WO2004096752A1 - Amino-propanol derivatives as sphingosine-1-phosphate receptor modulator - Google Patents

Amino-propanol derivatives as sphingosine-1-phosphate receptor modulator Download PDF

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Publication number
WO2004096752A1
WO2004096752A1 PCT/EP2004/004569 EP2004004569W WO2004096752A1 WO 2004096752 A1 WO2004096752 A1 WO 2004096752A1 EP 2004004569 W EP2004004569 W EP 2004004569W WO 2004096752 A1 WO2004096752 A1 WO 2004096752A1
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Prior art keywords
alkyl
phenyl
substituted
formula
compound according
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PCT/EP2004/004569
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French (fr)
Inventor
Klaus Hinterding
Carsten Spanka
Frédéric ZECRI
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Novartis Ag
Novartis Pharma Gmbh
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Priority claimed from GB0329505A external-priority patent/GB0329505D0/en
Priority claimed from GB0329500A external-priority patent/GB0329500D0/en
Priority to US10/554,556 priority Critical patent/US7625950B2/en
Priority to AT04730206T priority patent/ATE547395T1/en
Priority to MXPA05011596A priority patent/MXPA05011596A/en
Priority to EP04730206A priority patent/EP1622860B1/en
Application filed by Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Priority to ES04730206T priority patent/ES2383298T3/en
Priority to JP2006505327A priority patent/JP4603531B2/en
Priority to BRPI0410025-5A priority patent/BRPI0410025A/en
Priority to CA002523582A priority patent/CA2523582A1/en
Priority to CN2004800110595A priority patent/CN1777575B/en
Priority to AU2004234066A priority patent/AU2004234066B2/en
Publication of WO2004096752A1 publication Critical patent/WO2004096752A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/72—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/094—Esters of phosphoric acids with arylalkanols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems

Definitions

  • the present invention relates to amino-propanol derivatives, process for their production, their uses and pharmaceutical compositions containing them.
  • R 2 is phenyl; naphthyl; C 3 . 6 cycloalkyl; heteroaryl; a heterocyclic residue; phenylC 1- alkyl; C 3 . 6 cycloalkylC ⁇ -2 alkyl; heteroarylC ⁇ . 2 alkyl; heterocyclicC 1-2 alkyl residue; wherein each may be ring-substituted by 1 to 5 substituents selected from hydroxy, halogen, C 1-4 alkyl, C 1- alkyl substituted by 1 to 5 fluorine atoms, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 alkoxy substituted by 1 to 5 fluorine atoms, C 3-6 cycloalkoxy, C 3 .
  • R 3 is Z-X 2 wherein Z is CH 2 , CHF or CF 2 and X 2 is OH or a residue of formula (a)
  • each of R 8 and R 9 independently, is H or C 1-4 alkyl optionally substituted by 1 , 2 or 3 halogen atoms
  • each of R and R 5 independently, is H; C 1-4 alkyl optionally substituted by 1 , 2 or 3 halogen atoms; or acyl
  • independently, is H; hydroxy; halogen; C 1- alkyl; C 1-6 cycloalkyl; C ⁇ ecycloalkoxy; C 3 . 6 cycloalkylC ⁇ -2 alkyl; or cyano
  • n is 2 or 3; in free form or in salt form.
  • Alkyl or alkyl moiety may be straight or branched chain.
  • Alkenyl may be e.g. vinyl.
  • Alkynyl may be e.g. propyn-2-yl.
  • Acyl may be a residue R-CO wherein R is C -6 alkyl, C 3-6 cycloalkyl, phenyl or phenyl C 1-4 alkyl.
  • Halogen may be fluorine, chlorine or bromine, preferably fluorine or chlorine. When alkyl is substituted by hydroxy, it is preferably on the terminal carbon atom.
  • PhenylC ⁇ alkyl may be e.g. benzyl.
  • Heteroaryl may be a 5 to 8 membered aromatic ring comprising 1 to 4 heteroatoms selected from N, O and S, e.g. pyridyl, pyrimidinyl, pyrazinyl, furyl, oxazolyl, isoxazolyl, thienyl, thia- zolyl, isothiazolyl, pyrrolyl, imidazolyl, or pyrazolyl.
  • N, O and S e.g. pyridyl, pyrimidinyl, pyrazinyl, furyl, oxazolyl, isoxazolyl, thienyl, thia- zolyl, isothiazolyl, pyrrolyl, imidazolyl, or pyrazolyl.
  • heterocyclic residue is meant a 3 to 8, preferably 5 to 8, membered saturated or unsaturated heterocyclic ring comprising 1 to 4 heteroatoms selected from N, O and S, e.g. tetrahydrofuryl, tetrahydropyranyl, aziridinyl, piperidinyl, pyrrolidinyl, piperazinyl.
  • the heterocyclic residue may also be fused to an optionally substituted aryl or heteroaryl, e.g. phenyl, wherein Y is bound to said aryl or heteroaryl; examples include e.g. benzo[1 ,3]dioxolyl.
  • Compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. inorganic acids, such as hydrochloride, hydrobromide or sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or ben- zenesulfonate salts.
  • inorganic acids such as hydrochloride, hydrobromide or sulfate
  • organic acids such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or ben- zenesulfonate salts.
