WO2004005299A1 - Formes polymorphiques d'un derive de 4h-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxyde - Google Patents

Formes polymorphiques d'un derive de 4h-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxyde Download PDF

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WO2004005299A1
WO2004005299A1 PCT/DK2003/000431 DK0300431W WO2004005299A1 WO 2004005299 A1 WO2004005299 A1 WO 2004005299A1 DK 0300431 W DK0300431 W DK 0300431W WO 2004005299 A1 WO2004005299 A1 WO 2004005299A1
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prevention
diabetes
treatment
type
gdm
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PCT/DK2003/000431
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Anne Frost Jensen
Finn Broni Junager
Claus Ulrich Jessen
Hanne Tøfting KORNØ
Peter Palitzsch
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Novo Nordisk A/S
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • 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

Definitions

  • the present invention relates to novel polymorphic/pseudopolymorphic forms of the potassium channel opener 6-chloro-3-(1 -methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4- thiadiazine 1 ,1-dioxide, their preparations, pharmaceutical compositions comprising the novel forms and their use as therapeutic agents.
  • Potassium channels play an important role in the physiological and pharmacological control of cellular membrane potential.
  • the different types of potassium channels are the ATP-sensitive (K A ⁇ p-) channels, which are regulated by changes in the intracellular concentration of adenosine triphosphate.
  • the K A ⁇ p-channels have been found in cells from various tissues such as cardiac cells, pancreatic cells, skeletal muscles, smooth muscles, central neurons and adenohypophysis cells.
  • the channels have been associated with di- verse cellular functions for example hormone secretion (insulin from pancreatic beta-cells, growth hormone and prolactin from adenohypophysis cells), vasodilation (in smooth muscle cells), cardiac action potential duration, neurotransmitter release in the central nervous system.
  • hormone secretion insulin from pancreatic beta-cells, growth hormone and prolactin from adenohypophysis cells
  • vasodilation in smooth muscle cells
  • cardiac action potential duration neurotransmitter release in the central nervous system.
  • Modulators of the K A ⁇ p-channels have been found to be of importance for the treat- ment of various diseases.
  • Certain sulphonylureas which have been used for the treatment of non-insulin-dependent diabetes mellitus, act by stimulating insulin release through an inhibition of the KATP -channels on pancreatic beta-cells.
  • the potassium channel openers which comprise a heterogeneous group of compounds, have been found to be able to relax vascular smooth muscles and have therefore been used for the treatment of hypertension.
  • potassium channel openers can be used as bronchodilators in the treatment of asthma and various other diseases.
  • potassium channel openers have been shown to promote hair growth, and have been used for the treatment of baldness.
  • Potassium channel openers are also able to relax urinary bladder smooth muscle and therefore, can be used for the treatment of urinary incontinence.
  • Potassium channel openers which relax smooth muscle of the uterus, can be used for treatment of premature labour.
  • potassium channel openers are found to be useful in the treatment of benign prostatic hyperplasia, erectile dysfunction and in contraception.
  • Potassium channel openers which inhibit insulin secretion by activating potassium channels of the beta-cell can be used alone or in combination with other compounds in order to treat or prevent Type-2 diabetes (non-insulin dependent diabetes mellitus, NIDDM), to prevent or intervent Type-1 diabetes (insulin dependent diabetes mellitus, IDDM) including prevention or slowing of progression of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).
  • Type-2 diabetes non-insulin dependent diabetes mellitus, NIDDM
  • IDDM insulin dependent diabetes mellitus
  • IGF impaired fasting glucose
  • ITT impaired glucose tolerance
  • K A ⁇ p-openers are able to antagonize vasospasms in basilar or cerebral arteries they can be used for the treatment of vasospastic disorders such as subarachnoid haemorrhage and migraine.
  • Potassium channel openers hyperpolarize neurons and inhibit neurotransmitter release and it is expected that these compounds can be used for the treatment of various diseases of the central nervous system, e.g. epilepsia, ischemia and neurodegenerative diseases, and for the management of pain.
  • WO 00/37474 discloses a class of potassium channel openers having the general formula
  • X and Y independently are hydrogen, halogen, perhalomethyl, d-e-alkyl or C 1-6 - alkoxy;
  • R 1 , R 2 and R 3 independently are C ⁇ -6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, carboxy, C -6 -aIkoxycarbonyl or aryl, all of which are optionally being mono- or polysubsti- tuted with halogen, hydroxy, oxo, or aryl; or
  • R 1 is as defined above and
  • thermodynamically stable polymorphs and polymorphs which have shown to be thermodynamically metastable over a considerable period of time, may have advantages in higher solubility.
  • thermodynamically stable/thermodynamically metastable polymorphs may possess higher bioavailability in human beings.
  • different polymorphic and pseudopolymorphic forms may also differ in hygroscopicity, possess different other physical properties such as tap and bulk density, angle of rest, particle size, or may possess different stabilities at various storage conditions, all of which are important parameters during formulation.
  • novel crystalline polymorphs designated A, B and D are pharmacologically advantageous to the crystal form of 6-chloro-3-(1-methylcyclopropyl)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1,1-dioxide disclosed in WO 00/37474, Example 3, since they are solvent free and thus posses no toxic potential from this source.
