WO2011069647A1 - New 2-aminothiadiazole derivatives - Google Patents

New 2-aminothiadiazole derivatives Download PDF

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WO2011069647A1
WO2011069647A1 PCT/EP2010/007467 EP2010007467W WO2011069647A1 WO 2011069647 A1 WO2011069647 A1 WO 2011069647A1 EP 2010007467 W EP2010007467 W EP 2010007467W WO 2011069647 A1 WO2011069647 A1 WO 2011069647A1
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group
thiadiazol
butyl
amine
methoxy
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PCT/EP2010/007467
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French (fr)
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Poveda1 Pedro Manuel Grima
Nuria Aguilar Izquierdo
Cepeda Marta Mir
Marta Carrascal Riera
Emma Terricabras Belart
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Almirall, S.A.
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Publication of WO2011069647A1 publication Critical patent/WO2011069647A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to 2-aminothiadiazole derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
  • These compounds are potent agonists of S1P1 receptors and thus, they are useful in the treatment, prevention or suppression of diseases and disorders known to be susceptible to improvement by sphingosine-1 -phosphate receptors agonists (S1 P1), such as autoimmune diseases, chronic immune and inflammatory diseases, transplant rejection, malignant neoplastic diseases, angiogenic-related disorders, pain, neurological diseases, viral and infectious diseases.
  • S1 P1 sphingosine-1 -phosphate receptors agonists
  • Sphingosine -1 phosphate is a pleiotropic lipid mediator that exhibits a broad spectrum of biological activities, including cell proliferation, survival, lymphocyte trafficking, cytoskeletal organization, and morphogenesis.
  • S1P is generated from endogenous sphingosine through phosphorylation by specific kinases, named sphingosine kinases 1 and 2.
  • the levels of S1 P in biological fluids and tissues are tightly regulated by the balance between its synthesis by sphingosine kinases and its degradation by S1 P lyase. This tight control is important since an excessive production of S1 P has been associated to various pathological conditions, such as angiogenesis and vascular permeability changes in cancer, inflammation, myocardial infarction or transplant rejection.
  • S1 P1 to S1 P5 G-protein coupled receptor subtypes
  • S1 P1 to S1 P5 G-protein coupled receptor subtypes
  • the interest on this family of receptors increased following the discovery that they were the pharmacological target of FTY720.
  • This compound a synthetic analog of a natural product derived from the fungus Isaria sinclairii, exhibited a peculiar immunomodulatory potential in vivo. When administered in vivo, it caused lymphopenia, due to the sequestration of lymphocytes from the blood into the lymph nodes and Peyer ' s patches.
  • FTY720P phosphorylated FTY720 in vivo
  • S1 P1 agonists have been recently disclosed for the treatment or prevention of autoimmune diseases, such as multiple sclerosis (WO2008000419, WO2008021532), rheumatoid arthritis or Crohn ' s disease (WO2007091501), chronic immune and inflammatory diseases such as asthma, transplant rejection (W0 99400943), cancer (WO2003097028), lymphoid malignancies (WO2007143081), angiogenic-related disorders, pain (WO2004110421 ,
  • autoimmune diseases such as multiple sclerosis (WO2008000419, WO2008021532), rheumatoid arthritis or Crohn ' s disease (WO2007091501), chronic immune and inflammatory diseases such as asthma, transplant rejection (W0 99400943), cancer (WO2003097028), lymphoid malignancies (WO2007143081), angiogenic-related disorders, pain (WO2004110421 ,
  • WO2007089715 neurological diseases such as neurodegeneration (WO2005025553) or dementia (WO2005058295), cardiovascular diseases (WO2004010987),.
  • Autoimmune diseases include but are not limited to rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases such as Crohn's diseases and ulcerative colitis, psoriatic arthritis, thyroiditis such as Hashimoto's thyroiditis, type I diabetes; systemic lupus erythematosis and Sjogrn's syndrome.
  • Rejection transplanted organs such as kidney, liver, heart, lung, pancreas, cornea and skin; graft-versus-hist disease brought about by stem cell transplantation.
  • Immune and inflammatory diseases which may be prevented or treated include but are not limited to asthma, COPD, respiratory distress syndrome, acute or chronic pancreatitis and hepatitis; chronic sarcoidosis, contact dermatitis, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, Behcet syndrome, inflammatory eye conditions such as conjunctivitis and uveitis.
  • Malignant neoplastic diseases that may be prevented or treated include but are not limited to solid cancer, tumor metastasis and lymphoid malignancies
  • Angiogenesis-related disorders that may be prevented or treated include but are not limited to hemangiomas, ocular neovascularization, macular degeneration or diabetic retinopathy.
