The combination may be (i) TT001, or a hydrochloric acid or sulfate thereof, and (ii) acepromazine.

The combination may be (i) TT001, or a hydrochloric acid or a sulfate thereof, and (ii) an oxicam.

The combination may be (i) TT001, or a hydrochloric acid or a sulfate thereof, and (ii) a propionic acid derivative. The combination may be (i) TT001, or a hydrochloric acid or a sulfate thereof and (ii) a coxib.

The additional therapeutic agent may be an opiate such as tramadol and tapentadol.

The combination may be (i) TT001, or a hydrochloric acid or a sulfate thereof, and (ii) tramadol.

The combination may be (i) TT001, or its hydrochloric acid or sulfate salt and (ii) tapentadol

The additional therapeutic agent may be an anesthetic selected from the group consisting of: acepromazine, morphine or propofol.

The combination may be (i) TT001, or a hydrochloric acid or sulfate thereof, and (ii) acepromazine. The combination may be (i) TT001, or a hydrochloric acid or sulfuric acid salt thereof, and (ii) morphine. The combination may be (i) TT001, or a hydrochloric acid or sulfate thereof, and (ii) propofol.

The combination may be used for the prevention and/or treatment of pain, such as chronic and/or peripheral pain and/or pain associated with arthritis, such as osteoarthritis, or the prevention and/or treatment of a) the pain in combination with b) GERD or c) anxiety.

Pharmaceutical composition

Ointment formulation

Active ingredient weight corresponding to TT 001: 0.1 to 50mg

The weight of the propylene carbonate is as follows: 50mg of

Hard paraffin weight: 30mg of

White beeswax weight: 35mg of

Weight of liquid paraffin: 110mg

White soft paraffin weight: 774.7mg

Cream formulation

TT001 weight: 0.1-100mg

The weight of the propylene glycol is as follows: 100mg of

Isopropyl myristate weight: 50mg of

Cetostearyl alcohol (cetostearyl alcohol) weight: 52.5mg

Citric acid monohydrate (e330) weight: 0.5mg

Weight of anhydrous disodium phosphate: 0.6mg

Weight of water: adding a sufficient amount to achieve a target weight of 30 or 100g

Weight of liquid paraffin: 400mg of

Polyethylene glycol cetostearyl ether (macrogol cetostearyl ether) weight: 7.5mg

Disodium phosphate dodecahydrate (e339) by weight: 1.5mg

Weight of prochloraz: 2mg of

Capsule preparation

TABLE 1.2mg and 8mg Components and amounts of TT001 Capsule

Preparation of the Compounds

Compounds TT00, TT001 and/or TT002 may be prepared as the free base or a pharmaceutically acceptable salt thereof by the processes described in US7,476,684B 2 or WO2007/040982 a1, which are included herein by reference.

Pharmaceutical composition

Formulation method for preparing TT001 for i.v. administration, 0.1 to 10mg/ml

The formulation method is suitable for use in formulations having concentrations between 0.1 and 10mg/ml, corresponding to 0.262 and 26.2. mu. mol/ml

TT001 M.W.:381.8g/mol

The solubility of TT001 was moderate, allowing several hours for complete dissolution.

Media

Preparation of a 40% w/v HP β CD solution in Water for injection

Excipients hydroxypropyl-beta-cyclodextrin, Klepotase, Roquette (HP. beta. CD)400mg (40% w/v)

1ml of water for injection (1.13g)

Clear appearance

Density 1.13g/cm³

Preparation

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

TT001 parent form 0.1-10mg

Vehicle (40% w/v HP β CD solution in water for injection) to 1ml (1.13g)

Clear appearance

Density 1.13g/cm³

Note

The solubility of TT001 was moderate, allowing several hours for complete dissolution.

Ointment formulation

Active ingredient weight corresponding to TT 001: 0.1 to 50mg

The weight of the propylene carbonate is as follows: 50mg of

Hard paraffin weight: 30mg of

White beeswax weight: 35mg of

Weight of liquid paraffin: 110mg

White soft paraffin weight: 774.7mg

Cream formulation

TT001 weight: 0.1-100mg

The weight of the propylene glycol is as follows: 100mg of

Isopropyl myristate weight: 50mg of

Hexadecanol octadecanol mixture weight: 52.5mg

Citric acid monohydrate (e330) weight: 0.5mg

Weight of anhydrous disodium phosphate: 0.6mg

Weight of water: adding a sufficient amount to achieve a target weight of 30 or 100g

Weight of liquid paraffin: 400mg of

Polyethylene glycol cetostearyl ether weight: 7.5mg

Disodium phosphate dodecahydrate (e339) by weight: 1.5mg

Weight of prochloraz: 2mg of

Capsule preparation

TABLE 1.2mg and 8mg Components and amounts of TT001 Capsule

Examples

Pharmaceutical composition

Ointment formulation

TT001 weight: 0.1-100mg

The weight of the propylene carbonate is as follows: 50mg of

Hard paraffin weight: 30mg of

White beeswax weight: 35mg of

Weight of liquid paraffin: 110mg

White soft paraffin weight: 774.7mg

Cream formulation

TT001 weight: 0.1-100mg

The weight of the propylene glycol is as follows: 100mg of

Isopropyl myristate weight: 50mg of

Hexadecanol octadecanol mixture weight: 52.5mg

Citric acid monohydrate (e330) weight: 0.5mg

Weight of anhydrous disodium phosphate: 0.6mg

Weight of water: adding a sufficient amount to achieve a target weight of 30 or 100g