  • FIG. 1 illustrates the DSC thermogram of polymorph A
  • Figure 2 illustrates the X-ray powder diffractogram of polymorph A
  • Figure 3 illustrates the DSC thermogram of polymorph B
  • Figure 4 illustrates the X-ray powder diffractogram of polymorph B
  • Figure 5 illustrates the DSC thermogram of pseudopolymorph C1 , a solvate of acetone
  • Figure 6 illustrates the TGA trace of pseudopolymorph C1 , a solvate of acetone
  • Figure 7 illustrates the X-ray powder diffractogram of pseudopolymorph C1 , a solvate of acetone
  • Figure 8 illustrates the DSC thermogram of pseudopolymorph C2, a solvate of 1-butanol
  • Figure 9 illustrates the TGA trace of pseudopolymorph C2, a solvate of 1-butanol
  • Figure 10 illustrates the X-ray powder diffractogram of pseudopolymorph C2, a solvate of 1-butanol
  • Figure 11 illustrates the DSC thermogram of pseudopolymorph C3, a solvate of 2- butanol
  • Figure 12 illustrates the TGA trace of pseudopolymorph C3, a solvate of 2-butanol
  • Figure 13 illustrates the X-ray powder diffractogram of pseudopolymorph C3, a solvate of 2-butanol
  • Figure 14 illustrates the DSC thermogram of pseudopolymorph C4, a solvate of 1,4- dioxane
  • Figure 15 illustrates the TGA trace of pseudopolymorph C4, a solvate of 1 ,4-dioxane
  • Figure 16 illustrates the X-ray powder diffractogram of pseudopolymorph C4, a solvate of 1 ,4-dioxane
  • Figure 17 illustrates the DSC thermogram of pseudopolymorph C5, a solvate of methylacetate
  • Figure 18 illustrates the TGA trace of pseudopolymorph C5, a solvate of methylacetate
  • Figure 19 illustrates the X-ray powder diffractogram of pseudopolymorph C5, a solvate of methylacetate
  • Figure 20 illustrates the DSC thermogram of pseudopolymorph C6, a solvate of methylethylketone
  • Figure 21 illustrates the TGA trace of pseudopolymorph C6, a solvate of methylethylketone
  • Figure 22 illustrates the X-ray powder diffractogram of pseudopolymorph C6, a solvate of methylethylketone
  • Figure 23 illustrates the DSC thermogram of pseudopolymorph C7, a solvate of THF
  • Figure 24 illustrates the TGA trace of pseudopolymorph C7, a solvate of THF
  • Figure 25 illustrates the X-ray powder diffractogram of pseudopolymorph C7, a solvate of THF
  • Figure 26 illustrates the DSC thermogram of pseudopolymorph C8, a solvate of toluene
  • Figure 27 illustrates the TGA trace of pseudopolymorph C8, a solvate of toluene
  • Figure 28 illustrates the X-ray powder diffractogram of pseudopolymorph C8, a solvate of toluene
  • Figure 29 illustrates the DSC thermogram of pseudopolymorph C9, a solvate of 1- pentanol
  • Figure 30 illustrates the TGA trace of pseudopolymorph C9, a solvate of 1-pentanol
  • Figure 31 illustrates the X-ray powder diffractogram of pseudopolymorph C9, a solvate of 1- pentanol
  • Figure 32 illustrate the DSC thermogram of polymorph D
  • Figure 33 illustrates the X-ray powder diffractogram of polymorph D
  • Figure 34 illustrates the X-ray powder diffractogram of a mixture of polymorphs A and B
  • Figure 35 illustrates the X-ray powder diffractogram of a mixture of polymorph B and pseudopolymorph Cj
  • the present invention relates to novel polymoiphic/pseudopolymorphic forms or mixtures thereof of the potassium channel opener 6-chloro-3-(1 -methylcyclopropyl)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1,1-dioxide of formula (I)
  • a number of polymorphic/pseudopolymorphic forms of 6-chloro-3-(1-methyl- cyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide or mixtures thereof have been identified.
  • the polymorphic forms identified have been designated A, B and D.
  • the mixtures of polymorphic/pseudopolymorphic forms identified have been designated AB and BC.
  • the polymorphic/pseudopolymorphic forms or mixtures thereof may be obtained from the following solvents: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butylacetate, butylmethylether, cumene, DMSO (dimethylsulfoxide), ethanol, 1- propanol, 2-propanol, ethylacetate, ethylether, ethylformate, formic acid, heptane, iso-butylacetate, iso-propylacetate, methanol, methylacetate, 3-methyl-1-butanol, methylethyl ketone, methyl iso-butyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, propanolacetate, water or any combinations thereof.
  • solvents acetic acid, acetone, anisole, 1-butanol, 2-butanol, butylacetate, butylmethylether
  • a pharmaceutical composition comprising a polymorphic/pseudopolymorphic form of 6-chloro-3-(1-methylcyclopropyl)amino- 4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1,1-dioxide or a mixture thereof, optionally in combination with one or more pharmaceutically acceptable carriers or excipients.
  • a process for the preparation of the polymorphic/pseudopolymorphic forms of 6-chloro-3-(1-methylcyclopropyl)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide or mixtures thereof which processes comprises suspending or dissolving 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4- thiadiazine 1 ,1 -dioxide in an appropriate solvent or a mixtures of solvents and crystallizing the various forms from the solution.