  • Pain including neuropathic pain, that may be prevented or treated include but are not limited to prophylaxis or treatment of chronic pain, wherein chronic pain is selected from chronic muscular diseases such as back pain, pain during menstruation, pain during osteoarthritis, pain during rheumatoid arthritis, pain during gastrointestinal inflammation, pain during inflammation of the heart muscle, pain during multiple sclerosis, pain during neuritis, pain during AIDS, pain during chemotherapy, tumor pain, neuropathic pain e. g. after amputation, trigeminal neuralgia, migraine or post herpetic neuralgia.
  • chronic pain is selected from chronic muscular diseases such as back pain, pain during menstruation, pain during osteoarthritis, pain during rheumatoid arthritis, pain during gastrointestinal inflammation, pain during inflammation of the heart muscle, pain during multiple sclerosis, pain during neuritis, pain during AIDS, pain during chemotherapy, tumor pain, neuropathic pain e. g. after amputation, trigeminal neuralgia, migraine or post her
  • Cardiovascular diseases which may be prevented or treated include but are not limited to chronic heart failure, congestive heart failure, arrhythmia or tachyarrythmia, unstable angina, acute myocardial infarction or complications from cardiac surgery or for improving heart energy efficiency or cardiac output.
  • Neurological diseases including neurodegeneration, dementia or brain degeneration that may be prevented or treated include but are not limited to neurological disorders including Parkinson's desease, Parkinsonian disorders, Huntington's disease,
  • Alzheimer's disease amyotrophic lateral sclerosis, spinal ischemia, ischemic stroke, spinal cord injury, cancer-related brain injury, and cancer-related spinal cord injury, Shy-Drager syndrome, progressive supranuclear palsy, Lewy body disease, stroke, cerebral infarction, multi-infarct dementia, and geriatric dementia,
  • Viral diseases which may be prevented or treated include but are not limited to HIV infection, hepatitis C and cytomegalovirus infection. Infectious diseases which may be prevented or treated include but are not limited to pathogenic fungal diseases.
  • EP 0 356 333 A1 is concerned with compounds with antihistamine and anticholinergic activity.
  • the majority of the compounds described in EP 0 356 333 A1 are secondary amines.
  • Compound SR 45530 described in EP 0 356 333 A1 has a methyl moiety attached to the amine nitrogen atom. It is therefore different from the compounds of Formual (I) set out below.
  • the corresponding moiety (R 3 ) in Formula (I) below is an alkyl group, it is necessarily a C 2- 4 alkyl group.
  • n is an integer having a value from 0 to 2
  • R 1 represents a pyridyl group or an imidazo[1 ,2-a]pyridinyl group, wherein the pyridyl group is substituted with one or more substituents selected from halogen atoms, a hydroxy group, a linear or branched d-4 alkyl group and a alkoxy group, or
  • R 1 represents a group of formula:
  • R a and R b independently represent a hydrogen atom, a halogen atom or a linear or branched Ci_4 alkyl group
  • R c represents a hydroxy group, a linear or branched alkyl group or C 1-4 alkoxy group wherein the alkyl and the alkoxy groups independently are optionally substituted with one or more substituents selected from hydroxy group, a cyano group and a - NR'R" group and wherein
  • ⁇ R' represents a hydrogen atom or a linear or branched C 1-4 alkyl group
  • ⁇ R" represents a hydrogen atom or a linear or branched alkyl group optionally substituted with a hydroxycarbonyl group
  • R 2 represents a pyridyl group, a cycloalkyl group or a phenyl group which is optionally substituted with one or more substituents selected from halogen atoms, cyano group, and C 1-4 alkoxy group;
  • R 3 represents a cycloalkyl group, a cycloalkyl-C ⁇ alkyl group or a linear or branched C 2- 4 alkyl group optionally substituted with one or more substituents selected from halogen atoms and C 1-2 alkoxy group;
  • Further objectives of the present invention are to provide a method for preparing said- compounds; pharmaceutical compositions comprising an effective amount of said compounds; compounds for use in the treatment of a human or animal body, in particular, for the treatment of pathological conditions or diseases susceptible to improvement by sphingosine-1 -phosphate receptors agonists (S1 P1), wherein the pathological condition or disease is selected from autoimmune diseases, chronic immune and inflammatory diseases, transplant rejection, malignant neoplastic diseases, angiogenic-related disorders, pain, neurological diseases.viral and infectious diseases.
