NZ719532B2 - Salts of 1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1r)- 4-(trifluormethyl)-2,3-dihydro-1h-inden-1-yl]-1,2,3,4-tetrahydropyrimidin-5-carboxylic acid - Google Patents

Salts of 1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1r)- 4-(trifluormethyl)-2,3-dihydro-1h-inden-1-yl]-1,2,3,4-tetrahydropyrimidin-5-carboxylic acid Download PDF

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NZ719532B2
NZ719532B2 NZ719532A NZ71953214A NZ719532B2 NZ 719532 B2 NZ719532 B2 NZ 719532B2 NZ 719532 A NZ719532 A NZ 719532A NZ 71953214 A NZ71953214 A NZ 71953214A NZ 719532 B2 NZ719532 B2 NZ 719532B2
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New Zealand
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salt
dihydro
jennyp
compound
dioxo
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NZ719532A
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NZ719532A (en
Inventor
Jens Ackerstaff
Chantal Furstner
Martin Holger Hinz
Mario Jeske
Birgit Keil
Britta Olenik
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Bayer Pharma Aktiengesellschaft
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Priority claimed from PCT/EP2014/073801 external-priority patent/WO2015067652A1/en
Publication of NZ719532A publication Critical patent/NZ719532A/en
Publication of NZ719532B2 publication Critical patent/NZ719532B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention relates to novel salts of 1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)- 4-(trifluormethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidin-5-carboxylic acid of the formula (I), in particular amino acid salts such as lysine salt and alkali metal salts such as sodium salt and potassium salt, to a method for producing same, to medication containing same, and to the use thereof in treating diseases. as sodium salt and potassium salt, to a method for producing same, to medication containing same, and to the use thereof in treating diseases.

Description

SALTS 0F 1- 3-METHYLOXO-2 -DIHYDRO-l 3-BENZOXAZOL—6-YL -2 4-DIOXO-3— 1TRIFLUORMETHYL{-ZQ-DIHYDRO-lH-INDEN-l-YL|-l,2,§,4-TETRAHYDROPYRIMIDIN-S- CARBOXYLIC ACID The invention relates to novel salts of 1-(3-methyloxo-2,3-dihydro-1,3-benzoxazolyl)-2,4-dioxo[(1R)- 4-(trifluoromethyl)-2,3-dihydro-1H-inden-l-yl]~l,2,3,4-tetrahydropyrimidine-S-carboxylic acid of the a (I), in particular to amino acid salts such as the lysine salt and to alkali metal salts such as the sodium salt and the potassium salt, to ses for their preparation, to medicaments comprising them and their use for control- ling diseases. l-(3-Methyloxo-2,3—dihydro-1,3-benzoxazolyl)-2,4~dioxo[(1R)(t1ifluoromethyl)—2,3-dihydro-1H- inden-l-y1]-1,2,3,4—tetrahydropyn'midinecarboxylic acid, its preparation and its use as chymase inhibitor is described in the patent application (see Example 189) and ponds to the compound of the formula (I): Hereinbelow, the compound of the formula (I) is referred to as free acid.
It has now been found that, for some applications, the free acid has insufficient solubility and is therefore not unconditionally suitable for use in formulations.
Surprisingly, we have now found novel salts. These salts have ly different and in each case characteristic X-ray diffiractograms (Table 1, Figures 1, 2 and 3).
The present invention provides the compound of the formula (I) in the form of its amino acid salts and alkali metal salts.
The present ion provides the compound of the a (I) in the form of its lysine salt, in particular in the form of its L-lysine salt, or in the form of its sodium salt or potassium salt.
The present invention provides the compound of the formula (I) in the form of its L-lysine salt which, in the X- ray ctograrn, has essentially the following preferred peak maximum of the 2 theta angle at 16.9.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The t invention preferably provides the compound of the a (I) in the form of its L-lysine salt which, in the X-ray diffractogram, has essentially the following preferred peak maxima of the 2 theta angle at 16.9, 22.3 and 20.0.
The present invention furthermore preferably provides the compound of the formula (I) in the form of its L- lysine salt which, in the X-ray diffractogram, has essentially the following preferred peak maxima of the 2 theta angle at 16.9, 22.3, 20.0, 16.7, 19.2, 10.9 and 12.2.
The present invention rmore preferably provides the compound of the formula (I) in the form of its L- lysine salt which, in the X-ray diffractogram, has essentially the following preferred peak maxima of the 2 theta angle at 16.9, 22.3, 20.0, 16.7, 19.2, 9.9 and 21.6. , 10.9, 12.2, Moreover, the present invention provides the compound of the formula (I) in the form of its sodium salt which, in the X—ray diffractogram, has essentially the following preferred peak maximum of the 2 theta angle at 17.6.
The present invention preferably es the compound of the formula (I) in the form of its sodium salt which, in the X-ray diffractogram, has essentially the following preferred peak maxima of the 2 theta angle at 17.6, 17.9 and 19.1.
The present invention furthermore preferably provides the compound of the formula (I) in the form of its sodi~ um salt which, in the X-ray diffractogram, has essentially the following preferred peak maxima of the 2 theta angle at 17.6, 17.9, 19.1, 18.1, 12.8, 5.9 and 18.9.
The present invention furthermore preferably provides the compound of the formula (I) in the form of its sodi- um salt which, in the X-ray diffractogram, has ially the following preferred peak maxima of the 2 theta angle at 17.6, 17.9, 19.1, 18.1, 12.8, 5.9, 29.0 and 19.6. , 18.9, Moreover, the present invention es the compound of the formula (I) in the form of its potassium salt which, in the X-ray diffractogram, has ially the following preferred peak maximum of the 2 theta angle at 23.7.
The present ion preferably provides the nd of the a (I) in the form of its potassium salt which, in the X-ray diffractograin, has essentially the following red peak maxima of the 2 theta angle at 237,153 and 20.5.