  • the process for the preparation of the various polymorphic forms of the present invention comprises: a) suspending or dissolving 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4- thiadiazine 1 ,1 -dioxide in an appropriate solvent or a mixture of solvents, b) optionally heating the mixture to 60-120°C depending on the boiling point of the appropriate solvent or solvent mixture so that the solution becomes clear, and filtering the clear solution, c) optionally adding a co solvent at 60-120°C, d) optionally distilling off solvent, e) slowly cooling the solution to 0-50°C, or adding the solution to a third solvent or mixture of solvents, or adding solvent or a mixture of solvents to the solution or combinations thereof whereby crystals are formed, g) filtrating the resulting suspension, > h) washing the filter cake with an appropriate solvent or mixture of solvents and drying the filter cake to constant weight.
  • solvents include but are not limited to: water, hydrocarbons (aromatic, aliphatic, unsaturated, aromatic) such as pentane, heptane, cumene or toluene; alcohols (monohydric or polyhydric aliphatic, unsaturated, aromatic) such as methanol, ethanol, 1- propanol, 2-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol; ethers (open chain or cyclic) such as ethyl ether, tert-butyl methyl ether, anisole, 1 ,4-dioxane or tetrahydro- furane; carbonyls (aldehydes, ketones) such as acetone, methyl ethyl ketone, methyl isobutyl ketone; carbonic acids such as formic acid, acetic acid; carbon
  • the present invention relates to the use of the polymorphic/pseudopolymorphic forms of 6-chloro-3-(1-methylcyclopropyl) amino-4H-thieno[3,2- e]-1 ,2,4-thiadiazine 1 ,1 -dioxide or mixtures thereof, for the preparation of a pharmaceutical composition for the treatment of various diseases of the cardiovascular system, e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart diseases; the pulmonary system; the gastrointestinal system; the central nervous system and the endocrinological system.
  • various diseases of the cardiovascular system e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart diseases
  • the pulmonary system e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris and coronary heart diseases
  • the pulmonary system e.g. cerebral ischemia, hypertension, ischemic heart diseases, angina pectoris
  • potassium channel openers hyperpolarize neurons and inhibit neurotransmitter release and hence the polymorphic/pseudopolymorphic forms of 6-chloro-3- (1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide or mixtures thereof, can be used in the preparation of a pharmaceutical composition for the treatment of various diseases of the central nervous system, e.g. epilepsia, ischemia and neurodegenerative diseases, and for the management of pain.
  • various diseases of the central nervous system e.g. epilepsia, ischemia and neurodegenerative diseases
  • potassium channel openers promote hairgrowth, therefore, the polymorphic/pseudopolymorphic forms of 6-chloro-3-(1 -methylcyclopropyl)amino-4H- ' thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide or mixtures thereof, can be used for the for the preparation of a pharmaceutical composition for the treatment of baldness.
  • NIDDM non-insulin dependent diabetes
  • Potassium channel openers and hence the poly- morphic/pseudopolymorphic forms of 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2- e]-1 ,2,4-thiadiazine 1 ,1 -dioxide or mixtures thereof, can be used for counteracting the hyperinsulinemia and thereby prevent diabetes and reduce obesity.
  • polymorphic/pseudopolymorphic forms of the compound 6-Chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4- thiadiazine 1,1-dioxide or mixtures thereof can be used for the preparation of a pharmaceutical composition for the treatment or prevention of Type-2 diabetes or Type-2 prevention in prior GDM.
  • potassium channel openers in early cases of insulin dependent diabetes (IDDM) or in pre- diabetic cases, potassium channel openers and hence the novel polymorphic/pseudopolymorphic forms of 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4- thiadiazine 1 ,1 -dioxide or mixtures thereof, can be used to induce pancreatic beta-cell rest which may prevent the progression of the autoimmune disease.
  • the potassium channel openers of the present invention can be administred in combination with an immunosuppressant or with an agent like nicotinamide, which will reduce autoimmune degeneration of beta-cells.
  • beta-cell rest with a treatment protecting the beta-cells against cytokine , ⁇ mediated beta-cell impairment/cytotoxicity is another aspect of this invention.
  • Insulin requiring orType-1 diabetes as well as late onset IDDM (also known : as type 1.5.
  • IDDM non-insulin-requiring Type-2 diabetes
  • NIDDM non-insulin-requiring Type-2 diabetes
  • TNFa tumour necrosis factor a
  • IFNg interferon g
  • Nicotinamide belongs to the B-vitamin family and is derived from nicotinic acid by amidation of the carboxyl group. It processes none of nicotine's pharmacological properties. NA is converted into NAD+, which acts as a coenzyme for proteins involved in tissue respiration. NA has been proposed to influence several of the putative intracellular molecular events following immune attack on the beta-cells. Animal experiments and early non-blinded experiments in humans have indicated a protective role of this compound against IDDM as well as in cytokine/immune mediated beta-cell destruction.
  • the application concerns the use of the polymorphic/pseudopolymorphic forms of 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4- , thiadiazine 1 ,1 -dioxide alone or in combination with the inhibitor of cytokine/immune medi- ated beta-cell impairment, in transplantation, e.g. islet transplantation into diabetes patients.
  • the use of one or both of these treatments may reduce the risk of rejection of the transplanted islets/beta-cells/engineered beta-cells/pancreas.
