GB2428675A

GB2428675A - Ifenprodil derivatives

Info

Publication number: GB2428675A
Application number: GB0515699A
Authority: GB
Inventors: Andrew Douglas Baxter; Andrea Walmsley
Original assignee: Arakis Ltd
Current assignee: Sosei R&D Ltd
Priority date: 2005-07-29
Filing date: 2005-07-29
Publication date: 2007-02-07
Also published as: GB0515699D0

Abstract

Compounds of general formula (1): <EMI ID=1.1 HE=22 WI=63 LX=738 LY=728 TI=CF> <PC>wherein R1 is CHCF2, CH2F, COR2, CH(OR3)R2 or C4-6heterocycloalkyl; R2 is optionally substituted C1-4alkyl, aryl, heteroaryl, C3-6 carbocycloalkyl or C4-6heterocycloalkyl; R3 is hydrogen or C1-4alkyl; or a salt, solvate or hydrate thereof may be useful in the treatment of: pain conditions, such as chronic pain, malignant pain, chronic headache (including migraine and cluster headaches) or arthritic pain; an inflammatory condition, such as rheumatoid arthritis, osteoporosis, osteoarthritis, multiple sclerosis, a respiratory disease (including chronic obstructive pulmonary disease (COPD) and asthma), ulcerative colitis, Crohn's disease, atopic dermatitis, psoriasis, diabetic nephropathy, Parkinson's disease or Alzheimer's disease. Pharmaceutical compositions comprising these compounds are also outlined. A preferred compound is 4-(2-(4-benzylpiperidin-1-y1)-1-hydroxypropy1)phenyl tetrahydro-2H-pyran-4-carboxylate.

Description

I

PRODRUGS

Field of the Invention

The present invention relates to pro-drugs of ifenprodil that are potent analgesic and anti-inflammatory agents, processes for their preparation and their utility in the treatment of pain, inflammation and neurodegenerative diseases.

Background to the Invention

Ifenprodil is an NMDA antagonist. It has also been reported that ifenprodil is a cytokine modulator and has anti-inflammatory properties. The oral bioavailability of ifenprodil is limited by high first-pass metabolism and this precludes utility of the agent in chronic indications.

Summary of the Invention

We have discovered that bioavailability of ifenprodil can be improved significantly by utilising a pro-drug of the metabolically labile phenol. Influencing the stability of the pro-drug has been shown to improve absorption and eliminate gut wall metabolism. Influencing the physical properties of the pro-drug eliminates first pass metabolism. A pro-drug strategy around the ifenprodil template has provided a series of agents that are potent in animal models of pain when delivered by the oral or intra-nasal route. Such agents have the potential to be low dose analgesics and anti-inflammatories suitable for the treatment of a broad spectrum of conditions such as chronic, acute and neuropathic pain, inflammatory diseases including, but not exclusive to, autoimmune diseases involving multiple organs, such as systemic lupus erythematosus (SLE) and scleroderma, specific tissues or organs such as the musculoskeletal tissue (rheumatoid arthritis, ankylosing spondylitis), gastro-intestinal tract, (Crohn's disease and ulcerative colitis), the central nervous system (Alzheimers, Multiple sclerosis, motor neurone disease, Parkinson's disease and chronic fatigue syndrome), pancreatic beta cells (insulin dependent diabetes mellitus), the adrenal gland (Addison's diseae), the kidney (Goodpasture's syndrome, IgA nephropathy, interstitial nephritis) exocrine glands (Sjogrens syndrome and autoimmune pancreatitis) and skin (psoriasis and atopic dermatitis), chronic inflammatory diseases such as osteoarthritis, periodontal disease, diabetic nephropathy, chronic obstructive pulmonary disease, artherosclerosis, graft versus host disease, chronic pelvic inflammatory disease, endometriosis, chronic hepatitis and tuberculosis, angiogenesis driven diseases such as cancer, age related macular degeneration and diabetic retinopathy, lgE mediated (Type I) hypersensitivities such as rhinitis, asthma, anaphylaxis and dermatitis.

Dermatitis conditions include; actinic keratosis, acne rosacea, acne vulgaris, allergic contact dermatitis, angioedema, atopic dermatitis, bullous pemiphigoid, cutaneous drug reactions, erythema multiforme, lupus erythrametosus, photodermatitis, psoriasis, psoriatic arthritis, scieroderma and urticaria.

These compounds are of general formula (1): R1AJ (1) wherein: R1 is CHCF2, CH2F, COR2, CH(0R3)R2 orC46 heterocycloalkyl; R2 is optionally substituted C14a1ky1, aryl, heteroaryl, C36 carbocycloalkyl or C46 heterocycloalkyl; and R3 is H or C14 alkyl; and the salts, solvates and hydrates thereof.

Description of Preferred Embodiments

It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centres in a compound of formula (1) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.

