WO2022253943A1

WO2022253943A1 - Crystalline forms of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3r)-tetrahydrofuran-3-yloxy]-n-{(1r)-1-[2-(trifluoro-methyl)pyrimidin-5-yl]ethyl}-benzamide

Info

Publication number: WO2022253943A1
Application number: PCT/EP2022/065015
Authority: WO
Inventors: Olenik Britta; Keil Birgit; Nico BRÄUER
Original assignee: Bayer Aktiengesellschaft; Bayer Pharma Aktiengesellschaft
Priority date: 2021-06-04
Filing date: 2022-06-02
Publication date: 2022-12-08

Abstract

This present invention relates to crystalline form of 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)- tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoro-methyl)pyrimidin-5-yl]ethyl}-benzamide which is the modification II, to processes for its preparation, to pharmaceutical compositions comprising it and to its use in the control of disorders.

Description

Crystalline forms of 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1- [2-(trifluoro-methyl)pyrimidin-5-yl]ethyl}-benzamide The present invention relates to solid forms of 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)- tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoro¬methyl)pyrimidin-5-yl]ethyl}-benzamide, in particular to the modification II, to processes for their preparation, to pharmaceutical compositions comprising them and to use thereof in the control of disorders. 3-(5-Methyl-1,3-thiazol-2-yl)-5- [(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoro-methyl)pyrimidin-5-yl]ethyl}benzamide, also known as Eliapixant, corresponds to the compound of formula (I):

Eliapixant is a potent and selective P2X3 receptor antagonists. As the P2X3 receptor is mainly expressed in dorsal root ganglia, it plays a prominent role in nociception and inflammation. WO2016/091776, WO2019/219674 as well as WO2019/219672 illustrate its utility as active ingredient in pharmaceutical compositions for the treatment of neurogenic disorders as persistent chronic cough, endometriosis, overactive bladder, neuropathic low back pain and diabetic neuropathic pain. Therefore, the compound of formula (I) is suitable as medicine for the treatment of the above mentioned diseases. Crystalline forms of the compound of formula (I) have been identified which are modification I, modification II, modification III, modification IV and a pseudopolymorphic form which is a dihydrate. In this context, modifications, polymorphic forms and polymorphs have the same meaning. In addition, an amorphous form exists. All together – the polymorphic forms, the pseudopolymorphic form and the amorphous form – are different solid forms of the compound of formula (I). Modification II of the compound of the formula (I) is the thermodynamically stable form in a temperature range of 0°C und 80°C. Surprisingly, the modification II of the compound of formula (I) shows beneficial properties over the other solid forms of the compound of formula (I) with regard to crystallization properties, habitus, and improved handling during the chemical synthesis, in particular for work-up and isolation. Modification II is therefore suitable and preferred over the other solid forms of the compound of formula (I) for use in the pharmaceutical field, in particular suitable for pharmaceutical compositions. In particular modification II of the compound of the formula (I) ensures that an undesired conversion into another form of the compound of formula (I) and an associated change in the properties as described above is prevented. This increases the safety and quality of preparations and formulations comprising of the compound of the formula (I) and the risk to the patient is reduced. A pharmaceutical composition according to the present invention comprises the modification II of the compound of formula (I) and optionally further pharmaceutically acceptable excipients. A preferred embodiment of the present invention is a pharmaceutical composition comprising modification II of the compound of the formula (I) mainly and no significant fractions of another form of the compound of the formula (I) and optionally further pharmaceutically acceptable excipients. More preferably the pharmaceutical composition contains more than 85 percent by weight, more preferably more than 90 percent by weight, most preferably more than 95 percent by weight, of the modification II of the compound of the formula (I) related to the total amount of all forms of the compound of the formula (I) present in the composition. The different forms of the compound of formula (I) can be distinguished by X-ray powder diffraction, and differential scanning calorimetry (DSC). The modification I of the compound of formula (I) can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections 15.5, 17.5, and 22.3, preferably at least the following reflections: 15.5, 17.5, 22.3, 24.4, and 7.7, more preferably at least the following reflections: 15.5, 17.5, 22.3, 24.4, 7.7, 11.5 and 10.1, most preferably at least the following reflections: 17.5, 22.3, 24.4, 7.7, 11.5, 10.1, 14.4 and 37.0 each quoted as 2Ɵ value ± 0.2°. The modification I of the compound of formula (I) can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 1. The modification II of the compound of formula (I) can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 8.7, 12.4 and 14.1, preferably at least the following reflections: 8.7, 12.4, 13.5, 14.1, and 24.6, more preferably at least the following reflections: 8.7, 12.4, 13.5, 14.1, 24.6, 25.6, and 26.5, most preferably at least the following reflections: 8.7, 12.4, 13.5, 14.1, 24.6, 25.6, 26.5 and 26.8, each quoted as 2Ɵ value ± 0.2°. The modification II of the compound of formula (I) can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) as shown in Figure 2. The modification III of the compound of formula (I) can be characterized unambiguously by a X- Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 15.7, 19.0, and 25.3, preferably at least the following reflections: 15.7, 19.0, 25.3, 12.0 and 16.4, more preferably at least the following reflections: 15.7, 19.0, 25.3, 12.0 16.4, 17.1 and 13.3, most preferably at least the following reflections: 15.7, 19.0, 25.3, 12.016.4, 17.1, 13.3, 9.9, 10.8, and 28.9, each quoted as 2Ɵ value ± 0.2°. The modification III of the compound of formula (I) can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 3. The dihydrate form of the compound of formula (I) can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 14.7, 25.1, and 22.5 preferably at least the following reflections: 14.7, 25.1, 22.5, 20.7, and 21.8, more preferably at least the following reflections: 14.7, 25.1, 22.5, 20.7, 21.8, 19.5, and 33.3, most preferably at least the following reflections:14.7, 25.1, 22.5, 20.7, 21.8, 19.5, 33.3, 27.9, 28.4, and 13.1, each quoted as 2Ɵ value ± 0.2°. The dihydrate form of the compound of formula (I) can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 4. Process for preparing: Mod. II as well as mixtures of Mod. II and Mod. III were suspended in different solvents and stirred at 0°C, 25°C and 60°C. Some suspensions of Mod. II were seeded with Mod. III and Mod. I. At the end of the stirring time the residues were filtered off and dried at room temperature and ambient humidity. The results are summarized in Table 1. Table 1: Slurry experiments