  • S1 P1 sphingosine-1 -phosphate receptors agonists
  • the present invention further provides the use of the compounds in the manufacture of a medicament for the treatment of such pathological condition or diseases and methods of treatment of such pathological conditions or diseases susceptible to amelioration by sphingosine-1 -phosphate receptors agonists (S1 P1), wherein the pathological condition or disease is selected from autoimmune diseases, chronic immune and inflammatory diseases, transplant rejection, malignant neoplastic diseases, angiogenic-related disorders, pain, neurological diseases, viral and infectious diseases comprising the administration of the compounds of the invention to a subject in need of treatment.
  • S1 P1 sphingosine-1 -phosphate receptors agonists
  • alkyl embraces linear or branched hydrocarbon radicals having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl and ter-butyl radicals.
  • alkoxy embraces linear or branched oxy-containing radicals each having 1 to 4 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, /- propoxy, n-butoxy, and terf-butoxy radicals.
  • cycloalkyl embraces saturated carbocyclic radicals and, unless otherwise specified, a cycloalkyl radical typically has from 3 to 6 carbon atoms, preferably from 3 to 4 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the 4 to 6-membered saturated heterocyclic ring which R' and R" may form together with the nitrogen to which they are attached is a saturated C 4 -C 6 carbocyclic ring system in which one of the carbon atoms is replaced by N and optionally in which 1 further carbon atom is replaced by a heteroatom selected from N, O and S.
  • said 4 to 6-membered saturated heterocyclic group contains, as heteroatoms, the N atom to which R' and R" are attached and 0 or 1 further N, O or S atoms.
  • 4 to 6-membered saturated heterocyclic radicals include azetidyl, piperidyl, pyrrolidyl, piperazinyl, morpholinyl and thiomorpholinyl. Azetidyl and piperidyl are preferred.
  • R 3 represents a cycloalkyl-C 1-2 alkyl group
  • the 2 alky' portion is preferably bonded to the nitrogen atom of the molecule as depicted in formula (I).
  • atoms, radicals, moieties, chains or cycles present in the general structures of the invention are "optionally substituted".
  • substituents can be either unsubstituted or substituted in any posiition by one or more, for example 1 , 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains or cycles are replaced by chemically acceptable atoms, radicals, moieties, chains or cycles.
  • substituents may be the same or different.
  • halogen atom embraces chlorine, fluorine, bromine or iodine atoms typically a fluorine, chlorine or bromine atom, most preferably chlorine or fluorine.
  • pharmaceutically acceptable salt embraces salts with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic,
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, for example alkyl amines, arylalkyl amines and heterocyclic amines.
  • alkali metal e.g. sodium or potassium
  • alkali earth metal e.g. calcium or magnesium
  • organic bases for example alkyl amines, arylalkyl amines and heterocyclic amines.
  • Other preferred salts according to the invention are quaternary ammonium compounds wherein an equivalent of an anion (X-) is associated with the positive charge of the N atom.
  • X- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate.
  • X- is chloride, bromide, trifluoroacetate or methanesulphonate.
  • N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • L represents a direct bond.
  • n has a value of 1 or 2, preferably 1.
  • R represents a pyridyl group substituted with one or two substituents selected from halogen atoms, a methyl group and a methoxy groups, or R represents a group of formula:
  • R a and R b independently represent a hydrogen atom or a linear or branched d.
  • R c represents a hydroxy group, a linear or branched alkyl group or C 1-4 alkoxy group wherein the alkyl and the alkoxy groups independently are optionally substituted with one or more substituents selected from a hydroxy group, a cyano group and a -NR'R" groups wherein
  • ⁇ R' represents a hydrogen atom or a methyl group
  • ⁇ R" represents a hydrogen atom or a linear or branched alkyl group optionally substituted with a hydroxycarbonyl group
  • R 1 represents a pyridyl group substituted with one substituent selected from a methyl group and a methoxy gro 1 represents a group of formula:
  • R° represents a hydroxy group, a methoxy group or a C 2-4 alkoxy group substituted with one or two substituents selected from a hydroxy group and a -NR'R" groups wherein
  • ⁇ R' represents a hydrogen atom or a methyl group
  • R" represents a hydrogen atom, a C 1-2 alkyl group substituted with a hydroxycarbonyl group; or R' and R" together with the nitrogen atom to which they are attached form a 4 to 6 membered, saturated heterocyclic ring substituted with a hydroxycarbonyl group.