The present invention furthermore preferably es the compound of the a (I) in the form of its potas— sium salt which, in the X-ray diffractogram, has essentially the following preferred peak maxima of the 2 theta angle at 23.7, 15.3,, 20.5, 10.4, , 30.0, 21.7 and 6.00.
The present invention furthermore preferably provides the compound of the formula (I) in the form oifinas- sium salt which, in the X-ray diffractogram, has essentially the following preferred peak maxima of heta angle at 23.7, 15.3, , 20.5, 10.4, , 30.0, 21.7, 6.0, 19.8 and 18.0.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp General aspects in connection with the present invention are pharmacological properties, processability, prepa— ration process, ffect profile, stability and pharmacological activity in particular of the salt with L-lysine of the compound of the formula (I).
Surprisingly, the L-lysine salt and the sodium and ium salt of the compound of the formula (I) are crystal- line and, even after processing via suspensions, e-stable. Accordingly, they are particularly suitable for use in pharmaceutical formulations such as suspensionen or creams, but also in other preparations prepared via the suspended active nd, such as, for example, in the case ofwet granulation or wet grinding.
In pharmaceutical ations, the salts according to the invention of the compound of the formula (I), in par- ticular the L—lysine salt and the sodium and potassium salt, are employed in high purity. For reasons of stability, a pharmaceutical formulation comprises mainly a salt of the nd of the formula (I), in ular either the L-lysine salt or the sodium or potassium salt, and no r tions of any other form of the compound of the formula (I). Preferably, the medicament comprises more than 90 t by weight, ularly prefera< bly more than 95 percent by , of the compound of the formula (I) in the form of the corresponding salt, based on the total amount of the compound of the formula (I) present.
The salts of the invention have valuable pharmacological properties and can be used for treatment and/or prophylaxis of diseases in humans and animals. The salts of the invention are chymase inhibitors and are there- fore suitable for treatment and/or prophylaxis of cardiovascular, inflammatory, allergic and/or fibrotic disorders.
In the context of the present invention, disorders of the cardiovascular system or vascular disorders are understood to mean, for example, the following disorders: acute and chronic heart failure, arterial hypertension, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, shock, sclerosis, cardiac hypertrophy, cardiac fibrosis, atrial and ventricular arrhythmias, transitory and ischaem- ic attacks, stroke, pre-eclampsia, inflammatory cardiovascular disorders, peripheral and cardiac vascular disor- ders, peripheral perfusion disorders, arterial pulmonary hypertension, spasms of the coronary arteries and pe- ripheral arteries, thromboses, thromboembolic disorders, edema deve10pment, for example pulmonary edema, cerebral edema, renal edema or heart failure-related edema, and restenoses such as after thrombolysis treat- ments, percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart trans- plants and bypass operations, and micro- and ascular damage (vasculitis), reperfusion damage, al and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, peripheral and cardiac vascular disorders, peripheral perfusion disorders, heart failure»related edema, elevated levels of fibrin- ogen and of low—density LDL and elevated concentrations of plasminogen tor/inhibitor I (PAI-l).
In the context of the present invention, the term "heart failure" also includes more specific or related types of disease, such as acutely decompensated heart e, right heart failure, left heart failure, global failure, is- chaemic cardiomyopathy, dilated cardiomyopathy, congenital heart s, heart valve defects, heart e associated with heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosflortic valve insufficiency, tiicuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve in- sufficiency, combined heart valve defects, myocardial mation (rnyocarditis), c myocarditis, acute [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, and diastolic and ic heart failure.
The salts according to the ion are further suitable for the laxis and/or treatment of polycystic kid« ney e (PCKD) and of the syndrome of inapprOpriate ADH secretion (SIADH). The salts of the invention are also suitable for treatment and/or prOphylaxis of kidney disorders, in particular of acute and chronic renal insufficiency and acute and chronic renal failure.
In the context of the t invention, the term "acute renal insufficiency" encompasses acute manifestations of kidney disease, of kidney failure and/or renal iciency with and without the need for dialysis, and also ying or d renal disorders such as renal hypoperfusion, intradialytic hypotension, volume deficiency (eg. dehydration, blood loss), shock, acute glomerulonephn'tis, hemolytic-uremic syndrome (HUS), vascular catastrophe (arterial or venous thrombosis or embolism), cholesterol embolism, acute Bence-Jones kidney in the event of plasmacytoma, acute supravesicular or subvesicular efflux obstructions, immunological renal ers such as kidney transplant rejection, immune x-induced renal disorders, tubular dilatation, hyperphos- phatemia and/or acute renal disorders characterized by the need for dialysis, including in the case of partial re- sections of the kidney, dehydration through forced is, uncontrolled blood pressure rise with malignant hy~ pertension, urinary tract obstruction and infection and amyloidosis, and systemic disorders with glomerular fac- tors, such as rheumatological-immunological systemic disorders, for example lupus erythematodes, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, and X-ray contrast agent- and ment-induced acute titial renal disorders.
In the context of the present invention, the term "chronic renal insufficiency" encompasses chronic sta- tions of kidney disease, of kidney failure and/or renal insufficiency with and without the need for dialysis, and also underlying or d renal disorders such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomeruIOpathy, glomerular and tubular nuria, renal edema, hematuria, primary, secondary and chronic glomerulonephritis, membranous and membranoproliferative glomerulonephritis, Alport syndrome, glomerulosclerosis, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, renal inflammation, immunological renal disorders such as kidney transplant rejection, immune com- plex~induced renal disorders, diabetic and abetic pathy, ephritis, renal cysts, nephrosclero- sis, hypertensive nephrosclerosis and nephrotic syndrome, which can be characterized diagnostically, for exam- ple, by abnormally reduced creatinine and/or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and/or creatinine, altered activity of renal enzymes, for example glutamyl synthetase, al- tered urine osmolarity or urine volume, elevated microalbuminuiia, macroalbuminuria, glomerular and arterio- lar lesions, tubular dilatation, hyperphosphatemia and/or the need for is, and in the event of renal cell car- cinoma, after partial resections of the kidney, dehydration through forced diuresis, uncontrolled blood pressure rise with malignant hypertension, urinary tract obstruction and ion and amyloidosis, and systemic disor- ders with glomerular factors, such as rheumatological-immunological systemic disorders, for example s er- ythematodes, and also renal artery stenosis, renal artery osis, renal vein osis, analgesic ntgopathy and renal tubular is. In addition, X-ray contrast agent— and medicament-induced chronic interstitial [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp renal disorders, metabolic syndrome and dyslipidernia. The present ion also encompasses the use of the compounds of the invention for the ent and. or prophylaxis of sequelae of renal insufficiency, for example pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (for example hyperkalernia, hyponatremia ) and disorders in bone and carbohydrate metabolism.