  • Compounds of formula I and their salts, in hydrate or solvate form are also part of the invention.
  • the compounds of formula I When the compounds of formula I have asymetric centers in the molecule, various optical isomers are obtained.
  • the present invention also encompasses enantiomers, racemafes, diastereoisomers and mixtures thereof.
  • the central carbon atom bearing Ri, R 3 and NR 4 R 5 may have the R or S configuration.
  • Compounds having the following 3- dimensional configuration are generally preferred:
  • the present invention embraces cis-compounds, trans-compounds and mixtures thereof. Similar considerations apply in relation to starting materials exhibiting asymetric carbon atoms or unsaturated bonds as mentioned above, e.g. compounds of formula II, III or IV as indicated below.
  • X is O
  • Y is O or S
  • ⁇ is CH 3 or CH 2 -OH
  • R 2 is phenyl; phenyl substituted by 1 or 2 substituents selected from halogen, C ⁇ alkyl or C 1-2 alkoxy; cyanophenyl; naphthyl; or benzo[1,3]dioxol-5-yl;
  • R 3 is CHa-OH or CH 2 -OPO 3 H 2 ;
  • each of R 4 and R 5 is hydrogen
  • R 6 is hydrogen, methoxy, methyl, or chloro
  • R 7 is hydrogen, methoxy, methyl, or chloro.
  • the present invention also includes a process for the preparation of a compound of formula I which process comprises a) for a compound of formula I wherein R 3 is Z-X 2 , X 2 being OH, removing the protecting group present in a compound of formula II
  • R' 3 is Z-X 2 wherein X is OH and R' 5 is an amino protecting group, or b) for a compound of formula I wherein R 3 is Z-X 2 , X 2 being a residue of formula (a), removing the protecting groups present in a compound of formula III
  • R' 8 or R' 9 is a hydrolysable or hydrogenolysable group or R' 8 and R' 9 form together a divalent bridging residue optionally fused to a ring (e.g. benzene ring), and, where required, converting the compounds of formula I obtained in free form into the desired salt form, or vice versa.
  • a ring e.g. benzene ring
  • Process step a) may be carried out in accordance with methods known in the art.
  • the removal of the amino protecting groups may conveniently be performed according to methods known in the art, e.g. by hydrolysis, e.g. in an acidic medium, for example using hydrochloric acid.
  • Examples of protecting groups for amino groups are e.g. as disclosed in "Protective Groups in Organic Synthesis” T.W. Greene, J.Wiley & Sons NY, 2 nd ed., chapter 7, 1991, and references therein, e.g.
  • benzyl p-methoxybenzyl, methoxymethyl, tetrahydropyranyl, trialkylsilyl, acyl, tert.-butoxy-carbonyl, benzyloxycarbonyl, 9-fluorenyl methoxy car- bonyl, trifluoroacetyl, and the like.
  • each of R' 8 and R' 9 may have the significance of e.g. tert-butyl, phenyl or benzyl or form together a cyclic system such as in 1 ,5-dihydro-2,4,3- benzodioxaphosphepin.
  • Process step b) may be performed according to methods known in the art, e.g. by hydrolysis, e.g. in a basic medium when R' 6 and R' 7 are each a hydrolysable group, for example using a hydroxide such as barium hydroxide or in an acidic medium when R' 6 and R' 7 are each a tert-butyl group. It may also be performed by hydrogenolysis, e.g. in the presence of a catalyst, e.g. Pd/C, followed by hydrolysis, e.g. in an acidic medium, for example HCI.
  • a catalyst e.g. Pd/C
  • the present invention also includes a process for the preparation of a compound of formula II which process comprises transforming a compound of formula IV wherein R ⁇ R' 3) R and R' 5 are as defined above, to introduce the desired residue -(CH 2 ) n -Y- R 2 e.g. by an alkylation.
  • Alkylation of the compounds of formula IV may be performed according to methods known in the art, e.g. by nucleophilic substitution, e.g. by reaction with an alkylating agent R -Y-(CH 2 )n-X 3 wherein X 3 is mesylate, tosylate, triflate, nosylate, chloride, bromide or iodide.
  • the alkylation may also be carried out by following the Mitsunobu protocol using R 2 -Y-(CH 2 ) n -OH (e.g. as disclosed in Hughes, Organic Preparations and Procedures International 28, 127-64, 1996 or D.L. Hughes, Org. React. 42, 335, 1992), in solution or on solid phase support synthesis, e.g. by attaching the compound of formula IV to a resin.
  • R 2 -Y-(CH 2 ) n -OH e.g. as disclosed in Hughes, Organic Preparations and Procedures International 28, 127-64, 1996 or D.L. Hughes, Org. React. 42, 335, 1992
  • solid phase support synthesis e.g. by attaching the compound of formula IV to a resin.
  • triphenylphosphine or diethyl azocarboxylate bound to a resin e.g. polystyrene
  • fe/i-butyl (R)-(3- ⁇ 4-[2-(4-Chloro-phenoxy)-ethoxy]-phenyl ⁇ -1 -hydroxymethyl-1 -methyl-propyl)- carbamate may be prepared according to the following procedure:
  • Example 26 (+/-) Mono-(2-Amino-4- ⁇ 4-[2-phenoxy-ethoxy]-phenyl ⁇ -2-ethoxy-butan) phosphate.