With the exception of acetonitrile/water (1 : 1) the residues proved to be Mod. II. Only in acetonitrile/ water (1 : 1) the Dihydrate formed. Method for treatment The present invention also relates to a method for using a compound of formula (I) and compositions thereof, to treat mammalian neurogenic diseases and disorders. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of formula (I) or composition thereof, which is effective to treat the disease or disorder. Neurogenic diseases and disorders include but are not limited to genitourinary, gastrointestinal, respiratory diseases, cardiovascular disease associated with autonomic imbalance caused by increased chemoreceptor sensitivity, and pain as such as well as pain-related diseases, conditions and disorders, gynecological diseases, urinary tract disease states, pain-related diseases and disorders, pain-associated diseases and disorders, neurological diseases and disorders, neurodegenerative diseases and disorders and dermatological diseases and disorders. Gynecological diseases include but are not limited to dysmenorrhea (primary and secondary dysmenorrhea), dyspareunia, endometriosis, and adenomyosis; endometriosis-associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular dysmenorrhea, dyspareunia, dysuria, or dyschezia; endometriosis-associated proliferation; pelvic hypersensitivity. Preference is given to endometriosis and to moderate to severe pain associated with endometriosis in women of reproductive age. Urinary tract disease states include, but are not limited to those associated with the bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive urinary bladder and symptoms related to overactive urinary bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular Interstitial cystitis; idiopathic bladder hypersensitivity and bladder pain syndrome,. Preference is given to overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, urinary frequency and nocturia. Furthermore, preference is given to interstitial cystitis and bladder pain syndrome as well. Neurological diseases and disorders include, but are not limited to epilepsy, partial and generalized seizures. Respiratory diseases and disorders include, but are not limited to asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute cough, chronic cough including chronic idiopathic and refractory and/ or unexplained chronic cough, persistent chronic cough, bronchospasm and interstitial lung disease (including idiopathic pulmonary fibrosis). Preference is given to refractory and/ or unexplained chronic cough. Cardiovascular diseases and disorders include, but are not limited to those associated with nerve fiber sensitization, and/or other pathological conditions associated with autonomic imbalance caused by increased chemoreceptor sensitivity, in particular for the treatment of breathing disorders, Cheyne Stokes respiration, central and obstructive sleep apnea, cardiovascular disease, hypertension, resistant hypertension, and heart failure, which are related to increased activity of P2X3 receptors. Gastrointestinal dieases and disorders include, but are not limited to irritable bowel syndrome (IBS), epigastric pain syndrome (functional dyspepsia syndrome), functional abdominal bloating with distension, inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS; gastroesophageal reflux, gastrointestinal distension, ulcerative colitis (Crohn’s disease). Preference is given to irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Furthermore, irritable bowel syndrome with diarrhea (IBS D) is preferred. Neurodegenerative diseases and disorders include, but are not limited to Alzheimer's disease, Multiple Sclerosis, Parkinson’s disease, Brain ischemia and traumatic brain injury. Dermatological diseases and disorders include, but are not limited to Prurigo nodularis, chronic pruritus of unknown origin, pruritus due to kidney or liver disease, Brachioradial pruritus, Rosacea, Chronic hand eczema, Dyshidrotic eczema, Atopic dermatitis and Psoriasis. Pain-related diseases and disorders include, but are not limited to acute, chronic, inflammatory and neuropathic pain syndromes. Pain-related diseases and disorders include, but are not limited to pain syndromes selected from the group consisting of acute, chronic, inflammatory and neuropathic pain, preferably inflammatory pain, low back pain, surgical pain, postsurgical neuropathic pain, posttraumatic neuropathic pain, visceral pain, dental pain, periodontitis, premenstrual pain, endometriosis-associated pain, pain associated with fibrotic diseases, central pain, pain due to burning mouth syndrome, pain due to burns, pain due to migraine, cluster headaches, pain due to nerve injury, pain due to neuritis, neuralgias, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, cancer- related neuropathic pain, chemotherapy-related neuropathic pain, pain due to viral, parasitic or bacterial infections, pain due to traumatic nerve-injury, pain due to post-traumatic injuries (including fractures and sport injuries), pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, postherpetic neuralgia, chronic lower back pain, neck pain phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, bladder pain syndrome, pain associated with gastrointestinal distension, chronic arthritic pain and related neuralgias, and pain associated with cancer, Morphine- resistant pain, pain associated with chemotherapy, HIV and HIV treatment-induced neuropathy; and pain associated with diseases or disorders selected from the group consisting of hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis). Pain-associated diseases and disorders include, but are not limited to hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome), gout, arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headaches, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries), neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy, pruritus; impaired wound healing and disease of the skeleton like degeneration of the joints. Preference is given to neuropathic pain, in particular to peripheral neuropathic pain. Furthermore, preference is given to neuropathic pain associated with diabetic peripheral neuropathy (NP-DPN). Furthermore, preference is given to cancer and/ or chemotherapy related neuropathic pain, to postherpetic neuralgia and to postsurgical and/ or posttraumatic neuropathic pain. The present invention relates to a method for using the compounds of the present and compositions thereof to treat inflammation, in particular neurogenic inflammation. The term "inflammation" is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including, inter alia, acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever. The present invention relates to a method for using the compounds of the present invention and compositions thereof to treat fibromyalgia, myofascial disorders, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, surgical or dental procedures, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, stroke, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, sarcoidosis and any other disease with an inflammatory component. The present invention relates to a method for using the compounds of the present invention and compositions thereof to treat mammalian, including human disorders and diseases which are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject. Diseases that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases. These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals and can be treated by administering the amorphous solid dispersion of the present invention. Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of neurogenic diseases and disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The present invention further provides the use of a compound of formula (I) for the preparation of a amorphous solid dispersion (ASD) for the treatment of the aforesaid disorders. An aspect of the invention of particular interest is a method for treating endometriosis and moderate to severe pain associated with endometriosis in women of reproductive age, for treating overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, urinary frequency and nocturia, for treating interstitial cystitis and/ or bladder pain syndrome, for treating refractory and/ or unexplained chronic cough, for treating neuropathic pain associated with diabetic peripheral neuropathy (NP-DPN), for treating cancer and/ or chemotherapy related neuropathic pain, for treating postherpetic neuralgia and to postsurgical and/ or posttraumatic neuropathic pain, for treating irritable bowel syndrome with diarrhea (IBS D), for treating Prurigo nodularis, chronic pruritus of unknown origin, itch, for treating heart failure and/ or central and obstructive sleep apnea with an amorphous solid dispersion (ASD) of the present invention comprising Eliapixant, preferably in amorphous form, preferably a tablet, most preferably an immediate release tablet. Combination with other pharmaceutical agents