The term C14 alkyl" refers to a straight or branched chain alkyl moiety having from one to four carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like.

The term "C36 carbocycloalkyl" refers to a carbocyclic ring containing from three to six carbon atoms, including for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl rings.

The term "C46 heterocycloalkyl" refers to a heterocyclic ring containing from four to six atoms. One of these atoms is taken from the list 0, N or S and as such ring systems can include azetidirie, oxetane, pyrrolidine, piperidine, tetrahydropyran and the like.

There term "aryl" means an optionally substituted phenyl or naphthyl group with the substituent(s) being selected, for example, from halogen, trifluoromethyl, CN, C14 alkyl, alkoxy, phenyl and the like.

The term "heteroaryl" refers to optionally substituted aromatic ring systems of five to ten atoms or which at least one atom is selected from the group, 0, N, or S and includes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like. The substituent(s) are selected, for example, from halogen, trifluoromethyl, CN, C14 alkyl, alkoxy, phenyl and the like.

The term uhalogenul means fluorine, chlorine, bromine or iodine.

Compounds of the general formula (1) may be prepared by any suitable method known in the art and/or by the following process, which itself forms part of the invention. It will be appreciated that where a particular stereoisomer of formula (1) is required, the synthetic processes described herein may be used with the appropriate homochiral starting material and/or isomers maybe resolved from mixtures using conventional separation techniques (e.g. HPLC). Further, it will be appreciated that functional groups, such as amino, hydroxyl or carboxyl groups, and which it is desired to retain, may need to be in protected form before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art.

The process comprises conversion of ifenprodil (R1 = H) to the corresponding prodrug (1) by protection methods that are well known to people who are skilled in the art of synthetic organic chemistry. For specific details, see "Protective Groups in Organic Synthesis", Wiley lnterscience, T W Greene, PGM Wuts.

Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances.

The compounds of formula (1) according to the invention exhibit analgesic activity in animal models. The activity of the compounds may be determined by use of the appropriate in vivo assay.

This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat or fur industries or as pets) suffering from chronic, acute or neuropathic pain and inflammatory conditions.

Accordingly, the compounds of formula (1) can be used among other things in the treatment of pain conditions such as acute and chronic pain (as well as, but not limited to, pain associated with cancer, surgery, arthritis, dental surgery, trauma, musculo-skeletal injury or disease, visceral diseases) and migraine headache. Additionally the painful conditions can be neuropathic (post-herpetic neuralgia, diabetic neuropathy, drug induced neuropathy, HIV mediated neuropathy, sympathetic reflex dystrophy or causalgia, fibromyalgia, myofacial pain, entrapment neuropathy, phantom limb pain, trigeminal neuralgia.

Neuropathic conditions include central pain related to stroke, multiple sclerosis, spinal cord injury, arachnoiditis, neoplasms, syringomyelia, Parkinson's and epilepsia. The compounds of formula (1) can also be used to treat inflammatory diseases including, but not exclusive to, autoimmune diseases involving multiple organs, such as systemic lupus erythematosus (SLE) and scleroderma, specific tissues or organs such as the musculoskeletal tissue (rheumatoid arthritis, ankylosing spondylitis), gastro-intestinal tract, (Crohn's disease and ulcerative colitis), the central nervous system (Alzheimers, Multiple sclerosis, motor neurone disease, Parkinson's disease and chronic fatigue syndrome), pancreatic beta cells (insulin dependent diabetes mellitus), the adrenal gland (Addison's diseae), the kidney (Goodpasture's syndrome, IgA nephropathy, interstitial nephritis) exocrine glands (Sjogrens syndrome and autoimmune pancreatitis) and skin (psoriasis and atopic dermatitis), chronic inflammatory diseases such as osteoarthritis, periodontal disease, diabetic nephropathy, chronic obstructive pulmonary disease, artherosclerosis, graft versus host disease, chronic pelvic inflammatory disease, endometriosis, chronic hepatitis and tuberculosis, angiogenesis driven diseases such as cancer, age related macular degeneration and diabetic retinopathy, IgE mediated (Type I) hypersensitivities such as rhinitis, asthma, anaphylaxis and dermatitis. Dermatitis conditions include; actinic keratosis, acne rosacea, acne vulgaris, allergic contact dermatitis, angioedema, atopic dermatitis, bul bus pemiphigoid, cutaneous drug reactions, erythema multiforme, lupus erythrametosus, photodermatitis, psoriasis, psoriatic arthritis, scleroderma and urticaria.

For the treatment of pain and inflammatory conditions the compounds of formula (1) may be administered orally (including sublingual), topically, parenterally, dermally, by inhalation or nasal spray or rectally in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats etc, the compounds of the invention are effective in the treatment of humans.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the US Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsules where in the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate polyvinyl- pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.

Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3- butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of formula (1) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc containing the compounds of formula (1) are employed. (For purposes of this application, topical application shall include mouth washes and gargles).

Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the aboveindicated conditions (about 2.5 mg to about 7 gms per patient per day). For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 gms per patient per day).

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may vary from about 5 to about 95 percent of the total composition Dosage unit forms will generally contain between from about I mg to about 500 mg of an active ingredient.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The following example illustrates the invention:

Example I

4-(2-(4-benzylpi pendin-1 -yl)-1 -hydroxypropyl)phenyl tetrahydro-2Hpyran4- carboxylate Erythro-lfenprodi I hemi-tartrate (12. 7g) in dichloromethane (250mL) was treated with triethylamine (4.42mL) at RI for lhr. An aqueous work-up with sodium carbonate, drying over sodium sulfate and concentration under vacuum gave the free base (7.9g).

A suspension of the free base (7.6g) in dichloromethane (200mL) was treated with triethylamine (3.26mL) and the solution cooled to 0 C.

Tetrahydropyranyl carbonylchioride (3.47g) in dichloromethane (4OmL) was added dropwise and then the solution allowed to reach RI over 2hrs. The solution was washed with water and brine, dried over sodium sulfate and concentrated to give 6.2g of the title material, 60%.

I H NMR: 0.97 (3H, d), 1 20-1.32 (2H, m), 1.50-1.71 (3H, m), 1.78-1.90 (2H, m), 1.92-2.05(2H, m), 2.31-2.51 (4H, m), 2.69-2.74(1H, m),2.81-2.89(IH, m),2. 92- 3.10 (2H, m), 3.49-3.55 (2H, m), 3.95-3.99 (2H, m), 4.90-4.96(1 H, m), 7. 02 (2H, d), 7.13 (2H, d), 7.05-7.12 (1H, m), 7.20-7.28 (2H, m), 7.35 (2H, d).

LCMS: 438.80 (M+H)

Claims

1. A compound of general formula (1): R1)LJ (1) wherein: R1 is CHCF2, CH2F, COR2, CH(0R3)R2 or C heterocycloalkyl; R2 is optionally substituted C14aIkyl, aryl, heteroaryl, C36 carbocycloalkyl or C46 heterocycloalkyl; and R3 is H or C14 alkyl; or a salt, solvate or hydrate thereof

2. A pharmaceutical composition for use in therapy, comprising a compound of claim 1 and a pharmaceutically acceptable diluent or carrier.

3. Use of a compound of claim 1, for the manufacture of a medicament for the treatment of a pain condition.

4. Use according to claim 3, wherein the pain condition is chronic pain such as chronic back pain, malignant pain, chronic headache (including migraine and cluster headaches) or arthritic pain.

5. Use according to claim 3, wherein the pain condition is acute pain such as post-operative pain, post-traumatic pain or acute disease induced pain.

6. Use according to claim 3, wherein the pain condition is neuropathic pain.

7. Use of a compound of claim 1, for the manufacture of a medicament for the treatment of an inflammatory condition.

8. Use according to claim 7 wherein the condition is a chronic degenerative disease such as rheumatoid arthritis, osteoarthritis or osteoporosis.

9. Use according to claim 7 wherein the condition is a chronic demyelinating disease such as multiple sclerosis.

10. Use according to claim 7 wherein the condition is a respiratory disease such as asthma or chronic obstructive pulmonary disease.

11. Use according to claim 7 wherein the condition is an inflammatory bowel disease (IBD) such as ulcerative colitis or Crohn's disease.

12. Use according to claim 7 wherein the condition is a dermatological condition such as psoriasis, scleroderma or atopic dermatitis.

13. Use according to claim 7 wherein the condition is a dental disease such as periodontal disease or gingivitis.

14. Use according to claim 7, wherein the condition is diabetic nephropathy, lupus nephritis, IgA nephropathy or glomerulonephrjtis.

15. Use according to claim 7 wherein the condition is systemic lupus erythematosus (SLE).

16. Use according to claim 7 wherein the condition is graft vs host disease.

17. Use of a compound of claim 1, for the manufacture of a medicament for the treatment of a neurodegenerative disease such as Parkinson's disease or Alzheimers disease.

18. Use of a compound of claim 1, for the manufacture of a medicament for the treatment of cancer, age-related macular degeneration or diabetic retinopathy.

19. Use according to any preceding claim wherein the patient is also administered another therapeutic agent selected from corticosterojds, cytotoxics, antibiotics, immunosupressants, non-steroidal antiinflammatory drug, a narcotic analgesic, a local anaesthetic, an NMDA antagonist, a neuroleptic, an anti- convulsant, an anti-spasmodic, an anti-depressant and a muscle relaxant.

20. Use according to claim 19 wherein compound (I) and said another agent are provided in combination.