  • R 2 represents a phenyl group which is substituted with one or two substituents selected from chlorine atoms, fluorine atoms, cyano group and methoxy group, preferably fluorine atoms, chlorine atoms and cyano groups.
  • R 3 represents a linear or branched C 2- 4 alkyl group optionally substituted with one or more substituents selected from a halogen atom and a C 1-2 alkoxy group.
  • R 3 represents a propyl or a butyl group, more preferably a butyl group.
  • L represents a direct bond
  • n has a value of 1
  • R 1 represents a pyridyl group substituted with one substituent selected from a methyl group and a methoxy group
  • R 1 represents a group of formula:
  • o R° represents a hydroxy group, a methoxy group or a C 2- 4 alkoxy group substituted with one or two substituents selected from a hydroxy group, and a
  • ⁇ R' represents a hydrogen atom or a methyl group
  • ⁇ R" represents a hydrogen atom, a C 2 alkyl group substituted with a hydroxycarbonyl group
  • R 2 represents a phenyl group which is substituted with one or two substituents selected from chlorine atoms, fluorine atoms and a cyano group
  • R 3 represents a butyl group.
  • R represents a pyridyl group or an imidazo[1 ,2-a]pyridinyl group, wherein the pyridyl group is substituted with one or more substituents selected from chlorine atoms, a hydroxy group, a methyl group and a methoxy group
  • R 1 represents a group of formula:
  • R a and R independently represent a hydrogen atom, a chlorine atom or a methyl group
  • R c represents a hydroxy group, a linear or branched C 1-4 alkyl group or alkoxy group wherein the alkyl and the alkoxy groups independently are optionally substituted with one or more substituents selected from a hydroxy group, a cyano group and a -NR'R" groups and wherein
  • ⁇ R' represents a hydrogen atom or a methyl group
  • ⁇ R" represents a hydrogen atom, a C 1-2 alkyl group optionally substituted with a hydroxycarbonyl group
  • R 2 represents a pyridyl group, a cyclobutyl group or a phenyl group which is optionally substituted with one or more substituents selected from chlorine atoms, fluorine atoms, a cyano group and a methoxy group
  • R 3 represents a cyclopentyl group, a cylopropylmethyl group, ethyl group, isopropyl group, a propyl group, n-butyl group, 4- trifluorobutyl group or a methoxyethyl group.
  • Particular individual compounds of the invention include:
  • Compounds of general formula (I) may be prepared by the reaction of 1 ,3,4-thiadiazol- 2-ylamine derivatives (II), wherein R 1 and R 3 are as described above, with the corresponding alkylating agent (III), wherein L is a direct bond, R 2 is as described above and X is an halogen atom such as chlorine, bromine or iodide or a sulphonate such as mesylate, tosylate or triflate, in basic media such as sodium hydride in a solvent such as THF or DMF at a temperature from 0 to 150°C. Microwave may be used as an alternative heating procedure.
  • n has a value of 0, the presence of a palladium catalyst such as palladium acetate and a phospine such as BINAP (2,2'- bis(diphenylphosphino)-1 , 1'-binaphthyl) or other palladium catalysts such as tetrakistriphenylphosphine palladium (0), tris(dibenzylideneacetone)palladium (0) or bis(tri-orfo-tolylphosphine) palladium (II) chloride and a base such as soidum tert- butoxide or sodium bis(trimethylsilyl)amide in an solvent such as toluene or xylene must be required.
  • the reaction may be performed from room temperature to the solvent boiling point.
  • Compounds of general formula (II) may be prepared by condensation of the compounds of formula (V) with the corresponding acid derivative (IVa) using POCI 3 Alternatively they may be prepared by condensation of compounds of formula (V) with the corresponding nitrile (IVb) in the presence of trifluoroacetic acid. Both reactions
  • Intermediates of formula (V) may be obtained by the reaction of hydrazine hydrate with the corresponding isothiocyanate (VI) in a solvent such as THF, methanol or ethanol and at a temperature from 0 to 40°C.
  • Intermediates of general formula (II) may be prepared by reductive amination of compounds of general formula (VIII) with the corresponding aldehyde (VII) in acid media such as acetic acid and in a protic solvent such as methanol or ethanol and with a reductive agent such as sodium borohydride, triacetoxybotohydride or sodium cyanoborohydride at a temperature from 0°C to the boiling point of the solvent.
  • acid media such as acetic acid and in a protic solvent such as methanol or ethanol
  • a reductive agent such as sodium borohydride, triacetoxybotohydride or sodium cyanoborohydride
  • a Lewis acid such as zinc chloride can be used.