  • the polymorphic/pseudopolymorphic forms of 6- chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1,1-dioxide or mix- tures thereof may be used for the preparation of a pharmaceutical composition for treatment or prevention of diseases of the endocrinological system such as treatment of hyperinsu- linaemia, treatment or prevention of Type-2 diabetes, prevention of Type-2 diabetes in prior GDM, prevention and intervention of Type-1 diabetes, prevention or slowing of progression of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), gestational diabetes mellitus (GDM) or obesity.
  • IGF impaired fasting glucose
  • ITT impaired glucose tolerance
  • GDM gestational diabetes mellitus
  • the present invention relates to polymorphic/pseudopolymorphic forms of 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide or mixtures thereof, for use as a therapeutically acceptable substances, preferably for use as therapeutically acceptable substances in the treatment or prevention of diseases of the en- docrinological system such as treatment of hyperinsulinaemia, treatment or prevention of Type-2 diabetes, prevention of Type-2 diabetes in prior GDM, prevention and intervention of Type-1 diabetes, prevention or slowing of progression of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), gestational diabetes mellitus (GDM) or obesity.
  • IGF impaired fasting glucose
  • ITT impaired glucose tolerance
  • GDM gestational diabetes mellitus
  • the invention also relates to the use of the novel polymor- phic/pseudopolymorphic forms of 6-chloro-3-(1 -methylcyclopropyl)amino-4H-thieno[3,2-e]- 1 ,2,4-thiadiazine 1,1-dioxide or mixtures thereof, as pharmaceutical compositions useful for treating or preventing diseases of the endocrinological system, such as treating hyperinsulinaemia, treating or preventing Type-2 diabetes, preventing Type-2 diabetes in priorGDM, preventing and interventing Type-1 diabetes, prevention or slowing of progression of im- paired fasting glucose (IFG) and impaired glucose tolerance (IGT), gestational diabetes mellitus (GDM) or obesity.
  • IGF im- paired fasting glucose
  • ITT impaired glucose tolerance
  • GDM gestational diabetes mellitus
  • treatment or prevention is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complica- tions, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • prevention and intervention of Type-1 diabetes is defined as follows: prevention is defined as the management and care of an individual at risk of developing Type 1 diabetes prior to the clinical onset of the disease. Intervention is defined as the management and care of a Type 1 diabetes patient at diagnosis or later.
  • the purpose of prevention and intervention is to combat the disease, condition, or disorder and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • the pharmaceutical composition of the invention may comprise a polymorphic/pseudopolymorphic form of 6-chloro-3-(1-methylcyclopropyl)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1,1-dioxide combined with one or more other pharmacologically active compounds, e.g. an antidiabetic or other pharmacologically active material.
  • Suitable antidiabetics comprise short and long acting insulins, insulin analogues, insulin sensitiz- ers, insulin secretagogues as well as orally active hypoglycaemic agents such as sulphony- lureas, e.g.
  • glibenclamide and glipizide biguanides, e.g. metformin; benzoic acid derivatives, e.g. repaglinide; thiazolidinediones, e.g. rosiglitazone, pioglitazone and ciglitazone; glucagon like peptide 1 (GLP-1 ), GLP-1 derivatives and GLP-1 analogues; peroxisome proliferating activated receptor (PPAR) ligands including the PPAR-alpha, PPAR-gamma and PPAR-delta subtypes; inhibitors of ⁇ -glucosidase, e.g. acarbose and voglibose, inhibitors of hepatic enzymes responsible for the biosynthesis of glucose, e.g. glycogen phosphorylase inhibitors.
  • biguanides e.g. metformin
  • benzoic acid derivatives e.g. repaglinide
  • polymo ⁇ hic/pseudopolymorphic forms of 6-chloro-3-(1- methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide or mixtures thereof may be administered in combination with nateglinide.
  • polymo ⁇ hic/pseudopolymorphic forms of 6-chloro-3-(1 - methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide or mixtures thereof may be administered in combination with one or both of metformin and repaglinide.
  • the present compounds are administered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference.
  • a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120,
  • the present compounds may be admin- istered in combination with an insulin sensitizer eg such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr.
  • an insulin sensitizer eg such as Gl 262570, YM-440, MCC-555, JTT-501 , AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
  • the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells eg tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.
  • the present compounds may be administered in combination with nateglinide.
  • the present compounds are administered in combination with an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • the present compounds are administered in combination with more than one of the above-mentioned compounds eg in combination with metformin and a sulphonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc.
  • a sulphonylurea such as glyburide
  • a sulphonylurea and acarbose such as glyburide
  • a sulphonylurea and acarbose such as glyburide
  • the polymo ⁇ hic/pseudopolymorphic forms of 6-chloro-3-(1 - methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide or mixtures thereof reduces blood glucose and triglyceride levels and are accordingly useful for the treatment and/or prevention of ailments and disorders such as diabetes and/or obesity.
  • polymorphic/pseudopolymorphic forms of 6-chloro-3-(1- methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxideor mixtures thereof are useful for the treatment and/or prophylaxis of dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, insulin resistance, hyperglycaemia, atherosclerosis, hyperlipidemia, coronary artery disease, myocardial ischemia and other cardiovascular disorders.