In addition, the salts according to the invention are also suitable for treatment and/or prophylaxis of pulmonary al hypertension (PAH) and other forms of ary hypertension (PH), of chronic obstructive ary disease (COPD), of acute respiratory distress syndrome (ARDS), of acute lung injury (ALI), of alpha antitrypsin deficiency (AATD), of pulmonary fibrosis, of pulmonary emphysema (for example pulmonary em- physema caused by cigarette , of cystic s (CF), of acute coronary me (ACS), heart muscle inflammation (myocarditis) and other autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis, aorti— tis, cardiomyopathy), genic shock, aneurysms, sepsis (SIRS), multiple organ failure (MODS, MOP), in- flammation disorders of the kidney, chronic intestinal disorders (IBD, Crohn's Disease, UC), pancreatitis, peri- tonitis, rheumatoid disorders, inflammatory skin disorders and atory eye disorders.
The salts according to the invention can rmore be used for ent and/or prophylaxis of asthmatic dis- orders of varying severity with intermittent or persistent teristics (refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma), of various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), of Bronchiolitis obliterans, bron- chiectasis, pneumonia, idiopathic interstitial pneumonia, farmer's lung and related disorders, of coughs and colds (chronic inflammatory cough, iatrogenic cough), ation of the nasal mucosa (including medica- ment~related is, vasomotoric rhinitis and seasonal allergic rhinitis, for example hay fever) and ofpolyps.
The salts ing to the invention are also suitable for treatment and/or prophylaxis of fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders. In the context of the present invention, the term "fibrotic dis- orders" encompasses particularly the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, cardiomyopathy, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage ing from es, bone marrow fibrosis and similar fibrotic disorders, sclerodemra, a, ke- loids, hypertrophic scarring (also ing surgical procedures), rraevi, diabetic retinopathy and proliferative vitroretinopathy.
The salts according to the invention are also suitable for controlling postoperative scarring, for example as a re- sult of glaucoma operations.
Furthermore, the salts according to the invention can also be used cosmetically for ageing and keratinized skin.
In addition, the salts of the invention can also be used for treatment and/or prophylaxis of dyslipidemias (hyper- terolemia, hypertriglyceridemia, elevated trations of the andial plasma triglyceridespoal- phalipoproteinemia, combined hyperlipidenrias), nephropathy and neuropathy), cancers (skin cancer, rain tu- mors, breast cancer, bone marrow tumors, leukemias, liposarcomas, carcinoma of the gastrointestinal tract, of [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp the liver, as, lung, kidney, urinary tract, prostate and genital tract, and also malignant tumors in the lyin- liferative system, for example Hodgkin‘s and non—Hodgkin's lymphoma), of ers of the gastrointes- tinal tract and of the abdomen (glossitis, gingivitis, periodontitis, esophagitis, philic gastroenteritis, mas- tocytosis, Crohn‘s e, colitis, proctitis, pruritus ani, diarrhea, celiac disease, hepatitis, chronic hepatitis, hepatic fibrosis, cirrhosis of the liver, pancreatitis and cholecystitis), skin disorders (allergic skin disorders, psoria- sis, acne, eczema, neurodennitis, various forms of dermatitis, and also keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupus erythematodes, erythema, lymphoma, skin cancer, Sweet's syndrome, Weber-Christian syndrome , ng, warts, chillblains), of disorders of the skeletal bone and of the joints, and also of the skeletal muscle (various forms of arthritis, various forms of arthropathies, sclerodenna and of r disorders with an inflammatory or immunological component, for example paraneoplastic me, in the event of rejection re- actions afier organ transplants and for wound healing and angiogenesis, especially in the case of chronic wounds.
The salts according to the invention are additionally suitable for ent and/or prophylaxis of ophthalmolog- ic disorders, for example ma, normotensive glaucoma, high intraocular pressure and combinations there- of, of age-related r degeneration (AMD), of dry or udative AMD, moist or exudative or neovascu- lar AMD, choroidal neovascularization (CNV), detached retina, ic retinopathy, atrophic changes to the retinal pigment epithelium (RPE), hypertrophic s to the retinal pigment epithelium (RPE), ic macular edema, retinal vein occlusion, choroidal retinal vein occlusion, macular edema, macular edema due to retina] vein occlusion, angiogenesis at the front of the eye, for example corneal angiogenesis, for example fol- lowing keratitis, cornea transplant or keratoplasty, corneal angiogenesis due to hypoxia (extensive wearing of contact ), pterygium ctiva, subretinal edema and intraretinal edema.
In addition, the salts according to the invention are suitable for the ent and/or prophylaxis of elevated and high intraocular re resulting from traumatic hyphema, periorbital edema, postoperative viscoelastic reten- tion, intraocular inflammation, use of corticosteroids, pupillary block or idiopathic causes, and of elevated in- traocular pressure following trabeculectomy and due to pure-operative conditions.
The present invention further provides for the use of the salts according to the invention for treatment and/or prophylaxis of disorders, especially the disorders mentioned above.
The present invention further provides for the use of the salts according to the invention for production of a me- dicament for treatment and/or prophylaxis of disorders, especially the disorders ned above.