  • Intermediates of general formula (VIII) may be prepared by condensation of hydrazinecarbothioamide of formula (A) with the corresponding acid derivative (IVa) using POCI 3 or with the corresponding nitrile derivative (IVb) in the presence of TFA. Both reactions may be performed without a solvent in a solvent such as dioxane or THF or dichloromethane at a temperature from 20 to 100°C.
  • the compounds of formula (la) may be obtained by the reaction of 1 ,3,4-thiadiazol-2- amine derivatives (II), wherein R 1 and R 3 are as described above, with the corresponding sulphonylating agent (IX) in which X is an halogen atom such as chlorine, in the presence of a base such as triethylamine, diisopropylethyiamine or pyridine and a catalytic amount of 4-dimethylaminopyridine in a solvent such as
  • Compounds of general formula (lb) may be prepared by the reaction of 1 ,3,4- thiadiazol-2-ylamine derivatives (XI), wherein R 1 and R 2 are as described above, with the corresponding alkylating agent (XII), wherein X is an halogen atom such as chlorine, bromine or iodide or a sulphonate such as mesylate, tosylate or triflate in basic media such as sodium hydride in a solvent such as THF or DMF at a temperature from 0 to 150°C. Microwave may be used as an alternative heating procedure.
  • Rc represents a C 1-4 alkoxy group of formula -OG, wherein G represents the alkyl radical of the alkoxy group which is substituted with one or more substituents, the compounds of formula (lc) may be obtained following the synthetic path shown in Figure 4.
  • the compounds of formula (lc) may be obtained by the reaction of 1 ,3,4-thiadiazol-2- aminophenol derivatives of formula (Ih), wherein Ra, Rb, R 2 , R 3 are as described above, with the corresponding alkylating agent (XlVa), wherein X is an halogen atom such as chlorine, bromine or iodide or a sulphonate such as mesylate, tosylate or triflate in basic media such as sodium hydride in a solvent such as THF or DMF at a temperature from 0 to 150°C.
  • XlVa alkylating agent
  • the phenolic functionality of (Ih) may be coupled to suitable alcohol derivatives (XlVb) HO-G, wherein G is as defined, above, using a Mitsunobu coupling procedure (Mitsunobu, O., Synthesis 1 (1981)).
  • Preferred coupling conditions include the use of a trialkylphosphine or triarylphosphine, such as tri-n-butylphosphine or triphenylphosphine, in a suitable solvent, such as tetrahydrofuran or dichloromethane, and an azodicarbonyl reagent, such as diethyl azodicarboxylate or 1 ,1'-(azodicarbonyl)dipiperidine.
  • a suitable solvent such as tetrahydrofuran or dichloromethane
  • an azodicarbonyl reagent such as diethyl azodicarboxylate or 1 ,1'-(azodicarbonyl)dipiperidine
  • the compounds of general formula (Ih) may be prepared by demethylation of the corresponding compound of general formula (Id) using BBr 3 or AIBr 3 or BF 3 or iodotrimethylsilane as demethylating agent in a solvent such as dichloromethane or 1 ,2-dichloroethane, chloroform at a temperature between 0 and the 60°C.
  • a solvent such as dichloromethane or 1 ,2-dichloroethane, chloroform at a temperature between 0 and the 60°C.
  • compounds of general formula (Ih) may be prepared by demethylation using HBr in acetic acid as a solvent.
  • R 1 represents a group of formula
  • Rc is a methyl group substituted with one or more -NR'R" substituents, wherein R' and R" are as defined above and L is a direct bond, the compounds of formula (le) may be obtained following the synthetic path shown in Figure 5.
  • Compounds of general formula (le), wherein R 2 , R 3 , R a , R R' and R" are as described above may be prepared by the reductive amination of the aldehyde derivatives of general formula (XVI) with the corresponding amines of formula (XV) in acidic media such as acetic acid and in a protic solvent such as methanol or ethanol and with a reductive agent such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride at a temperature from 0°C to the boiling point of the solvent.
  • acidic media such as acetic acid and in a protic solvent such as methanol or ethanol
  • a reductive agent such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride at a temperature from 0°C to the boiling point of the solvent.
  • a Lewis acid such as zinc chloride can be used.
  • aldehyde derivatives of general formula (XVII) may be obtained by reduction of the corresponding nitrile of general formula (Ha), wherein A represents CN, by using a reductive agent such as diisobutylaluminium hydride (DIBAL-H) in a solvent such as dichloromethane, THF or dioxane at a low temperature from -78° to 0°C.