  • polymo ⁇ hic/pseudopolymorphic forms of 6-chloro-3-(1 - methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide or mixtures thereof may also be useful for treating diabetic complications, gestational diabetes mellitus (GDM), polycystic ovarian syndrome (PCOS) and smoke reduction or cessation.
  • GDM gestational diabetes mellitus
  • PCOS polycystic ovarian syndrome
  • compositions containing the polymorphic/pseudopolymorphic forms of 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide or mixtures thereof, and optionally other compounds as mentioned underneath may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19 th Ed., 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • 4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide or mixtures thereof may also be administered in combination with one or more further pharmacologically active substances eg. selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • pharmacologically active substances eg. selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • polymorphic/pseudopolymorphic forms of 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide or mixtures thereof may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotro- pin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic
  • Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise sulphonylureas, bigua- nides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase- IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as HMG CoA inhibitors (statins), and compounds lowering food intake.
  • sulphonylureas bigua- nides, meglitinides, glu
  • polymo ⁇ hic/pseudopolymorphic forms of 6-chloro-3-(1- methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide or mixtures thereof may be administered in combination with an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • polymorphic/pseudopolymorphic forms of 6-chloro-3-(1- methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide or mixtures thereof may be administered in combination with more than one of the above-mentioned compounds eg. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
  • polymo ⁇ hic/pseudopolymorphic forms of 6-chloro-3-(1 - methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1,1-dioxide or mixtures thereof may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents examples include ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, pro- pranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ - blockers such as doxazosin, urapidil, prazosin and terazosin.
  • ACE angiotensin converting enzyme
  • compositions include the polymorphic/pseudopolymorphic forms of 6-chloro- 3-(1 -methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide or mixtures thereof, associated with a pharmaceutically acceptable excipient, which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier, which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier, which can be in the form of a capsule, sachet, paper or other container.
  • conventional techniques for the preparation of pharmaceutical compositions may be used.
  • the active polymorphic/pseudopolymorphic forms of 6-chloro-3-(1-methylcyclopropyl)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide or mixtures thereof will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of a am- poule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be solid, semi-solid, or liquid material, which acts as a vehicle, excipient, or medium for the active compound.
  • the active polymo ⁇ hic/pseudopolymo ⁇ hic forms of 6-chloro-3-(1- methylcyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide or mixtures thereof, can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohol's, polyethylene glycol's, polyhydroxyethoxy- lated castor oil, peanut oil, olive oil, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentae- rythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active ingredient.
  • the route of administration may be any route, which effectively transports the active ingredient to the appropriate or desired site of action, such as oral, nasal, pulmonary, trans- dermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain the active ingredient of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • solubilizing agents e.g. propylene glycol
  • surfactants e.g. propylene glycol
  • absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin
  • preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain: Active ingredient 5.0 mg
  • the present polymorphic/pseudopolymo ⁇ hic forms of 6-chloro-3-(1-methyl- cyclopropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide or mixtures thereof may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of diseases related to the regulation of blood sugar.
  • mammals include also animals, both domestic animals, e.g. household pets, and non- domestic animals such as wildlife.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, e.g. from about 0.01 to about 50 mg/kg body weight per day, or e.g. from about 0.05 to about 20 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, e.g. from about 0.1 to about 500 mg, or e.g. from about 0.5 mg to about 200 mg.
  • the polymorphic/pseudopolymorphic forms of 6-chloro-3-(1-methylcyclopropyl)- amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1,1-dioxide or mixtures thereof were prepared synthesized as described in the following examples, which however, are not to be construed as limiting the scope of protection.
  • the features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof.
  • Mp is melting point as detected by Differential Scanning Calorimetry (DSC), and is given in °C.
  • DSC Differential Scanning Calorimetry
  • the DSC analysis is an enthalpy-change method in which the difference in en- ergy inputs into a substance and a reference material is measured as a function of temperature by which a thermogram is recorded. The thermic events in the sample are reflected by the thermogram where an endothermic peak (the sample is absorbing heat) can be a solid ⁇ solid state transition or a melting of the substance.
  • An exotherm peak means that the sample is giving off heat and the underlying process can be a recrystallization or a simple degrada- tion/combustion.
  • TGA thermogravimetric analysis
  • a crystal is a solid state material whose atomic structure is periodic in three dimensions.
  • the crystallinity is measured by powder X-ray diffraction (PXRD).
  • PXRD powder X-ray diffraction
  • the technique is based upon the interaction between electrons and X-ray radiation.
  • the X- ray radiation is diffracted by the electrons of the atoms at the lattice planes and each set of parallel planes gives rise to a peak in the diffraction pattern.
  • the intensity of the diffracted radiation is measured as a function of scattering angle 2 ⁇ by which a diffractogram is recorded. A higher scattering angle corresponds to a smaller spacing between the lattice planes in the set.
  • the position of the peaks is related to the physical dimensions of the crystal building stone, the unit cell, whereas the peak heights, i.e. the intensities are related to the arrangement and type of atoms residing on the set of planes in question.
  • a chemical com- pound may exist in different crystalline forms each with a characteristic three-dimensional atomic arrangement. These are called polymorphs. Each polymorph will have a unique X-ray diffraction pattern (diffractogram) and the technique is therefore widely used in the analysis of polymorphism.