Weight of liquid paraffin: 400mg of

Polyethylene glycol cetostearyl ether weight: 7.5mg

Disodium phosphate dodecahydrate (e339) by weight: 1.5mg

Weight of prochloraz: 2mg of

Pain relief test

Among the protocols that can be used to assess pain relief in dogs are:

kinetic Data with Force Plates and Pressure walkways (Kinetic Data with Force Plates and a Pressure walk)

-Helsinki Chronic Pain Index (HCPI)

Concise pain scale for dogs (CBPI)

-cincinnati orthopaedic Disability Index (cincinnati Orthopedic Disability Index) (CODI)

-Liverpool Osteoarthritis Osteoarthritis in Dogs (LOAD)

Since chronic pain is also assessed by the owner, a so-called "owner questionnaire" is often used for the effectiveness assessment of pain products.

Dog gait analysis is an important tool for objective assessment of normal and abnormal gait. Although there are many ways to collect the temporal and spatial parameters of gait analysis, force-measuring plates (FP) are currently considered the gold standard for measuring Ground Reaction Forces (GRFs) and related metrics generated by these forces. The data collected from the FP has proven to be an effective method for assessing lameness in dogs with musculoskeletal pathology, as well as the success or failure of medical or surgical interventions or combinations.

Example 1

To be able to assess pain, validated pain models can be used, such as kinetic data with force plates and pressure walkways. This should be combined with validated pain regimens such as the Helsinki Chronic Pain Index (HCPI), the canine compact pain scale (CBPI), or the philips dog osteoarthritis (LOAD).

Test of

To be included in the trial, the dog should have OA and the veterinarian will decide whether or not the dog should be included in the trial.

The owner will answer the question according to the scheme on the first meeting.

The owner's dogs with OA are then guided onto a pressure walkway with gyroscopes (gyros) attached to their legs and head. The pressure on the walkway is recorded as well as the data from the gyroscope. The video is also recorded while walking.

Dogs with OA exert more weight on the unaffected limbs when walking, which is recorded by both the pressure walkway and the gyroscope.

After initial walking, the dogs will be treated with TT001 formulated as an oral or topical transdermal formulation and then returned to home. One week later, the owners brought the dogs back. During that week, the dogs had been treated by the owners with TT 001.

At a second meeting one week later, the dogs will walk the walkway again. The owner will answer the question according to the scheme.

The third and last meeting is one week later and the procedure will be the same as the previous week.

Data from the walkway, gyroscope and video is processed. The algorithm will compare the different data sets and present any differences in dog gait. This in turn will be the basis for evaluating the effect of TT001 on pain.

This example is expected to show that TT001 actually has an effect on pain in dogs with OA and has no known toxic effects from NSAIDs.

Example 2

The toxic effects of NSAIDs are due in part to the inhibition of the production of prostaglandins that protect kidney and gastrointestinal homeostasis. Cats are particularly susceptible to the toxic effects of certain NSAIDs because of their lack of a hepatic glutathione-dependent enzyme system involved in the metabolism of many NSAIDs. Toxic side effects include: gastric irritation, progression to vomiting, ulceration and bleeding, enteritis leading to diarrhea, dyscrasia, occasional hepatotoxicity and/or nephrotoxicity. Nephrotoxicity is more likely to occur in animals that are dehydrated, hypovolemic or hypotensive, animals that are undergoing anesthesia, or animals that are being treated with other drugs that have potential nephrotoxicity.

It is understood that senior cats are more susceptible to Osteoarthritis (OA) than senior cats and that these older cats have a much higher incidence of kidney problems. Since the treatment of OA is life-long, it is important that pharmacotherapy does not have any adverse effects on the kidney of the cat. TT001 did not show any adverse effects on the kidney.

We aimed to show that cats with OA in clinical trials will obtain pain relief after treatment with TT 001.

To be able to assess pain, validated pain models can be used, such as kinetic data with force plates and pressure walkways. This should be combined with validated pain regimens such as the Helsinki Chronic Pain Index (HCPI), the canine compact pain scale (CBPI), or the leips dog osteoarthritis (LOAD).

Test of

To be included in the trial, the cat should have OA and the veterinarian will decide whether or not the cat should be included in the trial.

The owner will answer the question according to the scheme at the first meeting.

The owner's cat with OA is then guided onto the pressure walkway with gyroscopes attached to their legs and head. The pressure on the walkway is recorded as well as the data from the gyroscope. The video is also recorded while walking.

Cats with OA will exert more weight on the unaffected limb when walking, which is recorded by both the pressure walkway and the gyroscope.

After initial walking, cats will be treated with TT001 formulated as an oral or topical transdermal formulation and then returned to home. One week later, the owner brings the cat back. During that week, the cats had been treated with TT001 by the owners.

At a second meeting one week later, the cat will walk on the walkway again. The owner will answer the question according to the scheme.

The third and last meeting is one week later and the procedure will be the same as the previous week.

Data from walkways, gyroscopes and video are processed. The algorithm will compare the different data sets and present any differences in cat gait. This in turn will be the basis for assessing the effect of TT001 on pain.

This example is expected to show that TT001 actually has an effect on pain in cats with OA and has no known toxic effects from NSAIDs.