  • DIBAL-H diisobutylaluminium hydride
  • compounds of general formula (XVII) may also be obtained by reduction of the corresponding ester (Ha), wherein A represents a -COOR radical, to the alcohol using LiAIH 4 as reductive agent in a solvent such as THF followed by oxidation to the corresponding aldehyde of formula (XVII) by a standard Swern oxidation or other oxidazing agents such as Dess-Martin reagent.
  • an oxidazing agent such as osmium tetroxide
  • a cooxidant such as N-methylmorpholine-N-oxide
  • a cosolvent such as methanol may be then added to the reaction mixture and the reaction is performed at room temperature.
  • compounds of formula (XVI) may be obtained from compounds of formula (XVIII) according to the methods described above, depending on the nature of A.
  • Compounds of formula (XVIII) can be obtained from compounds of formula (I la) following the same procedures described for the obtention of intermediates of formula (XVI) from intermediates of formula (XVII).
  • R 1 represents a group of formula
  • Rc is a methyl group substituted with one -NR'R" substituents, wherein R' and R" are as defined above and L is a -S(0) 2 group, the compounds of formula (If) may be obtained following the synthetic path shown in Figure 6.
  • Compounds of general formula (If), wherein R 2 , R 3 , R a and R b are as described above may be prepared by the reductive amination of the aldehyde derivatives of general formula (XX) with the corresponding amines of formula (XV) in acidic media such as acetic acid and in a protic solvent such as methanol or ethanol and with a reductive agent such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride at a temperature from 0°C to the boiling point of the solvent.
  • acidic media such as acetic acid and in a protic solvent such as methanol or ethanol
  • a reductive agent such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride at a temperature from 0°C to the boiling point of the solvent.
  • a Lewis acid such as zinc chloride can be used.
  • compounds of formula (XX) may be obtained from compounds of formula (XXII) following the synthetic methods described in Figure 5, depending on the nature
  • compounds of general formula (If) can be obtained by sulphonylation of compounds of general formula (XXIII) with the corresponding sulphonylating agent of formula (IX) in which X is as described above by standard methods as described before.
  • Compounds of general formula (XXIII) can be in turn obtained by reductive amination of aldehydes of general formula (XVII) with amines of general formula (XV) by the methods described above.
  • Rc is an ethoxy group substituted with one or more -NR'R" substituents, wherein R' and R" are as defined above and L is direct bond, the compounds of formula (Ig) may be obtained following the synthetic path shown in Figure 7.
  • Compounds of formula (XXIV) may be obtained by alkylation of compounds of general formula (XXV) with the corresponding alkylating agent of formula (III) in wherein L is a direct bond, R 2 is as described above and X is an halogen atom such as chlorine, bromine or iodine or a sulphonate such as mesylate, tosylate or triflate by standard methods as described before.
  • Compounds of general formula (XXV) may be obtained by dihydroxylation and oxidative cleavage of the corresponding allyl derivative (lib) using a catalytic amount of an oxidazing agent such as osmium tetroxide and a cooxidant such as sodium periodate in a mixture of solvents such as methanol, acetonitrile, acetone and water at a temperature from 0°C to the boiling point of the mixture. This cleavage may also be performed by ozonolysis.
  • an oxidazing agent such as osmium tetroxide
  • a cooxidant such as sodium periodate
  • solvents such as methanol, acetonitrile, acetone and water
  • ozone is bubbled through a solution of compounds of general formula (lib) in a solvent such as dichloromethane at -78 °C followed by the addition of a reductive agent such as triphenylfosfine, thiourea, zinc dust or dimethylsulfide.
  • a reductive agent such as triphenylfosfine, thiourea, zinc dust or dimethylsulfide.
  • a cosolvent such as methanol may be then added to the reaction mixture and the reaction is performed at room temperature.
  • compounds of formula (XXIV) may be obtained from compounds of formula (XXVI) by oxidative cleavage, according to the method described above.
  • Compounds of formula (XXVI) can be obtained from compounds of formula (lib) by alkylation with compounds of general formula (III) following the same procedures described for the obtention of compounds of formula (XXIV) from intermediates of formula (XXV).
  • R 1 to R 3 and Ra to Rb are susceptible to chemical reaction under the conditions of the hereinbefore described processes or are incompatible with said processes, conventional protecting groups may be used in accordance with standard practice, for example see T.W. Greene and P.G.M.
  • the mobile phase was formic acid (0.4 ml_), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.46 mL), ammonia (0.115 mL) and water (1000 mL) (A), the gradients are specified in the following table for each methode used.