The present invention further provides the salts according to the invention for use in a method for treatment and/or prophylaxis of heart failure, pulmonary hypertension, c obstructive pulmonary e, , kidney failure, nephropathy, fibrotic disorders of the internal organs and dermatological fibroses.
The present invention further provides medicaments which comprise at least one compound of the ilqion, typically together with one or more inert, ic, phannaceutically suitable excipients, and for the use t ereof for the aforementioned purposes.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The salts of the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for e by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdennal, conjunctiva] or otic route, or as an implant or stent.
The salts of the invention can be administered in administration forms suitable for these administration routes, Suitable administration forms for oral administration are those which work according to the prior art and release the compounds of the invention rapidly and/or in a modified manner and which contain the compounds of the invention in crystalline and/or amorphized and/or dissolved form, for example tablets (uncoated or coated tab- lets, for example with gasnic juice-resistant or ed-dissolution or insoluble coatings which control the re- lease of the compound of the invention), tablets or films/oblates which disintegrate rapidly in the oral cavity, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated s, granules, pellets, powders, emulsions, suspensions, aerosols or ons. eral administration can bypass an tion step (eg. intravenously, intraarterially, intracardially, in- naspinally or intralumbally) or include an absorption (eg. tively, intramuscularly, subcutaneously, intra- cutaneously, percutaneously or inn‘aperitoneally). Administration forms suitable for parenteral stration e preparations for injection and infusion in the form of solutions, sions, emulsions, lyophilizates or sterile powders.
For the other administration , suitable examples are inhalation medicaments (including powder inhalers, nebulizers, aerosols), nasal drops, solutions or sprays; tablets for l, sublingual or buccal administration, films/oblates or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions ns, shaking es), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, dusting powders, implants or stents.
Oral and parenteral administration are preferred, especially oral, intravenous and inhalative administration.
The salts of the ion can be converted to the administration forms mentioned. This can be done in a man- ner known per se, by mixing with inert, nontoxic, pharmaceutically suitable excipients. These excipients in- clude carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene gly- cols), emulsifiers and dispersing or g agents (for example sodium dodecylsulfate, polyoxysorbitan 01eate ), s (for example polyvinylpyrrolidone), tic and natural polymers (for example n), stabi- lizers (eg. antioxidants, for example ascorbic acid), colorants (e.g. inorganic ts, for e iron oxides) and flavor and/or odor correctants.
In general, it has been found to be advantageous in the case of parenteral administration to administer amounts of about 0.00] to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieve effective results. In the case of oral administration the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mfi and most preferably 0.1 to 10 mg/kg ofbody weight.
The invention furthermore provides a process for preparing the salts according to the invention by dissolving the compound of the formula (I) in the form of the free acid for example in an inert solvent (optionally with addition of a cosolvent) and stirring or shaking with a on of the orming base at a temperature of 10°C to 60°C, preferably at 20°C to 40°C, particularly preferably at 25°C or at room temperature. The resulting crystals of the salts are separated off and the solvent present is removed by drying to constant weight at room temperature or ed temperature.
Suitable inert solvents are lower alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, secbutanol , isobutanol, 1-pentanol, ketones such as acetone, s such as ane, cyclopentane, n-hexane, cyclohexane, or tetrahydrofuran, acetonitrile, toluene, ethyl acetate, 1,4-dioxane or mixtures of the solvents mentioned. Preference is given to acetonitrile, e and isopropanol or mixtures of the solvents mentioned.
Optionally, a cosolvent may be employed. Suitable for this purpose are acetonitrile, acetone, anol, isopropyl acetate, 2-methyltetrafuran, toluene, oxane or else mixtures thereof. Depending on the salt-forming base used, preference is given to toluene, isopropyl acetate or acetonitrile. le salt-forming bases are, in principle, sodium hydroxide, potassium hydroxide, choline bicarbonate, am- monium carbonate, sodium carbonate, ium carbonate, L-lysine, tris(hydroxymethyl)aminomethane, N- methyl-D-glucamine, L-arginine, sodium bicarbonate or potassium bicarbonate. According to the ion, L- lysine, sodium bicarbonate and potassium bicarbonate have been found to be particularly suitable for salt formation.
The preparation processes are generally carried out under heric re. However, it is also possible to operate under elevated or reduced pressure, for example at from 0.5 to 5 bar.
The present invention as claimed herein is described in the following items 1 to 25: 1. A salt of 1-(3-methyloxo-2,3-dihydro-1,3-benzoxazolyl)-2,4-dioxo[(1R)(trifluoromethyl)- 2,3-dihydro-1H-indenyl]-1,2,3,4-tetrahydropyrimidinecarboxylic acid HO O N N H C O 3 N O (I) 17760162_1 (GHMatters) P102736.NZ - 8a - 2. The salt of item 1, which is an amino acid salt or alkali metal salt of 1-(3-methyloxo-2,3-dihydro-1,3- benzoxazolyl)-2,4-dioxo[(1R)(trifluoromethyl)-2,3-dihydro-1H-indenyl]-1,2,3,4- tetrahydropyrimidinecarboxylic acid. 3. The salt of item 1 or 2, which is the lysine salt of 1-(3-methyloxo-2,3-dihydro-1,3-benzoxazolyl)- 2,4-dioxo[(1R)(trifluoromethyl)-2,3-dihydro-1H-indenyl]-1,2,3,4-tetrahydropyrimidine carboxylic acid. 4. The salt of item 1, 2 or 3, which is the L-lysine salt of 1-(3-methyloxo-2,3-dihydro-1,3-benzoxazol yl)-2,4-dioxo[(1R)(trifluoromethyl)-2,3-dihydro-1H-indenyl]-1,2,3,4-tetrahydropyrimidine carboxylic acid. 5. The salt of item 4, characterized in that the X-ray diffractogram of the compound has a peak maximum of the 2 theta angle at 16.9. 6. The salt of item 4 or 5, characterized in that the X-ray diffractogram of the compound has peak maxima of the 2 theta angle at 16.9, 22.3 and 20.0. 7. The salt of item 1 or 2, which is the sodium salt of 1-(3-methyloxo-2,3-dihydro-1,3-benzoxazolyl)- 2,4-dioxo[(1R)(trifluoromethyl)-2,3-dihydro-1H-indenyl]-1,2,3,4-tetrahydropyrimidine carboxylic acid. 8. The salt of item 7, terized in that the X-ray diffractogram of the compound has a peak maximum of the 2 theta angle at 17.6. 9. The salt of item 7 or 8, characterized in that the X-ray diffractogram of the compound has peak maxima of the 2 theta angle at 17.6, 17.9 and 19.1.