  • Example 36 (R)-Mono-(2-amino-4-(4-r2-(4-chloro-phenoxv)-ethoxvl-phenvl ⁇ -2-methvl-buty ⁇ phosphate.
  • H 2 O 2 (30%, 91 ⁇ L, 0.89 mmol, 10 eq.) was injected at 0°C with vigorous stirring.
  • the reaction mixture was stirred for further 30 min, followed by addition of saturated sodium thiosulfate solution (1 mL).
  • the organic layer was separated and the aqueous phase was extracted with ether (3 x 1 mL).
  • the combined organic extracts were washed with brine, dried over MgSO 4 , and evaporated to dryness.
  • ⁇ (R)-1-Hydroxymethyl-1-methyl-3-[4-(3-phenoxy-propoxy)-phenyl]-propyl ⁇ -carbamic acid tert- butyl may be prepared according to the following procedure:
  • Example 54 (+/-) Mono Phosphoric acid mono- ⁇ 2-amino-2-hydroxymethyl-4-[4-(3-phenoxy- propoxy)-phenyl]-butyl ⁇ ester.
  • the compounds of formula I in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, e.g. lymphocyte recirculation modulating properties, e.g. as indicated in in vitro and in vivo tests and are therefore indicated for therapy.
  • useful pharmacological properties e.g. lymphocyte recirculation modulating properties, e.g. as indicated in in vitro and in vivo tests and are therefore indicated for therapy.
  • the compounds of formula I have binding affinity to individual human S1P receptors as determined in following assays:
  • S1P Sphingosine-1 -phosphate
  • EDG-1 SIP ⁇ , EDG-3 (S1P 3 ), EDG-5 (S1P 2 ), EDG-6 (S1P 4 ) and EDG-8 (S1P 5 ).
  • Functional receptor activation is assessed by quantifying compound induced GTP [ ⁇ - 35 S] binding to membrane protein prepared from transfected CHO or RH7777 cells stably expressing the appropriate human S1P receptor.
  • the assay technology used is SPA (scintillation proximity based assay).
  • DMSO dissolved compounds are serially diluted and added to SPA- bead (Amersham-Pharmacia) immobilised S1P receptor expressing membrane protein (10-20 ⁇ g/well) in the presence of 50 mM Hepes, 100 mM NaCI, 10 mM MgCI 2> 10 ⁇ M GDP, 0.1% fat free BSA and 0.2 nM GTP [ ⁇ - 35 S] (1200 Ci/mmol).
  • Luminescence of SPA beads triggered by membrane bound GTP [ ⁇ - 35 S] is quantified with a TOPcount plate reader (Packard).
  • EC 50 s are calculated using standard curve fitting software. In this assay, the compounds of formula I have a binding affinity to S1P ⁇ receptor ⁇ 50 nM.
  • Agon. agonist
  • a compound of formula I or the vehicle is administered orally by gavage to rats.
  • Tail blood for hematological monitoring is obtained on day -1 to give the baseline individual values, and at 2, 6, 24, 48 and 72 hours after application.
  • the compounds of formula I deplete peripheral blood lymphocytes when administered at a dose of 0.03 to 3 mg/kg. For example, following results are obtained: depletion of peripheral blood lymphocytes by more than 50%
  • Example 1 0.03 mg/kg p.o. after 6h, 0.02 mg/kg p.o. after 24h.
  • Example 3 0.01 mg/kg p.o. after 6h, ⁇ 0.03 mg/kg p.o. after 48h.
  • Example 7 0.03 mg/kg p.o. after 6h, 0.02 mg/kg p.o. after 48h.
  • Example 9 0.2 mg/kg p.o. after 6h, >1 mg/kg p.o. after 48h.
  • Example 53 0.1 mg/kg p.o. after 6h, 0.5 mg/kg p.o. after 48h.
  • the compounds of formula I are, therefore, useful in the treatment and/or prevention of diseases or disorders mediated by lymphocytes interactions, e.g. in transplantation, such as acute or chronic rejection of cell, tissue or organ allo- or xenografts or delayed graft function, graft versus host disease, autoimmune diseases, e.g.
  • rheumatoid arthritis systemic lupus erythematosus, hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or II and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic rhinitis/conjunctivitis, allergic contact dermatitis, inflammatory diseases optionally with underlying aberrant reactions, e.g.
  • inflammatory bowel disease Crohn's disease or ulcerative colitis
  • intrinsic asthma inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, ischemia/reperfusion injury, e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, traumatic shock, angiogenesis, Alzheimer's disease, cancer, e.g.
  • T cell lymphomas or T cell leukemias infectious diseases, e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, chronic bacterial infection, or senile dementia.
  • infectious diseases e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, chronic bacterial infection, or senile dementia.
  • cell, tissue or solid organ transplants include e.g. pancreatic islets, stem cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus.
  • the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 0.1 to 50 mg active ingredient.
  • the compounds of formula I may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form.
  • Pharmaceutical compositions comprising a compound of formula I in free form or in pharmaceutically acceptable salt form in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
  • the compounds of formula I may be administered in free form or in pharmaceutically acceptable salt form e.g. as indicated above.
  • Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
  • the present invention further provides:
  • a method for preventing or treating disorders or diseases mediated by lymphocytes, e.g. such as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
  • a method for preventing or treating acute or chronic transplant rejection or T-cell mediated inflammatory or autoimmune diseases, e.g. as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
  • a compound of formula I in free form or in a pharmaceutically acceptable salt form for use as a pharmaceutical, e.g. in any of the methods as indicated under 1.1 or 1.2 above.
  • a pharmaceutical composition e.g. for use in any of the methods as in 1.1 or 1.2 above comprising a compound of formula I in free form or pharmaceutically acceptable salt form in association with a pharmaceutically acceptable diluent or carrier therefor.
  • the compounds of formula I may be administered as the sole active ingredient or in conjunction with, e.g. as an adjuvant to, other drugs e.g. immunosuppressive or immunomodulating agents or other anti-inflammatory agents, e.g. for the treatment or prevention of allo- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders, or a chemotherapeutic agent, e.g a malignant cell anti-proliferative agent.
  • the compounds of formula I may be used in combination with a calcineurin inhibitor, e.g. cyclosporin A, FK 506 or ISA T ⁇ 247; a mTOR inhibitor, e.g.
  • rapamycin 40-O-(2- hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, TAFA- 93, biolimus 7 or biolimus 9; an ascomycin having immunosuppressive properties, e.g.
  • ABT- 281, ASM981, etc. corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40. CD45, CD58, CD80, CD86 or their ligands; other immunomodulatory compounds, e.g.
  • a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or a chemotherapeutic agent, e.g. paclitaxel, gemcitabine, cisplatinum, doxorubicin or 5-fluorouracil; or an anti-infectious agent.
  • a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-
  • the compounds of formula I are administered in conjunction with other immunosuppressive / immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infectious therapy
  • dosages of the co-administered immunosuppressant, immunomodulatory, anti- inflammatory, chemotherapeutic or anti-infectious compound will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a calcineurin inhibitor, on the specific drug employed, on the condition being treated and so forth.
  • the present invention provides in a yet further aspect:
  • a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective non-toxic amount of a compound of formula I and at least a second drug substance, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic drug, e.g. as indicated above.
  • a second drug substance e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic drug, e.g. as indicated above.
  • a pharmaceutical combination e.g. a kit, comprising a) a first agent which is a compound of formula I as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infectious agent.
  • the kit may comprise instructions for its administration.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound of formula I and a co- agent are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the administration of 3 or more active ingredients.

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Abstract

Compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, R7, X, Y and n are as defined in the specification, processes for their production, their uses and pharmaceutical compositions containing them.

Description

AMINO-PROPANOL DERIVATIVES AS SPHINGOSINE-1-PHOSPHATE RECEPTOR MODULATOR
The present invention relates to amino-propanol derivatives, process for their production, their uses and pharmaceutical compositions containing them.
More particularly, the invention provides a compound of formula I
Figure imgf000002_0001
wherein
RΪ is Cι.6alkyl; C1-6alkyl substituted by hydroxy, C1-2alkoxy or 1 to 6 fluorine atoms; C2-6alkenyl; or C2-6alkynyl; each of X, Y independently is O, CH2, or C=O;
R2 is phenyl; naphthyl; C3.6cycloalkyl; heteroaryl; a heterocyclic residue; phenylC1- alkyl; C3.6cycloalkylCι-2alkyl; heteroarylCι.2alkyl; heterocyclicC1-2alkyl residue; wherein each may be ring-substituted by 1 to 5 substituents selected from hydroxy, halogen, C1-4alkyl, C1- alkyl substituted by 1 to 5 fluorine atoms, C3-6cycloalkyl, C1-4alkoxy, C1-4alkoxy substituted by 1 to 5 fluorine atoms, C3-6cycloalkoxy, C3.6cycIoalkylC1-2alkyl, cyano, phenyl, and phenyl substituted by hydroxy, halogen, C1-4alkyl, C1-4alkyl substituted by 1 to 5 fluorine atoms, C1-4alkoxy, C1-4alkoxy substituted by 1 to 5 fluorine atoms, or cyano;
R3 is Z-X2 wherein Z is CH2, CHF or CF2 and X2 is OH or a residue of formula (a)
/OR8
II OR9
0 wherein Zi is a direct bond, CH2, CHF, CF2 or O, and each of R8 and R9, independently, is H or C1-4alkyl optionally substituted by 1 , 2 or 3 halogen atoms; and each of R and R5, independently, is H; C1-4alkyl optionally substituted by 1 , 2 or 3 halogen atoms; or acyl; each of R6 and R7| independently, is H; hydroxy; halogen; C1- alkyl; C1-6cycloalkyl;
Figure imgf000002_0002
C^ecycloalkoxy; C3.6cycloalkylCι-2alkyl; or cyano; and n is 2 or 3; in free form or in salt form. Alkyl or alkyl moiety may be straight or branched chain. Alkenyl may be e.g. vinyl. Alkynyl may be e.g. propyn-2-yl. Acyl may be a residue R-CO wherein R is C -6alkyl, C3-6cycloalkyl, phenyl or phenyl C1-4alkyl. Halogen may be fluorine, chlorine or bromine, preferably fluorine or chlorine. When alkyl is substituted by hydroxy, it is preferably on the terminal carbon atom. PhenylC^alkyl may be e.g. benzyl.