The compounds of the present invention can be combined with therapeutic agents or active ingredients, that are already approved or that are still under development for the treatment and/ or prophylaxis of diseases, which are related to or mediated by P2X3 receptor. Such therapeutic agents or active ingredients are for example, but not limited, to 5-(2,4-Diamino-pyrimidin-5-yloxy)-4- isopropyl-2-methoxy-benzenesulfonamide (Gefapixant/MK-7264/AF-219), (5-(5-iodo-2-isopropyl- 4-methoxy-phenoxy)pyrimidine-2,4-diamine (AF-353), 5-[2-isopropyl-4-methoxy-5- (methylsulfonyl)phenoxy]pyrimidine-2,4-diamine (AF-130), 2-[[4-amino-5-(5-iodo-4-methoxy-2- propan-2-yl-phenoxy)pyrimidin-2-yl]amino]propane-1,3-diol (AF-906), and (S)-methyl 2-((2-(2,6- difluoro-4-(methyl-carbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4- carboxylate (BLU-5937/ NEO 5937). The compounds of the present invention can be combined with therapeutic agents or active ingredients, that are already approved or that are still under development for the treatment and/ or prophylaxis of diseases, which are related to other targets like NK1 inhibitors, for example 2-(R)-(4- Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxohexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-piperidine-1- carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)ethyl]methylamide (Orvepitant), 3- [(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoro-methyl)phenyl]ethoxy}-4-(4-fluorophenyl)octa- hydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (Serlopitant), 5-[((2S,3R)-2- 5-([(2R,3S)-2-((R)-1- [3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluorophenyl)morpholino]methyl)-1H-1,2,4-triazol- 3(2H)-one (Aprepitant), [2-[1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-5-pyridin-4-yltriazol-4- yl]pyridin-3-yl]-(2-chlorophenyl)methanone (Tradipitant), (2R,4S)-4-(4-Acetylpiperazin-1-yl)-N-- 2-(4-fluoro-2-methyl-phenyl)-N-methylpiperidine-1-carboxamide (Casopitant), 2-[3,5-bis(trifluoro- methyl)phenyl]-N,2-dimethyl-N-[4-(2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)pyridin-3-yl]- propanamide (Netupitant), [3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoro-methyl)phenyl]ethoxy]-3-(4- fluoro-phenyl)morpholin-4-yl]methyl]-5-oxo-4H-1,2,4-triazol-1-yl]phosphonic acid (Fosapre- pitant), (5S,8S)-8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,9-diaza- spiro-[4.5]decan-2-one (Rolapitant), (2S)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4- fluoro-2-methylphenyl)-N-methylpiperazine-1-carboxamide (Vestipitant), 2-[1-[2-[(2R)-4-[2-[3,5- bis(trifluoromethyl)phenyl]-acetyl]-2-(3,4-dichlorophenyl)morpholin-2-yl]ethyl]piperidin-4-yl]-2- methylpropanamide (Burapitant), [4-[5-[[2-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-propanoyl]- methylamino]-4-(2-methylphenyl)pyridin-2-yl]-1-methylpiperazin-1-ium-1-yl]-methyl hydrogen phosphate (Fosnetupitant), or NK1/ NK3 inhibitors, for example N-[6-[(7S,9alphaS)-7-(hydroxy- methyl)-3,4,6,7,9,9alpha-hexahydro-1H-pyrazino[2,1-c][1,4]-oxazin-8-yl]-4-(4-fluoro-2-methyl- phenyl)pyridin-3-yl]-2-[3,5-bis(trifluoro-methyl)phenyl]-N,2-dimethylpropanamide (Elinzanetant), or with nicotinic Acetylcholine modulators, for example N-(2-((3-pyridinyl)Methyl)-1-aza- bicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide (Bradanicline/ ATA-101). The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with known indication agents. For example, the compounds of the present invention can be combined with known hormonal therapeutic agents. The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of the present invention can be combined with known hormonal therapeutic agents. In particular, the compounds of the present invention can be administered in combination or as comedication with hormonal contraceptives. Hormonal contraceptives can be administered via oral, subcutan, transdermal, intrauterine or intravaginal route, for example as Combined Oral Contraceptives (COCs) or Progestin-Only-Pills (POPs) or hormone-containing devices like implants, patches or intravaginal rings. COCs include but are not limited to birth control pills or a birth control method that includes a combination of an estrogen (estradiol) and a progestogen (progestin). The estrogenic part is in most of the COCs ethinyl estradiol. Some COCs contain estradiol or estradiol valerate. Said COCs contain the progestins norethynodrel, norethindrone, norethindrone acetate, ethynodiol acetate, norgestrel, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, dienogest, or nomegestrol acetate. Birth control pills include for example but are not limited to Yasmin, Yaz, both containing ethinyl estradiol and drospirenone; Microgynon or Miranova containing levonorgestrel and ethinyl estradiol; Marvelon containing ethinyl estradiol and desogestrel; Valette containing ethinyl estradiol and dienogest; Belara and Enriqa containing ethinyl estradiol and chlormadinonacetate; Qlaira containing estradiol valerate and dienogest as active ingredients; and Zoely containing estradiol and normegestrol. POPs are contraceptive pills that contain only synthetic progestogens (progestins) and do not contain estrogen. They are colloquially known as mini pills. POPs include but are not limited to Cerazette containing desogestrel; Microlut containing levonorgestrel and Micronor containing norethindrone. Other Progeston-Only forms are intrauterine devices (IUDs), for example Mirena containing levonorgestrel or injectables, for example Depo-Provera containing medroxyprogesterone acetate, or implants, for example Implanon containing etonogestrel. Other hormone-containing devices with contraceptive effect which are suitable for a combination with the compounds of the present invention are vaginal rings like Nuvaring containing ethinyl estradiol and etonogestrel or transdermal systems like a contraceptive patch, for example Ortho-Evra or Apleek (Lisvy) containing ethinyl estradiol and gestodene. A preferred embodiment of the present invention is the administration of a compound of general formula (I) in combination with a COC or a POP or other Progestin-Only forms as well as vaginal rings or contraceptive patches as mentioned above. The compounds of the present invention can be combined with therapeutic agents or active ingredients, that are already approved or that are still under development for the treatment and/ or prophylaxis of diseases which are related to or mediated by P2X3 receptor. For the treatment and/ or prophylaxis of urinary tract diseases, the compounds of the present invention can be administered in combination or as comedication with any substance that can be applied as therapeutic agent in the following indications: Urinary tract disease states associated with the bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive bladder and symptoms related to overactive bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis; idiopathic bladder hypersensitivity. For the treatment and/ or prophylaxis of overactive bladder and symptoms related to overactive bladder, the compounds of the present invention can be administered in combination or as comedication, independently or in addition to behavioral therapy like diet, lifestyle or bladder training, with anticholinergics like oxybutynin, tolterodine, propiverine, solifenacin, darifenacin, trospium, fesoterdine; ß-3 agonists like mirabegron; neurotoxins like onabutolinumtoxin A; or antidepressants like imipramine, duloxetine. For the treatment and/ or prophylaxis of interstitial cystitis, the compounds of the present invention can be administered in combination or as comedication, independently or in addition to behavioural therapy like diet, lifestyle or bladder training, with pentosans like elmiron; NSAIDS (Non-Steroidal Antiinflammatory Drugs), either unselective NSAIDS like ibuprofen, diclofenac, aspirin, naproxen, ketoprofen, indomethacin; as well as Cox-2 selective NSAIDS like Parecoxib, Etoricoxib, Celecoxib; antidepressants like amitriptyline, imipramine; or antihistamines like loratadine. For the treatment and/ or prophylaxis of gynaecological diseases, the compounds of the present invention can be administered in combination or as comedication with any substance that can be applied as therapeutic agent in the following indications: dysmenorrhea, including primary and secondary dysmenorrhea; dyspareunia; endometriosis; endometriosis-associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular dysmenorrhea, dyspareunia, dysuria, or dyschezia. For the treatment and/ or prophylaxis of dysmenorrhea, including primary and secondary dysmenorrhea; dyspareunia; endometriosis and endometriosis-associated pain, the compounds of the present invention can be administered in combination or as comedication with pain medicaments, in particular NSAIDS like ibuprofen, diclofenac, aspirin, naproxen, ketoprofen, indomethacin; as well as Cox-2 selective NSAIDS like Parecoxib, Etoricoxib, Celecoxib; or in combination with ovulation inhibiting treatment, in particular COCs as