  • the reequilibration time between two injections was 1 min.
  • the flow rate was 0.8 mlJmin for method A and 0.4 mL/min for method B and C.
  • the injection volume was 5 microliter for method A and B and 3 microliter for method C. Diode array chromatograms were collected at 210 nM.
  • dichloromethane (10.3 ml, 10.3 mmol) was added dropwise. It was stirred for 30 min under the previous conditions. It was left to warm up to room temperature and it was stirred for 12h. Water/ice were added and the mixture was diluted with more
  • the aqueous phase was extracted with more ethyl acetate and the organic phases were collected together, washed with water and brine, dried and concentrated in vacuo.
  • the residue obtained (3.42 g) was disolved in methanol (65 ml) and water (7 ml).
  • sodium periodate (2.75 g, 12.86 mmol) was added and it was stirred at room temperature overnight.
  • the mixture was concentrated in vacuo and water and ethyl acetate were added to the residue obtained.
  • the aqueous phase was extracted with more ethyl acetate and the organic phases were collected together, washed with water and brine, dried and concentrated in vacuo to yield 2.5 g (100%) of the title compound.
  • the 2-aminothiadiazole derivatives of the invention may also be combined with other active compounds in the treatment of diseases known to be susceptible to
  • S1 P1 sphingosine-1 -phosphate receptor agonist
  • the combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of autoimmune diseases, chronic immune and inflammatory diseases, transplant rejection, malignant neoplastic diseases, angiogenic-related disorders, pain, neurological diseases, viral and infectious diseases, such as (a) beta interferons such as Betaseron, Avonex or Rebif, (b), immunomodulators such as glatiramer acetate, (c) inhibitors of DNA synthesis and repair, such as Mitoxantrone, (d) anti-alpha 4 integrin antibodies, such as Natalizumab (Tysabri), (e) alpha 4 integrin antagonists such as R-1295 , TBC-4746, CDP-323,
  • ELND-002, Firategrast and TMC-2003 Firategrast and TMC-2003, (f), dyhydrofolate reductase inhibitors, such as Methotrexate or CH-1504, (g) glucocorticoids such as prednisone or
  • DHODH inhibitors such as Teriflunomide, (i) fumaric acid esters, such as BG-12, (j) immunomodulators such as Laquinimod, (k) anti-CD20 monoclonal antibodies such as Rituximab, Ocrelizumab Ofatumumab or TRU-015, (I) anti-CD52 such as alemtuzumab, (m) anti-CD25 such as daclizumab, (n) anti-CD88, such as eculizumab or pexilizumab, (o) calcineurin inhibitors such as cyclosporine A or tacrolimus, (p) IMPDH inhibitors, such as mycophenolate mophetyl, (q) cannabinoid receptor agonists such as Sativex, (r) chemokine CCR1 antagonists such as MLN- 3897 or PS-031291 , (s) chemokine CCR2 antagonists such
  • the combinations of the invention may be used in the treatment of disorders which are susceptible to amelioration by sphingosine-1-phosphate receptors agonists (S1 P1).
  • S1 P1 sphingosine-1-phosphate receptors agonists
  • the present application encompasses methods of treatment of these disorders, as well as the use of the combinations of the invention in the manufacture of a medicament for the treatment of these disorders.
  • Preferred examples of such disorders are multiple sclerosis, transplant rejection, systemic lupus erythematosus, asthma, psoriasis, rheumatoid arthritis, psoriatic arthritis and Crohn's disease, more preferably multiple sclerosis, transplant rejection, asthma and rheumatoid arthritis, and most preferably multiple sclerosis.
  • the active compounds in the combinations of the invention may be administered by any suitable route, depending on the nature of the disorder to be treated, e.g. orally (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc); topically (as creams, ointments, lotions, nasal sprays or aerosols, etc); by injection (subcutaneous, intradermic, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, a solution, a dispersion, etc).
  • suitable route e.g. orally (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc); topically (as creams, ointments, lotions, nasal sprays or aerosols, etc); by injection (subcutaneous, intradermic, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, a solution, a dispersion,
  • the active compounds in the combination i.e. the sphingosine-1 -phosphate agonist of the invention, and the other optional active compounds may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
  • One execution of the present invention consists of a kit of parts comprising a sphingosine-1 -phosphate agonist of the invention together with instructions for simultaneous, concurrent, separate or sequential use in combination with another active compound useful in the treatment of multiple sclerosis, transplant rejection, systemic lupus erythematosus, asthma, psoriasis, rheumatoid arthritis, psoriatic arthritis and Crohn's disease
  • Another execution of the present invention consists of a package comprising a sphingosine-1 -phosphate agonist of formula (I) and another active compound useful in the treatment of multiple sclerosis, transplant rejection, systemic lupus erythematosus, asthma, psoriasis, rheumatoid arthritis, psoriatic arthritis and Crohn's disease,
  • compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil- in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with flavouring or colouring agent.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with flavouring or colouring agent.