  • CDCI 3 deuterated chloroform
  • NMR Nuclear Magnetic Resonance s: singlet peak (in 1 H-NMR spectra) d: doublet of peaks (in 1 H-NMR spectra) t: triplet of peaks (in 1 H-NMR spectra) q: quartet of peaks (in 1 H-NMR spectra) p: penta (5) quintet of peaks (in 1 H-NMR spectra) br. s: broad singlet peak (in 1 H-NMR spectra)
  • 1,1-dioxide was suspended in 100 mL 1-propanol and heated to reflux (95°C) while stirring. At reflux, 15 mL water was added slowly. The solution became clear. The mixture was slightly cooled. At 80°C the clear solution was treated with 1g active carbon and heated again to reflux. After 1 h, the mixture is filtered. The heating bath was removed and the mix- ture was allowed to equilibrate to room temperature. The mixture was then put on a ice bath and cooled to 5°C while stirring. After 2 h at 5°C the suspension was filtered and the filter cake washed with 10 mL 1-propanol. After drying, 8.3 g of 6-chloro-3-(1-methylcyclopropyl)- amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide crystal form A was obtained.
  • 1,1-dioxide was suspended in 150 mL 2-propanol and 23.5 mL water. While stirring, the mixture was heated to reflux and stirred until the mixture became clear. 1.5 g of active carbon was the added and reflux is maintained for another 1 h. The mixture was filtered on a preheated filter and the filter cake washed with a mixture of 9 mL 2-propanol and 1 mL water. 150 mL water was slowly added to the 75-80°C hot filtrate while stirring. At 73°C the crystallisation started. The mixture is slowly cooled to 5°C and stirred for another 2 h at 5°C. The mixture was filtered and the filter cake washed with 2 x 10 mL 2-propanol.
  • the polymorph A is characterised by having a DSC thermogram as shown in Figure 1 and a powder X-ray diffractogram (PXRD) as shown in Figure 2.
  • the crystal density is by crystal structure determination calculated to 1.560 g/cm 3 (at 120 K) while the experimental value de ⁇ termined by He-pychnometry is 1.546 g/cm 3 (at 295 K).
  • the melting point of polymorph A is 262.4°C (onset).
  • Figure 1 The DSC thermogram of polymorph A.
  • Figure 2 The X-ray powder diffractogram of polymorph A.
  • the polymorph B is characterised by having a DSC thermogram as shown in Figure 3 and a powder X-ray diffractogram (PXRD) as shown in Figure 4.
  • the crystal density of this polymorph is by crystal structure determination calculated to 1.494 g/cm 3 , while the experimental value determined by He-pychnometry is 1.499 g/cm 3 (both at 295 K).
  • the melting point of polymorph B is 268.9°C (onset).
  • Example 4 Process for the preparation of pseudopolymorph C1 of 6-chloro-3-(1-methyl- cyclopropyl)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide, a solvate of acetone
  • the pseudopolymorph C1 is characterised by having a DSC thermogram as shown in Figure 5; a TGA trace as shown in Figure 6 and a powder X-ray diffractogram (PXRD) as shown in Figure 7.
  • the melting point of polymorph C1 from acetone is 260.4°C (onset).
  • Figure 7 The X-ray powder diffractogram of pseudopolymorph C1, a solvate of acetone
  • Example 5 Process for the preparation of pseudopolymorph C2 of 6-chloro-3-(1- methylcyclopropy!)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide, a solvate of 1- butanol.
  • the pseudopolymorph C2 is characterised by having a DSC thermogram as shown in Figure 8; a TGA trace as shown in Figure 9 and a powder X-ray diffractogram (PXRD) as shown in Figure 10.
  • the melting point of polymorph C2 from 1-butanol is 260.0°C (onset).
  • Figure 10 The X-ray powder diffractogram of pseudopolymorph C2, a solvate of 1- butanol
  • Example 6 Process for the preparation of pseudopolymorph C3 of 6-chloro-3-(1- methylcyclopropyl)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide, a solvate of 2- butanol
  • the pseudopolymorph C3 is characterised by having a DSC thermogram as shown in Figure 11 ; a TGA trace as shown in Figure 12 and a powder X-ray diffractogram (PXRD) as shown in Figure 13.
  • the melting point of polymorph C3 from 2-butanol is 259.0°C (onset).
  • Figure 13 The X-ray powder diffractogram of pseudopolymorph C3, a solvate of 2- butanol
  • Example 7 Process for the preparation of pseudopolymorph C4 of 6-chloro-3-(1-methyl- cyclopropyl) amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide, a solvate of 1 ,4-dioxane
  • the pseudopolymorph C4 is characterised by having a DSC thermogram as shown in Figure 14; a TGA trace as shown in Figure 15 and a powder X-ray diffractogram (PXRD) as shown Figure 16.
  • the melting point of polymorph C4 from 1 ,4-dioxane is 253.4°C (onset).
  • Figure 16 The X-ray powder diffractogram of pseudopolymorph C4, a solvate of 1,4- dioxane
  • Example 8 Process for the preparation of pseudopolymorph C5 of 6-chloro-3-(1-methyl- cyclopropyl)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide, a solvate of methylacetate
  • the pseudopolymorph C5 is characterised by having a DSC thermogram as shown in Figure 17; a TGA trace as shown in Figure 18 and a powder X-ray diffractogram (PXRD) as shown in Figure 19.