mentioned above or contraceptive patches like Ortho- Evra or Apleek (Lisvy); or with progestogenes like dienogest (Visanne); or with GnRH analogous, in particular GnRH agonists and antagonists, for example leuprorelin, nafarelin, goserelin, cetrorelix, abarelix, ganirelix, degarelix; or with androgens: danazol. For the treatment and/ or prophylaxis of diseases which are associated with pain, or pain syndromes, or related to pain, the compounds of the present invention can be administered in combination or as comedication with any substance that can be applied as therapeutic agent in the following indications: pain-associated diseases or disorders like hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headache, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy. The compounds of the present invention can be combined with other pharmacological agents and compounds that are intended to treat inflammatory diseases, inflammatory pain or general pain conditions. In addition to well-known medicaments which are already approved and on the market, the compounds of the present invention can be administered in combination with inhibitors of P2X4, of NK1, of NK1/NK3, of PTGES (prostaglandin E synthase), of IRAK4 (interleukin-1 receptor- associated kinase 4) and with antagonists of the prostanoid EP4 receptor (prostaglandin E2 receptor 4). In particular, the compounds of the present invention can be administered in combination with pharmacological endometriosis agents, intended to treat inflammatory diseases, inflammatory pain or general pain conditions and/or interfering with endometriotic proliferation and endometriosis associated symptoms, namely with inhibitors of Aldo-keto-reductase1C3 (AKR1C3) and with functional blocking antibodies of the prolactin receptor. For the treatment and/ or prophylaxis of chronic cough, including chronic idiopathic and refractory and/ or unexplained chronic cough, persistent chronic cough, and symptoms related to said categories of chronic cough, the compounds of the present invention can be administered in combination or as comedication with cough suppressants like dextromethorphan, benzonatate, codeine or hydrocodone; with inhalative agents to treat eosinophilic bronchitis, COPD or asthma like budesonide, beclomethasone, fluticasone, theophylline, ipatropiumbromid, montelukast or salbutamol; with drugs like proton pump inhibitors which are used to treat acid reflux, for example omeprazole, esomeprazole, lansoprazole, ranitidine, famotidine, cimetidine; and promotility agents such as metoclopramide; with nasal or topical glucocorticoids like fluticasone or mometasone or triamcinolone; or with oral antihistamines like loratadine, fexofenadine or cetirizine. Furthermore, the compounds of the present invention can be combined with gabapentin, pregabalin, amytryptilin, or morphine. The compounds of the present invention can be combined with other pharmacological agents and compounds that are intended for the treatment, prevention or management of cancer. In particular, the compounds of the present invention can be administered in combination with 131I- chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, Iasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, perflubutane, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC- [Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin. Furthermore, the compounds of the present invention can be combined with active ingredients, which are well known for the treatment of cancer-related pain and chronic pain. Such combinations include, but are not limited to NSAIDS (either unselective NSAIDS like ibuprofen, diclofenac, aspirin, naproxen, ketoprofen and indomethacin; and Cox-2 selective NSAIDS like parecoxib, etoricoxib and celecoxib), step II opiods like codeine phosphate, dextropropoxyphene, dihydro-codeine, tramadol, step III opiods like morphine, fentanyl, buprenorphine, oxymorphone, oxycodone and hydromorphone; and other medications used for the treatment of cancer pain like steroids as dexamethasone and methylprednisolone; bisphosphonates like etidronate, clodronate, alendronate, risedronate, and zoledronate; tricyclic antidepressants like amitriptyline, clomipramine, desipramine, imipramine and doxepin; class I antiarrhythmics like mexiletine and lidocaine; anticonvulsants like carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, topiramate, alprazolam, diazepam, flurazepam, pentobarbital and phenobarbital. Generally, the use of the combinations of the present invention mentioned before will serve to: (1) provide for a higher response rate among treated patients, (2) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other agent combinations produce antagonistic effects. “Combination” means for the purposes of the invention not only a dosage form which contains all the components (so-called fixed combinations), and combination packs containing the components separate from one another, but also components which are administered simultaneously or sequentially, as long as they are employed for the prophylaxis or treatment of the same disease. Pharmaceutical compositions: It is possible for the crystalline form of the compound of formula (I) according to the present invention to have systemic and/or local activity. For this purpose, it can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent. For these administration routes, it is possible for the crystalline form of the compound of formula (I) according to the present invention to be administered in suitable administration forms. For oral administration, it is possible to formulate the crystalline form of the compound of formula (I) according to the present invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compound according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms. Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders. Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents. The crystalline form of the compound of formula (I) can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel^®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos^®)), • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins), • surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette^®), sorbitan fatty acid esters (such as, for example, Span^®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween^®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor^®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic^®), • buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), • isotonicity agents (for example glucose, sodium chloride), • adsorbents (for example highly-disperse silicas), • viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol^®); alginates, gelatine), • disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab^®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol^®)), • flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil^®)), • coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon^®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl- methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit^®)), • capsule materials (for example gelatine, hydroxypropylmethylcellulose), • synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit^®), polyvinylpyrrolidones (such as, for example, Kollidon^®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), • plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), • penetration enhancers, • stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), • preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), • colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide), • flavourings, sweeteners, flavour- and/or odour-masking agents. The present invention furthermore relates to a pharmaceutical composition which comprise at least the crystalline form of the compound of formula (I) according to the present invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention. Dosage of the pharmaceutical compositions of the present invention: Based upon laboratory techniques known to evaluate compounds useful for the treatment of disorders, by pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compound of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, preferably from about 0.01 mg/kg to about 50 mg/kg body weight per day. A unit dosage may contain from about 25, 50, 75 or 100 mg of active ingredient, and can be administered one or more times per day. Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests. The weight data in the tests and examples which follow are, unless stated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid/liquid solutions are based on each case on the volume. It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein. All publications, applications and patents cited above and below are incorporated herein by reference. The weight data are, unless stated otherwise, percentages by weight and parts are parts by weight. Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art. The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