Heteroaryl may be a 5 to 8 membered aromatic ring comprising 1 to 4 heteroatoms selected from N, O and S, e.g. pyridyl, pyrimidinyl, pyrazinyl, furyl, oxazolyl, isoxazolyl, thienyl, thia- zolyl, isothiazolyl, pyrrolyl, imidazolyl, or pyrazolyl.
By heterocyclic residue is meant a 3 to 8, preferably 5 to 8, membered saturated or unsaturated heterocyclic ring comprising 1 to 4 heteroatoms selected from N, O and S, e.g. tetrahydrofuryl, tetrahydropyranyl, aziridinyl, piperidinyl, pyrrolidinyl, piperazinyl. The heterocyclic residue may also be fused to an optionally substituted aryl or heteroaryl, e.g. phenyl, wherein Y is bound to said aryl or heteroaryl; examples include e.g. benzo[1 ,3]dioxolyl.
Compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. inorganic acids, such as hydrochloride, hydrobromide or sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or ben- zenesulfonate salts. Compounds of formula I and their salts, in hydrate or solvate form are also part of the invention.
When the compounds of formula I have asymetric centers in the molecule, various optical isomers are obtained. The present invention also encompasses enantiomers, racemafes, diastereoisomers and mixtures thereof. For example, the central carbon atom bearing Ri, R3 and NR4R5 may have the R or S configuration. Compounds having the following 3- dimensional configuration are generally preferred:
Figure imgf000003_0001
Moreover, when the compounds of formula I include geometric isomers, the present invention embraces cis-compounds, trans-compounds and mixtures thereof. Similar considerations apply in relation to starting materials exhibiting asymetric carbon atoms or unsaturated bonds as mentioned above, e.g. compounds of formula II, III or IV as indicated below.
In the compounds of formula I, the following significances are preferred individually or in any sub-combination:
1. X is O;
2. Y is O or S;
3. ^ is CH3 or CH2-OH;
4. R2 is phenyl; phenyl substituted by 1 or 2 substituents selected from halogen, C^alkyl or C1-2alkoxy; cyanophenyl; naphthyl; or benzo[1,3]dioxol-5-yl;
5. R3 is CHa-OH or CH2-OPO3H2;
6. each of R4 and R5 is hydrogen;
7. R6 is hydrogen, methoxy, methyl, or chloro; and
8. R7 is hydrogen, methoxy, methyl, or chloro.
The present invention also includes a process for the preparation of a compound of formula I which process comprises a) for a compound of formula I wherein R3 is Z-X2, X2 being OH, removing the protecting group present in a compound of formula II
Figure imgf000004_0001
wherein X, n, Ri, R2 and R are as defined above, R'3 is Z-X2 wherein X is OH and R'5 is an amino protecting group, or b) for a compound of formula I wherein R3 is Z-X2, X2 being a residue of formula (a), removing the protecting groups present in a compound of formula III
Figure imgf000004_0002
wherein X, n, R^ R2> R4 and R'5 are as defined above, and R"3 is Z-X2 wherein X2 is a residue of formula (a') /OR's
II OR,9 o wherein Zi is as defined above and each of R'8 or R'9 is a hydrolysable or hydrogenolysable group or R'8 and R'9 form together a divalent bridging residue optionally fused to a ring (e.g. benzene ring), and, where required, converting the compounds of formula I obtained in free form into the desired salt form, or vice versa.
Process step a) may be carried out in accordance with methods known in the art. The removal of the amino protecting groups may conveniently be performed according to methods known in the art, e.g. by hydrolysis, e.g. in an acidic medium, for example using hydrochloric acid. Examples of protecting groups for amino groups are e.g. as disclosed in "Protective Groups in Organic Synthesis" T.W. Greene, J.Wiley & Sons NY, 2nd ed., chapter 7, 1991, and references therein, e.g. benzyl, p-methoxybenzyl, methoxymethyl, tetrahydropyranyl, trialkylsilyl, acyl, tert.-butoxy-carbonyl, benzyloxycarbonyl, 9-fluorenyl methoxy car- bonyl, trifluoroacetyl, and the like.
In the residue of formula (a'), each of R'8 and R'9 may have the significance of e.g. tert-butyl, phenyl or benzyl or form together a cyclic system such as in 1 ,5-dihydro-2,4,3- benzodioxaphosphepin.
Process step b) may be performed according to methods known in the art, e.g. by hydrolysis, e.g. in a basic medium when R'6 and R'7 are each a hydrolysable group, for example using a hydroxide such as barium hydroxide or in an acidic medium when R'6 and R'7 are each a tert-butyl group. It may also be performed by hydrogenolysis, e.g. in the presence of a catalyst, e.g. Pd/C, followed by hydrolysis, e.g. in an acidic medium, for example HCI. Compounds of formulae II and III, used as starting materials, and salts thereof are also novel and form part of the invention.