  • the melting point of polymorph C5 from methylacetate is 258.0°C (onset).
  • Figure 9 The X-ray powder diffractogram of pseudopolymorph C5, a solvate of methylacetate
  • Example 9 Process for the preparation of pseudopolymorph C6 of 6-chloro-3-(1-methyl- cyclopropyl)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1,1-dioxide, a solvate of methylethylketone (or MEK or 2-butanone)
  • the pseudopolymorph C6 is characterised by having a DSC thermogram as shown in
  • FIG 20 a TGA trace as shown in Figure 21 and a powder X-ray diffractogram (PXRD) as shown in Figure 22.
  • the melting point of polymorph C6 from methylethylketone is 261.5°C (onset).
  • Figure 22 The X-ray powder diffractogram of pseudopolymorph C6, a solvate of methylethylketone
  • Example 10 Process for the preparation of pseudopolymorph C7 of 6-chloro-3-(1-methyl- cyclopropy!)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide, a solvate of tetrahydrofu- rane (THF)
  • the pseudopolymorph C7 is characterised by having a DSC thermogram as shown in Figure 23; a TGA trace as shown in Figure 24 and a powder X-ray diffractogram (PXRD) as shown in Figure 25.
  • the melting point of polymorph C7 from THF is 259.7°C (onset).
  • Figure 25 The X-ray powder diffractogram of pseudopolymorph C7, a solvate of THF
  • Example 11 Process for the preparation of pseudopolymorph C8 of 6-chloro-3-(1-methyl- cyclopropyl)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide, a solvate of toluene
  • the pseudopolymorph C8 is characterised by having a DSC thermogram as shown in Figure 26; a TGA trace as shown in Figure 27 and a powder X-ray diffractogram (PXRD) as shown in Figure 28.
  • the melting point of polymorph C8 from toluene is 249.1°C (onset).
  • Figure 28 The X-ray powder diffractogram of pseudopolymorph C8, a solvate of toluene
  • Example 12 Process for the preparation of pseudopolymorph C9 of 6-chloro-3-(1-methyl- cyclopropyl)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide, a solvate of 1-pentanol
  • the molar ratio of 1-pentanol to 6-chloro-3-(1-methylcyclopropyl)amino-4H- thieno[3,2-e]- 1 ,2,4-thiadiazine 1 ,1-dioxide was established by NMR spectroscopy to be 0.24 to 1.0.
  • the pseudopolymorph C9 is characterised by having a DSC thermogram as shown in Figure 29; a TGA trace as shown in Figure 30 and a powder X-ray diffractogram (PXRD) as shown in Figure 31.
  • the melting point of polymorph C9 from 1-pentanol is 260.2°C (onset).
  • Figure 31 The X-ray powder diffractogram of pseudopolymorph C9, a solvate of 1- pentanol
  • the pH of the resulting mixture was measured to 12.2 after addition of the NMP solution. Additional 0.6 mL acetic acid is added. A white, greasy precipitate is formed and is filtered off. To the filtrate is added 0.9 mL acetic acid. The pH is now 4.5. Additional 25 mL water is added to the solution. A white precipitate is formed. The solution is cooled on an ice bath and filtered. After drying of the filter cake to constant weight, 1.41 g of 6-chloro-3-(1-methylcyclopropyI)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1,1-dioxide crystals designated form D was obtained.
  • the polymorph D is characterised by having a DSC thermogram as shown in Figure 32 and a powder X-ray diffractogram (PXRD) as shown in Figure 33.
  • the melting point of polymorph D from 2-butanol is 248.0°C (onset).
  • Example 14 Process for the preparation of a mixture of form A and B of 6-chloro-3-(1- methylcyclopropyI)amino-4H- thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide, designated AB
  • Figure 34 The powder X-ray diffractogram of a mixture of polymorphs A and B.
  • Example 15 Process for the preparation of a mixture of form B and C of 6-chloro-3-(1- methylcyclopropyl)amino-4H- thieno[3,2-e]-1,2,4-thiadiazine 1 ,1-dioxide, designated BC
  • Figure 35 The powder X-ray diffractogram of a mixture of polymorph B and pseudopolymorph C j .
  • PHARMACOLOGICAL METHODS The ability of the compounds to interact with potassium channels can be determined by various methods. When patch-clamp techniques (Hamill O.P., Marty A., Neher E., Sak- mann B. and Sigworth F.J., Plugers Arch., 391. 85-100 (1981 )) are used the ionic current through a single channel of a ceil can be recorded.
  • the activity of the compounds as potassium channel openers can also be measured as relaxation of rat aorta rings according to the following procedure:
  • the preparations were contracted to achieve 80 % of the maximum response using the required concentration of phenylephrine.
  • potential vasodilator/ agents were added cumulatively to the bath in small volumes using half log molar increments at 2 min intervals. Relaxation was expressed at the percentage of the contracted tension. The potency of a compound was expressed as the concentration required to evoke a 50 % relaxation of the tissue.
  • the opening of the K A ⁇ p-channels can be determined by measuring the subsequent change in the concentration of cytoplasmic free Ca 2+ concentration according to the method of Arkhammar P. et al. , J. Bid. Chem., 262, 5448-5454 (1987).