Examples Preparation of the crystalline modifications Mod. I: 750 mg of the compound of formula (I) were melted in portions on the Kofler hot bench and quickly cooled to RT. The melts were then tempered for 15 min at 150°C in a drying oven. Mod. II: Method I) 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoro- methyl)pyrimidin-5-yl]ethyl}benzamide (Eliapixant) in crystalline modification II can be obtained by stirring Eliapixant in the amorphous form (optionally in a mixture with modification I and III) in an inert solvent and crystallising the compound of formula (I) in the crystalline modification II, Working example: 4.0 g 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoro- methyl)-pyrimidin-5-yl]ethyl}benzamide were stirred in 200 mL for 5 days at room temperature. Method II) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid (41.0 g, 95 % purity, 128 mmol) and (1R)‐1‐[2‐(Trifluoromethyl)pyrimidin‐5‐yl]ethan‐1‐amine hydrochloride (1:1) (30.5 g, 134 mmol) were stirred with N- (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluoro-phosphate (67.9 g, 179 mmol; CAS-RN:[148893-10-1]) and N,N-Diisopropylethylamine (88 ml, 510 mmol) in N,N-Dimethylformamide (DMF) (1.7 l, 22 mol; CAS-RN:[68-12-2]) for 17 hours at room temperature. DMF was evaporated, water and dichloromethane were added. The organic layer was extracted three times. The combined organic layers were evaporated to dryness. The residue was purified by Biotage IsoleraTM chromatography system using pre-packed silica and pre-packed modified silica cartridges eluting with EtOAc- heptane, heptane-acetone, or EtOAc-MeOH on a KP-SiO2 column.6.5 g of the compound of formula (I) were obtained and further purified by preparative HPLC. Following methods are useful: Method A: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; column: Chiralpak IE 5μ 250 x 30 mm; eluent A: ethanol + 0.1 Vol-% diethylamine (99%); eluent B: tert.-butyl methyl ether; isokratic: 5% A + 95 % B; flow 50.0 ml/min; UV 325 nm Method B: Instrument: Sepiatec: Prep SFC100; column: Chiralpak IF 5 μm 250 x 30 mm; eluent A: CO2, eluent B: ethanol; isokratic: 16 % B; flow 100.0 ml/min; temperature: 40°C; BPR: 150 bar; MWD @ 254 nm Method C: Instrument: Agilent PrepHPLC 1200, column: Chiralpak IC 5 μ 250 x 20 mm; eluent A: hexane; eluent B: 2-propanol; isokratic: 70 % A + 30 % B; flow 15.0 ml/min; UV @ 254 nm Method D: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IC 5 μ 250 x 30 mm; eluent A: hexane + 0.1 Vol-% diethylamine (99 %); eluent B: ethanol; isokratic: 80 % A + 20 % B; flow 50.0 ml/min; UV 254 nm Method E: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IC 5 μ 250 x 30 mm; eluent A: hexane + 0.1 Vol-% diethylamine (99 %); eluent B: ethanol; isokratic: 70 % A+30 % B; flow 50.0 ml/min; UV 254 nm Method F: Instrument: Sepiatec: Prep SFC100; column: LUNA HILIC 5 μm 250 x 30 mm; eluent A CO2, eluent B: methanol + 0.5 Vol-% ammonia (32 %); isokratic: 20 % B; flow 100.0 ml/min temperature: 40°C; BPR: 90 bar; MWD @ 254 nm Purification with Biotage IsoleraTM chromatography and preparative HPLC were repeated.630 mg of the compound of formula (I) in crystalline modification II were obtained. Mod. III: 2 x 0.5 g of modification II were dissolved in 60 ml ethanol at boiling temperature. The solutions were filtered and about 250 ml of water were quickly added immediately. The active ingredient precipitated. 2 x 0.5 g of modification II were dissolved in 60 ml ethanol at boiling temperature. The solutions were filtered and about 250 ml of water were quickly added after 5 minutes. The active ingredient precipitated. The next day the residues were filtrated and dried at room temperature and ambient humidity. All samples were combined into one sample. Dihydrate: 5.02 g of modification II were suspended in 70 ml ACN/ water (1 : 1). First 35 ml ACN and then 35 ml water were added. The suspension was stirred at RT for 30 min and then cooled to 0°C. After 14 day the suspension was filtered and the residue was dried at room temperature and ambient humidity. Amorphous form: Approx. 600 mg of modification II were melted in portions on the Kofler hot bench and quickly cooled to RT. Methods: DSC/TG DSC thermograms were recorded using Differential Scanning Calorimeters (model DSC7, Pyris-1 or Diamond) from Perkin-Elmer. The measurements were performed with a heating rate of 20 Kmin^-1 using non-gastight aluminium pans. Flow gas was nitrogen. TGA thermograms were recorded using thermobalances (model TGA 7 and TGA 8000) from Perkin- Elmer. The measurements were performed with a heating rate of 10 Kmin^-1 using open platinum pans. Flow gas was nitrogen. XRPD X-Ray diffraction patterns were recorded at room temperature using XRD–diffractometers X`Pert PRO (PANalytical) and STOE STADI-P (radiation Cu K alpha 1, wavelength 1.5406 Å). There was no sample preparation. All X-Ray reflections are quoted as °2Ɵ (theta) values (peak maxima) with a resolution of ± 0.2 Raman Raman spectra were recorded at room temperature using FT-Raman-spectrophotometers (model RFS 100 and MultiRam) from Bruker. Resolution was 2 cm^-1. Measurements were performed in glass vials or aluminium discs. IR IR-ATR-spectra were recorded at room temperature using a FT-IR-spectrophotometer Tensor 37 or Lumos from Bruker with universal diamond ATR device. Resolution was 2 cm^-1.