The present invention also includes a process for the preparation of a compound of formula II which process comprises transforming a compound of formula IV
Figure imgf000006_0001
wherein R^ R'3) R and R'5 are as defined above, to introduce the desired residue -(CH2)n-Y- R2 e.g. by an alkylation. Alkylation of the compounds of formula IV may be performed according to methods known in the art, e.g. by nucleophilic substitution, e.g. by reaction with an alkylating agent R -Y-(CH2)n-X3 wherein X3 is mesylate, tosylate, triflate, nosylate, chloride, bromide or iodide. The alkylation may also be carried out by following the Mitsunobu protocol using R2-Y-(CH2)n-OH (e.g. as disclosed in Hughes, Organic Preparations and Procedures International 28, 127-64, 1996 or D.L. Hughes, Org. React. 42, 335, 1992), in solution or on solid phase support synthesis, e.g. by attaching the compound of formula IV to a resin. Alternatively, e.g. triphenylphosphine or diethyl azocarboxylate bound to a resin, e.g. polystyrene, may be used.
Compounds of formula wherein R'8 and R'9 form a cyclic system, may be prepared as follows:
Figure imgf000006_0002
wherein X, Y, n, R1f R2, R4and R'5 are as defined above.
Insofar as the production of the starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter.
The following Examples are illustrative of the invention. Melting points are uncorrected. RT = room temperature
THF = tetrahydrofuran
DMF = dimethylformamide MTBE = methyl tert-butyl ether
AcOEt = ethyl acetate
Examβle_1j_(R)-2-Amino-4-{4-[2-(4-chloro-phenoxy)-ethoxy]-phenyl}-2-methyl-butan-1-ol Hydrochloride.
Figure imgf000007_0001
To tert. -butyl (R)-(3-{4-[2-(4-Chloro-phenoxy)-ethoxy]-phenyl}-1 -hydroxymethyl-1 -methyl- propyl)-carbamate (38 mg, 0.063 mmol) is added 4 M HCI in dry dioxane (1 mL). The clear colorless solution is stirred for 2 h protected from moisture. Then, the solution is evaporated to dryness and the partially crystalline residue is taken up in dry ether (5 mL). Sonication for 10 min gives a precipitate of colorless crystals. The product is filtered off, washed with cold ether (3 x 1 mL), and dried in vacuo to afford the title compound in form of a non hygroscopic colorless microcrystalline powder: HPLC: tR = 3.17 min., ESI+ MS: m/z = 350 /
352 (MH+).
fe/i-butyl (R)-(3-{4-[2-(4-Chloro-phenoxy)-ethoxy]-phenyl}-1 -hydroxymethyl-1 -methyl-propyl)- carbamate may be prepared according to the following procedure:
To a solution of tert-butyl [(R)-1-hydroxy-4-(4-hydroxy-phenyl)-2-methyl-but-2-yl]-carbamate (100 mg, 0.34 mmol) and 1-(2-bromoethoxy)-4-chlorobenzene (120 mg, 0.51 mmol, 1.5 eq.) in anhydrous DMF (2.5 mL) is added water free caesium carbonate (166 mg, 0.51 mmol, 1.5 eq.). The suspension obtained is stirred over night protected from moisture at 60°C. After cooling to RT the solids are filtered off and rinsed with DMF (2 x 1 mL). The combined filtrates are evaporated in a high vacuum to give a dark orange syrup. Purification by flash chromatography (FlashMaster II, MTBE/hexanes gradient 0% MTBE -> 40% MTBE within 45 min, then 40% MTBE 15 min) gives colorless crystals: HPLC: tR = 5.45 min., ESI+ MS: m/z = 450 / 452.
By following the procedure of Example 1 but using the appropriate starting materials, the compounds of formula A, wherein R2 and R6 are as indicated in Table 1 , may be prepared. -7
Figure imgf000008_0001
Table 1
Figure imgf000009_0002
Example 11 : 2-Amino-4-{4-[2-phenoxy-ethoxy]-phenyl}-2-ethoxy-butan-1 -ol Hydrochloride.
Figure imgf000009_0001
To a solution of 4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (300 mg, 1.27 mmol) in DMF (5 ml) was added Cs2CO3 (1.2 g, 3.83 mmol) and 2-phenoxyethyl bromide (770 mg, 1.27 mmol). The reaction mixture was stirred at 85°C for 4 hours. AcOEt and water were then added, the organic layer was separated and the aqueous phase was extracted with AcOEt (3 x 50 ml). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt / Hx 9:1) afforded (2-Methyl-4-{2-[4-(2-phenoxy-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4- yl)-methanol as colorless oil. To a solution of (2-methyl-4-{2-[4-(2-phenoxy-ethoxy)-phenyl]- ethyl}-4,5-dihydro-oxazol-4-yl)-methanol (50 mg, 0.14 mmol) in ethanol (2 ml) was added cone. HCI (2 ml). The reaction mixture was stirred at 85°C for 2 hours, then concentrated to dryness. The residue was re-dissolved in AcOEt and precipitated with hexanes. The solid was filtered off, washed with dry ether and dried in vacuo to afford 2-amino-4-{4-[2-phenoxy- ethoxy]-phenyl}-2-ethoxy-butan-1-ol hydrochloride as a colorless powder. ESI+ MS: m/z = 332.3 (M+H)+.