. The salt of item 1 or 2, which is the potassium salt of 1-(3-methyloxo-2,3-dihydro-1,3-benzoxazol yl)-2,4-dioxo[(1R)(trifluoromethyl)-2,3-dihydro-1H-indenyl]-1,2,3,4-tetrahydropyrimidine ylic acid. 11. The salt of item 10, characterized in that the X-ray diffractogram of the compound has a peak maximum of the 2 theta angle at 23.7. 12. The salt of item 10 or 11, characterized in that the X-ray diffractogram of the compound has peak maxima of the 2 theta angle at 23.7, 15.3 and 20.5. 13. The salt of any of items 1 to 12 for the treatment of ers. 14. A medicament comprising a salt of any of items 1 to 12 and no r proportions of any other form of the compound of the formula (I). 17760162_1 (GHMatters) P102736.NZ - 8b - . A medicament comprising a compound according to any of items 1 to 12 in more than 90 percent by weight based on the total amount of the compound of the formula (I) present. 16. A process for preparing the compound of any of items 1 to 12, which comprises dissolving the compound of the formula (I) in the form of the free acid. 17. A process of item 16, wherein dissolving the compound of the a (I) in the form of the free acid comprises ng or shaking in an inert solvent with a solution of the salt-forming base at a temperature of 10°C to 60°C. 18. The use of a salt of any of items 1 to 12 in the manufacture of a medicament for the treatment and/or prophylaxis of disorders. 19. The use of item 18, wherein the disorders are cardiovascular, inflammatory, allergic and/or fibrotic disorders.
. The use of item 18 or 19, wherein the medicament comprises a salt of any of items 1 to 12 and no greater proportions of any other form of the nd of the formula (I). 21. The use of item 18 or 19, wherein the medicament comprises a compound ing to any of items 1 to 12 in more than 90 percent by weight based on the total amount of the compound of the a (I) present. 22. The salt of item 1 substantially as herein described with reference to any one of the Examples and/or Figures. 23. The medicament of item 14 or 15 substantially as herein bed with nce to any one of the Examples and/or Figures. 24. The process of item 16 substantially as herein described with reference to any one of the Examples and/or Figures.
. The use of item 18 substantially as herein described with reference to any one of the Examples and/or Figures.
Unless stated otherwise, the percentages in the tests and examples which follow are percentages by weight; parts are parts by weight. Solvent ratios, on ratios and concentration data for the liquid/liquid solutions are based in each case on volume. 17760162_1 (GHMatters) P102736.NZ - 8c - (The next page is page 9.) Experimental part The X-ray diffractograms were recorded at room temperature using an X`Pert PRO (PANalytical) XRD transmission /reflection diffractometer (radiation: , K1, wavelength: 1.5406 Å). There was no sample preparation.
Working examples Preparation of the compound of the formula (I) (free acid) (S)Trifluoromethylindanol 17760162_1 ters) P102736.NZ [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Under argon, a solution of 55.7 g (278.3 mmol) of 4-trifluoromethy1indanone, 194 ml (1.391 mol) of tri~ ethylamine and 1.60 g (2.50 mmol) of RuC1(p—cymene)[(S,S)-TsDPEN] (CAS No.: 1921395; TUPAC name: (S,S)-N-(p-toluenesulphonyl)—1,2-diphenylethanediamino(chloro)[1~methyl(propan yl)benzene]ruthenium(ll)) in 258 m1 of dichloromethane was heated to 35°C and, at this temperature, 52.5 ml (1.391 mol) of formic acid were added gradually ion time about 40 min). During the addition, the temper- ature of the reaction mixture increased to 42°C. After the addition was complete, the mixture was stirred at 38°C for a fithher 2 h. All volatile constituents were removed on a rotary evaporator and under HV. Subse- quently, the residue was ved in a little dichloromethane and purified using 1 kg of silica gel t: first 3 liters of cyclohexane/ethyl acetate 5:1, then 6 liters of cyclohcxane/ethyl acetate 1:1). The suitable fractions were concentrated on a rotary evaporator and the product was dried under HV. This gave 51.2 g (90% of theo- ry) of the title compound. 1Irl-NMR (400MHz, DMSO'dG): 6 [ppm]= 1.76 - 1.91 (m, 1H), 2.40 (ddt, 1H), 2.86 (dt, 1H), 3.01 - 3.13 (in, 1H), 5.09 (q, 1H), 5.45 (d, 1H), 7.38 - 7.48 (1n, 1H), 7.55 (d, 1H), 7.62 (d, 1H).