Example 1: Manufacture of polymorphic forms of eliapixant 1.1. Modification I of eliapixant 3 portions of compound of formula (I) in amorphous form were melted on a Kofler hot bench, quickly cooled to RT and then tempered at 150°C on a Kofler bench until the active ingredient has recrystallized (the originally clear melt was cloudy, duration approx. 1 h). The three samples were carefully ground together in a mortar and combined to form one sample. 1.2 Modification II of eliapixant 750 mg of modification II were melted in portions on a Kofler hot bench and quickly cooled to RT. The melts were then tempered for 15 min at 150°C in a drying oven. Subsequently they were carefully ground together in a mortar and combined to form one sample. The active substance (modification II) was dissolved in the respective solvent at boiling temperature. The solutions were filtered, divided in four, three or two portions (dependent on the solvent). The different portions were each stored at room temperature (a), in a refrigerator (b), and in a freezer (c) until the solvent had evaporated. An antisolvent was added to the fourth quarter (d). When water was added the substance precipitated. It was filtered off and dried at room temperature. When n- heptane was added no precipitation occurred. The solutions were allowed to stand at room temperature until the solvent has evaporated. The crystallization experiments are summarized in Table 2. Table 2: Crystallization experiments

The active ingredient was suspended in the respective solvent and stirred at different temperatures. Some suspensions were seeded. At the end of the stirring time the residues were filtered off and dried at room temperature and ambient humidity. The experiments are summarized in Table 3. Table 3: Slurry experiments