By following the procedure of Example 11 but using the appropriate starting materials, the compounds of formula B, wherein R2 is as indicated in Table 2, may be prepared.
Figure imgf000010_0001
Table 2
Figure imgf000010_0002
Figure imgf000011_0002
Example 26: (+/-) Mono-(2-Amino-4-{4-[2-phenoxy-ethoxy]-phenyl}-2-ethoxy-butan) phosphate.
Figure imgf000011_0001
To a solution of (2-methyl-4-{2-[4-(2-phenoxy-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)- methanol (200 mg, 0.56 mmol) and tetrazole (197 mg, 2.81 mmol, 5 eq., recrystallized from toluene) in dry THF (5 ml) was added di-tert-butyl-N.N-diisopropylphosphoramide (561 mg, 2.25 mmol, 4 eq.). After stirring under argon at RT for 3h, H2O2 (30%, 10 eq.) was slowly added at 0°C with vigorous stirring. The reaction mixture was stirred for further 30 min, followed by addition of saturated sodium thiosulfate solution (5 ml). The organic layer was separated and the aqueous phase was extracted with ether (3 x 20 ml). The combined organic extracts were washed with brine, dried over MgSO l and evaporated to dryness. Purification by flash chromatography (AcOEt / hexane 1:1) afforded phosphoric acid di-tert- butyl ester 2-methyl-4-{2-[4-(2-phenoxy-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-ylmethyl ester as colorles crystals. Finally, to a solution of phosphoric acid di-tert-butyl ester 2-methyl- 4-{2-[4-(2-phenoxy-ethoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-ylmethyl ester (150 mg, 0.27 mmol) in ethanol (5 ml) was added cone. HCI (5 ml). The reaction mixture was stirred at 50°C for 2 hours, then concentrated to dryness. The residue was re-dissolved in AcOEt and precipitated with hexanes. The solid was filtered off, washed with dry ether and dried in vacuo to afford mono-(2-amino-4-{4-[2-phenoxy-ethoxy]-phenyl}-2-ethoxy-butan) phosphate as a colorless powder. ESI+ MS: m/z = 410.2 (M-H)+.
By following the procedure of Example 26 but using the appropriate starting materials, the compounds of formula C, wherein R is as indicated in Table 3, may be prepared.
Figure imgf000012_0001
Table 3
Figure imgf000012_0002
Figure imgf000013_0002
Example 36: (R)-Mono-(2-amino-4-(4-r2-(4-chloro-phenoxv)-ethoxvl-phenvl}-2-methvl-butyπ phosphate.
Figure imgf000013_0001
terf.-butyl [3-{4-[2-(4-Chloro-phenoxy)-ethoxy]-phenyl}-1-(di-tert-butoxy-phosphoryloxy- methyl)-1-methyl-propyl]-carbamate (44 mg, 0.069 mmol) was dissolved in 4 M HCI in dioxane (2 mL). After stirring for 2h the slightly turbid solution was evaporated. The colorless semi-solid residue was sonicated with dry ether (5 mL) to give a colorless precipitate. The solid was filtered off, washed with dry ether and vacuum dried to afford a off white powder: HPLC: tR = 3.11 min., ESI+ MS: m/z = 430 / 432 (M-H+). te/£-butyl f3-(4-[2-(4-Chloro-phenoxy)-ethoxy1-phenyl)-1-(di-tert-butoxy-phosphoryloxy- methvD- 1 -methyl-propyn-carbamate be prepared according to the following procedure:
To a solution of te/t-butyl (R)-(3-{4-[2-(4-Chloro-phenoxy)-ethoxy]-phenyl}-1-hydroxymethyl- 1-methyl-propyl)-carbamate (40 mg, 0.089 mmol, Ex. 1a) and tetrazole (19 mg, 0.27 mmol, 3 eq., recrystallized from toluene) in dry THF (1 mL) was added di-terf.-butyl N,N-diethyl-phos- phoramidite (36 μL, 0.13 mmol, 1.5 eq.). The reaction mixture was stirred under argon at RT for 2h. Then, H2O2 (30%, 91 μL, 0.89 mmol, 10 eq.) was injected at 0°C with vigorous stirring. The reaction mixture was stirred for further 30 min, followed by addition of saturated sodium thiosulfate solution (1 mL). The organic layer was separated and the aqueous phase was extracted with ether (3 x 1 mL). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness. The crude material was purified by flash chromatography (FlashMaster II, MTBE/hexanes gradient 0% MTBE -> 50% MTBE within 45 min, then 50% MTBE 15 min) to afford colorless crystals: HPLC: tR = 6.64 min., ESI+ MS: m/z = 642 / 644 (MH+). By following the procedure of Example 36 but using the appropriate starting materials, the compounds of formula D, wherein R2 and R6 are as indicated in Table 4, may be prepared.
Figure imgf000014_0001
Table 4
Figure imgf000014_0003
Example 44: 2-Amino-2-{2-[4-(3-phenoxy-propoxy)-phenyl]-ethyl}-propane-1,3-diol
Hydrochloride.