Chiral analytical HPLC (Method 25): R1= 7.49 min; 99 % ee Ethyl _ 1:13-methyl~2—oxo-2,3-dihydr0-l,3-benchxazgl-6;xl_}¢2,4-dioxo—l ,2,3,4—tetrahydrogyg'mjdinej- carboxylate \—-o H3C\ ‘— N N O k E N o/ O H 40.0 g (243.7 mmol) of 6—aminomethyl-l,3-benzoxazol-2(3H)—one were initially charged in 2.5 l of ethanol, and 63.2 g (243.7 mmol) of ethyl 3~ethoxy[(ethoxycarbonyl)carbamoyl]acrylate (for preparation see: Senda, Shigeo; Hirota, Kosaku; Notani, , Chemical & Pharmaceutical Bulletin (1972), 20(7), 1380—8) were add- ed. After a few minutes, a thick suspension formed. This mixture was heated to reflux ature for 1.5 h. Af~ ter cooling slightly (about 60°C), 27.3 g (243.7 mmol) of potassium tert-butoxide were added and the reaction e was stirred further at reflux temperature for 4.5 h. For workup, the reaction suspension was cooled slightly (about 60°C), then stirred into about 10 liters of cold 1N hloric acid. The solid was 11le off with n, washed with water and dried in a vacuum drying cabinet at 70°C overnight. This gave 64.0 g (79% oftheory) of the title compound.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp LC-MS (Method 1): Rt = 0.59 min; MS (ESIpos): 1n/z = 332 (M+H)+. lH-NMR (400MHz, DMSO~d6): 5 [ppm] = 1.22 (t, 3H), 3.38 (s, 3H), 4.17 (q, 2H), 7.38 (s, 2H), 7.59 (s, 1H), 8.26 (s, IR), 1169 (s, 1H).
Ethyl 1~(3~methy1oxog 3-dih ro-l 3-benzoxazol 1 -2 4-diox0 rifluorometh l -2 3-dih dro_- ll—ljndeni—yl -1 2 3 4-tetrah dro ‘ idine-S-carboxylate (R enantiomer) H3CVO ¢o Method A: Under argon, a on of 200 mg (0.60 mmol) of ethyl ethyloxo-2,3-dihydro-1,3- benzoxazoly1)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-S-carboxylate (see above) and 475 mg (1.81 mmol) of tn'phenylphosphine in THF/DMF 1:1 (7.6 ml) was cooled to -30°C. 238 pl (1.20 mmol) of diisopropyl azodicarboxylate were added se and then a solution of 146 mg (0.69 trunol) of (lS)—4- (trifluoromethyl)indan~l-ol (see above) in about 1 ml of THF was added dropwise. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 min. For workup, the mixture was cooled to 0°C, 5 m1 of 1M hydrochloric acid were added and the mixture was warmed to room temperature and stirred for 30 min. The mixture was then extracted with ethyl acetate. The organic phase was washed twice with 1M hydrochloric acid and once with saturated sodium chloride solution, dried over magnesium sulfate and - trated under reduced pressure. The residue was ted to extractive stirring with ethanol, and the precipitated solid was filtered off with suction and discarded. The filtrate was concentrated, dissolved in a little dichloro~ methane and purified by flash chromatography (dichloromethane/methanol 120:1-) 20:1). This gave 135 mg (43% of theory) of the title compound in about 95% purity.
LC-MS (Method 1): R. = 1.13 min; m/z = 5 I6 (M+H)+. 1H-NMR (400MHz, DMSO-d5): 5 [ppm] = 1.22 (t, 3H), 2.37 — 2.43 (m, 1H), 2.43 ~ 2.48 (m, 1H, partially ob— scured by DMSO ), 3.03 — 3.14 (m, 1H), 3.22 - 3.30 (m, 1H, partially obscured by water signal), 3.38 (s, 3H), 4.18 (q, 2H), 6.34 - 6.56 (m, 1H), 7.32 - 7.43 (m, 3H), 7.45 - 7.50 (in, 1H), 7.53 (d, 1H), 7.55 ~ 7.64 (m, 1H), 8.35 (s, 1H).
In an analogous ment, it was possible to isolate a fraction with 99% purity. For this batch, the specific tical rotation measured was: Specific l rotation: 0. 02° = +132.9°, (chloroform, c = 0.395 g/100 ml).
Method B: Under argon, a solution of 5.0 g (15.1 mmol) of ethyl 1-(3-methyl-2—oxo-2,3-dih)gl,3- benzoxazolyl)—2,4-dioxo-I,2,3,4—tetrahydropyrimidine—S~carboxylate (see above), 6.73 g (25.7 rmnol) of tri- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp phenylphosphine and 3.66 g (18.1 mmol) of (1S)(trifluoromethyl)indan-l-ol (see above) was initially d in 240 ml of DMF/THF 2:1 (v/v) and cooled to -15°C. 4.76 ml (24.15 mmol) of diisopropyl azodicar- boxylate was slowly added dropwise at such a rate that the temperature of the reaction mixture did not rise above -10°C. At the end of the addition, the mixture was stirred at -10°C for another 1 h, then warmed to room temperature and poured onto 1.3 1 of water. The mixture was extracted twice with 300 ml each time of ethyl ac- etate. The combined organic phases were washed with a ted sodium chloride solution, dried over magne- sium sulfate and freed of the solvent on a rotary evaporator. The residue (18 g) was purified in two chromatog- raphy steps: first using a 200 g silica gel column with dichloromethane/acetone 97.5:2.5 as the mobile phase.
The ing product-containing fractions were concentrated and the residue was applied again to a 200 g silica gel . 2.5 l of exane/ethyl e 1:1 as mobile phase were used to elute fiirther impurities, then the desired product was eluted from the column with dichloromethane/methanol 95:5. This gave 3.40 g (44% of theory) of the title compound in 95% purity (the NMR showed about 5% ethyl acetate). A fimher 920 were obtainable by a new ation of a mixed fraction. Total yield: 4.32 g (56% of theory).
LC-MS (Method 1): R = 1.15 min; m/z = 516 (M+H)*.
'H-NMR (400MHz, CD2C12): 5 [ppm] = 1.31 (t, 3H), 2.37 - 2.49 (m, 1H), 2.59 (dtd, 1H), 3.14 (dt, 1H), 3.40 (s, 3H), 3.42 - 3.53 (m, 1H), 4.29 (q, 2H), 6.54 - 6.68 (m, 1H), 7.06 (d, 1H), 7.17 (d, 1H), 7.22 (s, 1H), 7.26 ~ 7.36 (111,211), 7.49 (d, 1H), 8.28 (s, 1H). 1—|3~Methylogto-2Q-dihydro-1,3—benzoxazolyll-2,4-dioxofl1R)—4-Lt_rifluoromethyll—2,3—dihydro-1H- inden-l ii I- l ,2,3,4-tetrahydropvrimidine-Scaribox‘vliciacid LR enantiomer) 3.40 g (6.60 nnnol) of ethyl 1-(3~methy1oxo-2,3-dihydro-1,3-benzoxazolyl)-2,4-dioxo[(1R) oromethyl)—2,3-dihydro-1H-inden-l-yl]-l,2,3,4-tetrahydropyrimidine-S—carboxylate (see above) were stirred in 44 m1 of glacial acetic acid and 22 ml of concentrated hydrochloric acid at reflux temperature for 1 h.