  • the effect of a K A ⁇ p-channel opener and a K A ⁇ p-channel blocker on pancreatic beta- cells can be determined by measuring the 86 Rb + efflux from a ⁇ -cell line according to the following method:
  • the plates were washed 4 times with Ringer buffer (150 mM NaCI, 10 mM Hepes, 3.0 mM KCI, 1.0 mM CaCI 2 , 20 mM Sucrose, pH 7.1). 80 ⁇ L Ringer buffer and 1 ⁇ L control- or test compound dissolved in DMSO was added. After incubation 1 h at room temperature with a lid, 50 ⁇ L of the supernatant was transferred to PicoPlates (Packard Instrument Company, CT, USA) and 100 ⁇ L MicroScint40 (Packard Instrument Company, CT, USA) added. The plates were counted in TopCount (Packard Instrument Company, CT, USA) for 1 min/well at the 32 P program.
  • Ringer buffer 150 mM NaCI, 10 mM Hepes, 3.0 mM KCI, 1.0 mM CaCI 2 , 20 mM Sucrose, pH 7.1
  • K A ⁇ p-channel modulators on pancreatic beta-cells can be determined by measuring qualitative changes in membrane potential in the insulin producing cell line ⁇ - TC3 using fluorescence imaging techniques.
  • the slow fluorescent membrane potential probe DiBAC was used.
  • the cells were kept in Ca 2+ -HEPES buffer supplemented with 10 mM glucose. After 5 sec of each 60 sec run the compound was added. 48 wells were run in each set, taking about 1 h. The same cells were then run again, now adding 25 mM KCI after 5 sec, and the depolarisation-induced increase in DiBAC fluorescence monitored for 55 sec.
  • K ATP -channel modulators on pancreatic beta-cells can be determined by measuring the increase or decrease in insulin release from insulin producing beta-cell lines or isolated islets.
  • K AT p-channel modulators can be measured using the following procedure: The beta cells are cultured with change of media every three-four days. Cells are then seeded in 96 well microtiter dishes and cultured for three day at 38 °C, 5 % CO 2 and 95 % humidity.
  • the cells are washed with NN -buffer (+10mM HEPES + 0.1 % BSA) for one minute and glucose (final cone. 22 mM), IBMX (final conc.O.lmM) and compounds (final cone, from 5 x 10 '5 M - 5 x 10 "8 M) added. All cells are then incubated for three h (38 °C, 5 % CO 2 and 95 % humidity). Supernates are harvested into Greiner minisorb microtiter wells and frozen. Insulin is measured using ELISA-techniques.
  • the compounds of the present invention show high potency in the insulin release test and high selectivity compared to the relaxation of rat aorta rings test.

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Abstract

La présente invention concerne de nouvelles formes polymorphiques/pseudopolymorphiques de 6-chloro-3-(1-méthylcyclopropyl)amino-4H-thiéno[3,2-e]-1,2,4-thiadiazine 1,1-dioxyde ou des mélanges correspondants, leur préparation et leur utilisation en tant qu'agents thérapeutiques.
PCT/DK2003/000431 2002-07-04 2003-06-24 Formes polymorphiques d'un derive de 4h-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxyde WO2004005299A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8858682B2 (en) * 2005-12-28 2014-10-14 Shimadzu Corporation Method for controlling pressure-difference bubble transfer

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037474A1 (fr) * 1998-12-18 2000-06-29 Novo Nordisk A/S Derives de 1,2,4-thiadiazine fusionnes, leur preparation et utilisation
WO2002000665A1 (fr) * 2000-06-26 2002-01-03 Novo Nordisk A/S Utilisation d'elements d'ouverture du canal a potassium, pour le traitement de l'insulite
WO2002000223A1 (fr) * 2000-06-26 2002-01-03 Novo Nordisk A/S Utilisation d'agonistes des canaux potassiques pour reduire la consommation d'aliments gras
WO2003045955A1 (fr) * 2001-11-30 2003-06-05 Novo Nordisk A/S Utilisation d'activateurs selectifs d'ouverture de canaux potassiques
WO2003045954A1 (fr) * 2001-11-30 2003-06-05 Novo Nordisk A/S Utilisation d'activateurs d'ouverture de canaux potassiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037474A1 (fr) * 1998-12-18 2000-06-29 Novo Nordisk A/S Derives de 1,2,4-thiadiazine fusionnes, leur preparation et utilisation
WO2002000665A1 (fr) * 2000-06-26 2002-01-03 Novo Nordisk A/S Utilisation d'elements d'ouverture du canal a potassium, pour le traitement de l'insulite
WO2002000223A1 (fr) * 2000-06-26 2002-01-03 Novo Nordisk A/S Utilisation d'agonistes des canaux potassiques pour reduire la consommation d'aliments gras
WO2003045955A1 (fr) * 2001-11-30 2003-06-05 Novo Nordisk A/S Utilisation d'activateurs selectifs d'ouverture de canaux potassiques
WO2003045954A1 (fr) * 2001-11-30 2003-06-05 Novo Nordisk A/S Utilisation d'activateurs d'ouverture de canaux potassiques

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8858682B2 (en) * 2005-12-28 2014-10-14 Shimadzu Corporation Method for controlling pressure-difference bubble transfer

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