  • composition is in the form of a tablet
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • examples of such carriers include magnesium stearate, talc, gelatine, acacia, stearic acid, starch, lactose and sucrose.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • compositions are in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatine capsule.
  • composition is in the form of a soft gelatine capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatine capsule.
  • Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
  • Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred.
  • a suitable powder base such as lactose or starch. Use of lactose is preferred.
  • Each capsule or cartridge may generally contain between 2 ⁇ g and 150 ⁇ g of each therapeutically active ingredient. Alternatively, the active ingredient (s) may be presented without excipients.
  • Packaging of the formulation for inhalation may be carried out by using suitable inhaler devices such as the Novolizer SD2FL which is described in the following patent applications: WO 97/000703, WO 03/000325 and WO 03/061742.
  • compositions for nasal delivery include those mentioned above for inhalation and further include non-pressurized compositions in the form of a solution or suspension in an inert vehicle such as water optionally in combination with
  • Typical dermal and transdermal formulations comprise a conventional aqueous or nonaqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
  • each active which is required to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under treatment, and the particular disorder or disease being treated.
  • Effective doses are normally in the range of 2-2000 mg of active ingredient per day.
  • Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.
  • the active ingredients are administered once or twice a day.
  • all active agents would be administered at the same time, or very close in time.
  • one or two actives could be taken in the morning and the other (s) later in the day.
  • one or two actives could be taken twice daily and the other (s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately.
  • At least two, and more preferably all, of the actives would be taken together at the same time.
  • at least two, and more preferably all actives would be administered as an admixture.
  • the following preparations forms are cited as formulation examples:
  • the above ingredients were sieved through a 60 mesh sieve, and were loaded into a suitable mixer and filled into 50,000 gelatine capsules.
  • All the powders were passed through a screen with an aperture of 0.6 mm, then mixed in a suitable mixer for 20 minutes and compressed into 300 mg tablets using 9 mm disc and flat bevelled punches.
  • the disintegration time of the tablets was about 3 minutes.

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WO2014036242A3 (en) * 2012-08-29 2015-07-16 Mount Sinai School Of Medicine Benzothiazole or benzoxazole compounds as sumo activators
WO2019194556A1 (ko) * 2018-04-03 2019-10-10 영남대학교 산학협력단 신규한 6-헤테로아릴아미노-2,4,5-트라이메틸피리딘-3-올 화합물, 또는 이를 포함하는 염증성 장질환 및 자가면역 질환의 예방 또는 치료용 약학 조성물
WO2021067943A1 (en) * 2019-10-04 2021-04-08 Bioventures, Llc Piezo1 agonists for the promotion of bone formation

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US8846729B2 (en) * 2012-11-14 2014-09-30 Allergan, Inc. 2-thio-1,3,4-oxadiazoles azetidine derivatives as sphingosine-1 phosphate receptors modulators
MA41139A (fr) 2014-12-11 2017-10-17 Actelion Pharmaceuticals Ltd Combinaison pharmaceutique comportant un agoniste sélectif du récepteur sip1

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* Cited by examiner, † Cited by third party
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WO2014036242A3 (en) * 2012-08-29 2015-07-16 Mount Sinai School Of Medicine Benzothiazole or benzoxazole compounds as sumo activators
US9845320B2 (en) 2012-08-29 2017-12-19 Icahn School Of Medicine At Mount Sinai Benzothiazole or benzoxazole compounds as sumo activators
US10501453B2 (en) 2012-08-29 2019-12-10 Icahn School Of Medicine At Mount Sinai Benzothiazole or benzoxazole compounds as SUMO activators
WO2019194556A1 (ko) * 2018-04-03 2019-10-10 영남대학교 산학협력단 신규한 6-헤테로아릴아미노-2,4,5-트라이메틸피리딘-3-올 화합물, 또는 이를 포함하는 염증성 장질환 및 자가면역 질환의 예방 또는 치료용 약학 조성물
WO2021067943A1 (en) * 2019-10-04 2021-04-08 Bioventures, Llc Piezo1 agonists for the promotion of bone formation

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