1.3 Modification III of eliapixant 4.05 g of modification II were dissolved in 80 ml of DMSO at boiling temperature. The solution was filtered, approx.300 ml of water was added (precipitation) and left to stand at RT. The next day the residue was filtered off, divided in two halfs, and air- dried at RT. After two days the still moist residues were washed several times in the filter with water and then left to stand open at RT. 6 x 0.5 g of modification II were dissolved in 60 ml of ethanol at boiling temperature. The solutions were filtered. /1 and /2: The solutions were slowly mixed with water immediately after filtration until the active ingredient precipitated (approx.250 ml water). /3 and /4: The solutions were quickly mixed with approx.250 ml of water immediately after filtration. The active ingredient precipitated. /5 and /6: After filtration the solutions were stored for 5 min at room temperature. Then approx.250 ml of water were quickly added. The active ingredient precipitated. All experiments were stored at room temperature. The next day the precipitates were filtered and dried at room temperature at ambient conditions. Each of -1 1,019 g -2 1,044 g -3 1,064 g -4 1,045 g -5 1,023 g of modification II were dissolved in 120 ml of ethanol at boiling temperature. The solutions were filtered and immediately mixed with about 380 ml of water until the drug precipitated. All experiments were stored at room temperature. The next day the precipitates were filtered and dried at room temperature at ambient conditions. Each of -1 1,013 g -2 1,004 g -3 1,010 g -4 1,005 g -5 1,007 g of modification II were dissolved in 120 ml of ethanol at boiling temperature. The solutions were filtered and -1 and -2: immediately mixed with about 280 ml of water until the drug precipitated. -3, -4 and -5: cooled to room temperature and quickly mixed with about 280 ml of water until the drug precipitated. All experiments were stored at room temperature. After five days the precipitates were filtered and dried at room temperature at ambient conditions. Each of -1 504 mg -2 502 mg -3 516 mg of modification II were dissolved in 60 ml of ethanol at boiling temperature. The solutions were filtered and about 300 ml of water were added after 5 min. The drug precipitated. Each of -4 508 mg -5 505 mg -6 501 mg of modification II were dissolved in 60 ml of ethanol at boiling temperature. The solutions were filtered and about 300 ml of water were added immediately. The drug precipitated. Each of -7 510 mg -8 507 mg -9 502 mg of modification II were dissolved in 60 ml of ethanol at boiling temperature. The solutions were filtered and dripped directly in 300 ml of water. The drug precipitated. All experiments were stored at room temperature. After three days the precipitates were filtered and dried at room temperature at ambient conditions. 1.4. Amorphous form of eliapixant 600 mg of modification II were melted in portions on a Kofler hot bench and quickly cooled to RT. Subsequently the melts were carefully ground together in a mortar and combined to form one sample. 1.5. Dihydrate of eliapixant 5.02 g of modification II were suspended in 70 ml ACN/ water (1 : 1). First 35 ml ACN and then 35 ml water were added. The suspension was stirred at RT for 30 min and then cooled to 0°C. After 14 day the suspension was filtered and the residue was dried at room temperature and ambient humidity. Example 2: Physical characterization of polymorphic forms of eliapixant 2.1 XRPD