After cooling slightly (about 60°C), the e was fully concentrated under reduced pressure. 50 m1 of iso~ propanol were added to the amorphous residue and the mixture was heated to reflux for 15 min, in the course of which a solid formed. The suspension was then cooled to 10°C and then the solid was filtered off with suction.
The solid was washed twice with 15 ml each time of isopropanol, filtered off with suction and dried under high vacuum. This gave 2.53 g (79% of theory) of the title compound. a LC-MS (Method 1): R1 = 1.12 min; m/z = 488 (M+H)*.
Chiral analytical HPLC (Method 14): R1: 13.3 min; about 99 % ee ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp IH-NMR (400MHz, CD2C12): 5 [ppm]: 2.40 - 2.52 (m, 1H), 2.59 - 2.72 (in, 11-1), 3.12 — 3.25 (m, 1H), 3.41 (s, 3H), 3.44 — 3.56 (m, 1H), 6.58 - 6.69 (m, 1H), 7.04 - 7.11 (m, 1H), 7.15 - 7.21 (m, 1H), 7.24 (br.s, 18), 7.29 - 7.38 (m, 2H), 7.53 (s, 1H), 8.54 (s, 1H), 12.39 (br. s, 1H).
Specific rotation 0. [>20 = +135.3° (methanol, 0 = 0.43).
In an analogous experiment, the specific rotation of the product was measured in chloroform: a 920 = +159.5° (chloroform, c = 0.395).
An X~ray structure analysis in the complex with e confirmed the R configuration for this enantiomer.
Example 1 Preparation of the L-lfiine salt of 1:13-mefl11112-gx0-2l3fijhydro-l,3—benzoxanxl)-2,4—dioxo—3—l (111)74- 1trifluoromethvl1-2.3-dihytirtz-l H-inden-l-yl|-1.2,3,4-tetrahydropm’midine-S-carboxxlic ac_id About 300 mg of 1-(3-methyloxo-2,3—dihydro-1,3-benzoxazolyl)-2,4-dioxo—3-[(1R)—4-(trifluoromethyl)- 2,3-dihydro-1H-indenyl]-1,2,3,4-tetrahydropy1imidinecarboxylic acid (free acid) were dissolved in 30 m1 of acetonitrile. With pivoting, 30 ml of toluene were added as cosolvent. A solution of 90 mg of ne in 10 m1 of water was then added, and the mixture was stirred at room temperature overnight. The suspension was then filtered and the residue was dried at room temperature and ambient humidity. The residue was examined by X-ray diffractometry and corresporids to the title compound.
Example 2 Emparation of the sodium salt of H3~methyl~2-ox0-2‘3;dihxdro-1,35benzoxazol—6-yl1-2.4-dioxoIf119-3; ttrifluorornethyl)-2,3-dihydro-11:I_;inden:l111;] -teu'ahxdropyrimidme-S-carboxylic acid About 300 mg of l-(3~methyloxo-2,3-dihydro-1,3-benzoxazolyl)-2,4-dioxo[(1R)—4—(trif1uoromethyl)- hydro—1H-inden-l-yI]-1,2,3,4—tetrahydropyrimidine-S-carboxylic acid (free acid) were dissolved in 30 ml of acetonitrile. With pivoting, 30 m1 of isopropyl acetate were added as cosolvent. A solution of 65.2 mg of so dium bicarbonate in 10 ml of water was then added, and the mixture was stirred at room temperature for 60 min. The suspension was then filtered and the residue was dried at room temperature and ambient humidity.
The residue was examined by X-ray diffractometry and corresponds to the title nd.
Example 3 Preparation of the potassium salt of 1- 3-meth Ioxo-2 3-dih dro-l 3-benzoxazolxl[-2.4-dioxol11R1 oromethyl)-2,3-dihydro- lH-inden- 1-v1|~1,2,3.4-tetrahytmmtnidinecarboxylic acid About 300 mg of 1-(3-methyloxo-2,3-dihydro-1,3-benzoxazolyl)-2,4-dioxo[(1R)(tn'fluoromethyl)- hydro-1H-indenyl]-1,2,3,4-tetrahydropyrimidinecarboxylic acid (free acid) were dissolved in 30 ml of acetonitrile. With pivoting, a further 30 ml of acetonitiile were added. A solution of 85.1 mg of p ium bicarbonate in 10 ml of water was then added, and the e was stirred at room temperature for 60 min. The [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp _13_ suspension was then filtered and the residue was dried at room temperature and ambient humidity. The residue was ed by X-ray diffractometry and corresponds to the title compound.