Figures: Figure 1: X-Ray powder diffractogram of the modification I Figure 2: X-Ray powder diffractogram of the polymorphic form II Figure 3: X-Ray powder diffractogram of the modification III Figure 4: X-Ray powder diffractogram of the Dihydrate Figure 5: X-Ray powder diffractogram of the amorphous form

Claims

Claims 1. A crystalline form of eliapixant which is the modification II. 2. The form of the compound of claim 1 characterized by a X-ray powder diffractogram measured at 25°C and with Cu-K alpha 1 as radiation source displaying at least the following reflections, quoted as 2Ɵ value ± 0.2°: 15.5, 17.5, and 22.3. 3. The form of the compound of claim 1 characterized by a X-ray powder diffractogram measured at 25°C and with Cu-K alpha 1 as radiation source displaying at least the following reflections, quoted as 2Ɵ value ± 0.2°: 15.5, 17.5, 22.3, 24.4, and 7.7. 4. The form of the compound of claim 1 characterized by a X-ray powder diffractogram measured at 25°C and with Cu-K alpha 1 as radiation source displaying at least the following reflections, quoted as 2Ɵ value ± 0.2°: 15.5, 17.5, 22.3, 24.4, 7.7, 11.5 and 10.1. 5. The form of the compound of claim 1 characterized by a X-ray powder diffractogram measured at 25°C and with Cu-K alpha 1 as radiation source displaying at least the following reflections, quoted as 2Ɵ value ± 0.

2°: 17.5, 22.

3, 24.

4, 7.7, 11.

5, 10.1, 14.4 and 37.0.

6. A pharmaceutical composition comprising modification II of the compound of formula (I) and optionally further pharmaceutically acceptable excipients.

7. The pharmaceutical composition of claim 7 comprising modification II of the compound of the formula (I) mainly and no significant fractions of another form of the compound of the formula (I) and optionally further pharmaceutically acceptable excipients

8. A crystalline form of the compound of any of claims 1 to 6 for use in the treatment and/or prophylaxis of neurogenic diseases and disorders.

9. A pharmaceutical composition of any of claims 7 to 8 for use in the treatment and/or prophylaxis of neurogenic diseases and disorders.

10. Use of a compound as defined in any of claims 1 to 6 for the manufacture of a pharma- ceutical composition for the treatment or prevention of neurogenic diseases and disorders.

11. A method of treating or preventing of neurogenic diseases and disorders in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound as defined in any of claims 1 to 6.