Table 1: X-ray tometry oftheflee acid ofI-(3-methyl0xo—2,3—dihydr0-1,3-benzoxazoIyl)-2,4-dz'oxo- 3-[(1R)(trzflu0romethyD-2,3-dihydro-1H»inden—1—yl]-1,2,3,4-tetrahydropyrimidine—5—carb0xylic acid and its salts Peak maximum [2 theta] Lysine salt Sodium salt Potassium salt [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Peak maximum {2 theta] Lysine salt Sodium salt Potassium salt 27.] 27.8 28.5 29.0 29.1 .1 .4 Briefdescription ofthefigures Figure 1: X-ray diffractogram of the L-lysine salt of l-(3-methyloxo-2,3-dihydro-l,3-benzoxazolyl)-2,4- dioxo[(1R)—4-(trifluoromethyl)-2,3~dihydro-1H-inden-l-y1]-1,2,3,4-tetrahydropyrimidinecarboxylic acid Figure 2: X-ray diffractogram of the sodium salt of 1-(3-methyloxo-2,3—dihydro—1,3-benzoxazol-6‘yl)-2,4- dioxo[(1 R)(trifluoromethyl)—2,3-dihydro-1H—inden—1-yl]- 1,2,3,4-tetrahydr0pyrimidine—5~carboxylic acid Figure 3: X-ray tog'ram of the potassium salt of 1—(3—methyloxo-2,3-dihydro-l,3-benzoxazolyl)- 2,4~dioxo[(1R)—4-(tn'fluoromethyl)—2,3-dihydro-lH-inden-l-yl]«1,2,3,4-tetrahydropyrimidine-5«carboxylic acid

Claims (22)

Claims
1. A salt of 1-(3-methyloxo-2,3-dihydro-1,3-benzoxazolyl)-2,4-dioxo[(1R)(trifluoromethyl)-
2,3-dihydro-1H-indenyl]-1,2,3,4-tetrahydropyrimidinecarboxylic acid HO O N N H C O 3 N O (I) 5 2. The salt as claimed in claim 1, which is an amino acid salt or alkali metal salt of 1-(3-methyloxo-2,3- dihydro-1,3-benzoxazolyl)-2,4-dioxo[(1R)(trifluoromethyl)-2,3-dihydro-1H-indenyl]- 4-tetrahydropyrimidinecarboxylic acid.
3. The salt as claimed in claim 1 or 2, which is the lysine salt of ethyloxo-2,3-dihydro-1,3- benzoxazolyl)-2,4-dioxo[(1R)(trifluoromethyl)-2,3-dihydro-1H-indenyl]-1,2,3,4- 10 ydropyrimidinecarboxylic acid.
4. The salt as claimed in claim 1, 2 or 3, which is the L-lysine salt of 1-(3-methyloxo-2,3-dihydro-1,3- benzoxazolyl)-2,4-dioxo[(1R)(trifluoromethyl)-2,3-dihydro-1H-indenyl]-1,2,3,4- tetrahydropyrimidinecarboxylic acid.
5. The salt as claimed in claim 4, characterized in that the X-ray diffractogram of the compound has a peak 15 maximum of the 2 theta angle at 16.9.
6. The salt as claimed in claim 4 or 5, characterized in that the X-ray diffractogram of the compound has peak maxima of the 2 theta angle at 16.9, 22.3 and 20.0.
7. The salt as claimed in claim 1 or 2, which is the sodium salt of 1-(3-methyloxo-2,3-dihydro-1,3- benzoxazolyl)-2,4-dioxo[(1R)(trifluoromethyl)-2,3-dihydro-1H-indenyl]-1,2,3,4- 20 tetrahydropyrimidinecarboxylic acid.
8. The salt as claimed in claim 7, characterized in that the X-ray ctogram of the compound has a peak maximum of the 2 theta angle at 17.6.
9. The salt as claimed in claim 7 or 8, characterized in that the X-ray diffractogram of the compound has peak maxima of the 2 theta angle at 17.6, 17.9 and 19.1. 17760162_1 (GHMatters) P102736.NZ
10. The salt as claimed in claim 1 or 2, which is the potassium salt of 1-(3-methyloxo-2,3-dihydro-1,3- benzoxazolyl)-2,4-dioxo[(1R)(trifluoromethyl)-2,3-dihydro-1H-indenyl]-1,2,3,4- tetrahydropyrimidinecarboxylic acid.
11. The salt as claimed in claim 10, characterized in that the X-ray diffractogram of the compound has a 5 peak maximum of the 2 theta angle at 23.7.
12. The salt as claimed in claim 10 or 11, characterized in that the X-ray diffractogram of the compound has peak maxima of the 2 theta angle at 23.7, 15.3 and 20.5.
13. The salt as claimed in any of claims 1 to 12 for the treatment of disorders.
14. A medicament sing a salt as claimed in any of claims 1 to 12 and no greater proportions of any 10 other form of the compound of the formula (I).
15. A medicament sing a compound according to any of Claims 1 to 12 in more than 90 percent by weight based on the total amount of the compound of the formula (I) present.
16. A process for preparing the nd as claimed in any of claims 1 to 12, which ses dissolving the compound of the formula (I) in the form of the free acid. 15
17. A process as claimed in claim 16, wherein dissolving the compound of the formula (I) in the form of the free acid comprises ng or shaking in an inert solvent with a solution of the salt-forming base at a temperature of 10°C to 60°C.
18. The use of a salt as claimed in any of claims 1 to 12 in the manufacture of a medicament for the treatment and/or prophylaxis of disorders. 20
19. The use as claimed in claim 18, wherein the disorders are cardiovascular, inflammatory, allergic and/or fibrotic disorders.
20. The use as claimed in claim 18 or 19, wherein the medicament comprises a salt as claimed in any of claims 1 to 12 and no greater proportions of any other form of the compound of the a (I).
21. The use as claimed in claim 18 or 19, n the medicament comprises a compound according to any 25 of Claims 1 to 12 in more than 90 percent by weight based on the total amount of the compound of the formula (I) present.
22. The salt as claimed in claim 1 substantially as herein described with reference to any one of the es and/or
NZ719532A 2013-11-08 2014-11-05 Salts of 1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1r)- 4-(trifluormethyl)-2,3-dihydro-1h-inden-1-yl]-1,2,3,4-tetrahydropyrimidin-5-carboxylic acid NZ719532B2 (en)

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EP13192177 2013-11-08
EP13192177.7 2013-11-08
PCT/EP2014/073801 WO2015067652A1 (en) 2013-11-08 2014-11-05 Salts of 1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1r)- 4-(trifluormethyl)-2,3-dihydro-1h-inden-1-yl]-1,2,3,4-tetrahydropyrimidin-5-carboxylic acid

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