Figure imgf000014_0002
To a solution of 4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (300 mg, 1.27 mmol) in DMF (5 ml) was added Cs2CO3 (1.2 g, 3.83 mmol) and (3-bromo- propoxy)-benzene (273 mg, 1.27 mmol). The reaction mixture was stirred at 85°C for 4 hours. AcOEt and water were then added, the organic layer was separated and the aqueous phase was extracted with AcOEt (3 x 50 ml). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt/Hexane 9:1) affords (2-methyl-4-{2-[4-(3-phenoxy-propoxy)-phenyl]- ethyl}-4,5-dihydro-oxazol-4-yl)-methanol as colorless oil. To a solution of (2-methyl-4-{2-[4- (3-phenoxy-propoxy)-phenyl]-ethyl}-4,5-dihydro-oxazoI-4-yl)-methanol (50 mg, 0.135 mmol) in ethanol (2 ml) was added cone. HCI (2 ml). The reaction mixture was stirred at 85°C for 2 hours, then concentrated to dryness. The residue was re-dissolved in AcOEt and precipitated with hexanes. The solid was filtered off, washed with dry ether and dried in vacuo to afford 2-amino-2-{2-[4-(3-phenoxy-propoxy)-phenyl]-ethyl}-propane-1 ,3-diol hydro- chloride as a colorless powder. ESI+ MS: m/z = 370.4 (M+H)+.
By following the procedure of Example 44 but using the appropriate starting materials, the compounds of formula E, wherein R2 and Y are as indicated in Table 5, may be prepared.
Figure imgf000015_0001
Table 5
Figure imgf000015_0002
Example 52: ((R)-2-Amino-2-methyl-4-[4-(3-phenoxy-propoxy)-phenyl]-butan-1-ol
Hydrochloride.
Figure imgf000016_0001
To {(R)-1 -Hydroxymethyl-1 -methyl-3-[4-(3-phenoxy-propoxy)-phenyl]-propyl}-carbamic acid tert-butyl (50 mg, 0.11 mmol) was added 4 M HCI in dry dioxane (1 mL). The clear colorless solution was stirred for 2 h protected from moisture. Then, the solution was evaporated to dryness and the partially crystalline residue was taken up in dry ether (5 mL). Sonication for 10 min gives a precipitate of colorless crystals. The product was filtered off, washed with cold ether (3 x 1 mL), and dried in vacuo to afford the title compound in form of a non hygroscopic colorless microcrystalline powder. ESI+ MS: m/z = 330.4 (MH+).
{(R)-1-Hydroxymethyl-1-methyl-3-[4-(3-phenoxy-propoxy)-phenyl]-propyl}-carbamic acid tert- butyl may be prepared according to the following procedure:
To a solution of tert-butyl [(R)-1-hydroxy-4-(4-hydroxy-phenyl)-2-methyl-but-2-yl]-carbamate (100 mg, 0.34 mmol) and (3-bromo-propoxy)~benzene (109.6 mg, 0.51 mmol, 1.5 eq.) in anhydrous DMF (2.5 mL) was added water free cesium carbonate (166 mg, 0.51 mmol, 1.5 eq.). The suspension obtained was stirred over night protected from moisture at 60°C. After cooling to RT the solids were filtered off and rinsed with DMF (2 x 1 mL). The combined filtrates were evaporated in a high vacuum to give a dark orange syrup. Purification by flash chromatography (FlashMaster II, MTBE/hexanes gradient 0% MTBE -> 40% MTBE within 45 min, then 40% MTBE 15 min) gave colorless crystals: ESI+ MS: m/z = 430.4.
Example 53: (R)-2-Amino-4-{4-[3-(5-bromo-2-methoxy-phenoxy)-propoxy]-phenyl}-2-methyl- butan-1-ol Hydrochloride.
Figure imgf000016_0002
The title compound was prepared as described in example 52 using 4-bromo-2-(3-bromo- propoxy)-1-methoxy-benzene instead of (3-bromo-propoxy)-benzene. ESI+ MS: m/z = 439.3 (M+H)+.
Example 54: (+/-) Mono Phosphoric acid mono-{2-amino-2-hydroxymethyl-4-[4-(3-phenoxy- propoxy)-phenyl]-butyl} ester.
Figure imgf000017_0001
To a solution of (2-methyl-4-{2-[4-(3-phenoxy-propoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4- yl)-methanol (200 mg, 0.54 mmol) and tetrazole (189 mg, 2.70 mmol, 5 eq., recrystallized from toluene) in dry THF (5 ml) was added di-tert-butyl-N,N-diisopropylphosphoramide (538.5 mg, 2.16 mmol, 4 eq.). After stirring under argon at RT for 3h, H2O2 (30%, 10 eq.) was slowly added at 0°C with vigorous stirring. The reaction mixture was stirred for further 30 min, followed by addition of saturated sodium thiosulfate solution (5 ml). The organic layer was separated and the aqueous phase was extracted with ether (3 x 20 ml). The combined organic extracts were washed with brine, dried over MgSO , and evaporated to dryness. Purification by flash chromatography (AcOEt / hexane 1:1) affords (+/-) phosphoric acid di-tert-butyl ester 2-methyl-4-{2-[4-(3-phenoxy-propoxy)-phenyl]-ethyl}-4,5-dihydro- oxazol-4-ylmethyl ester as colorless crystals. Finally, to a solution of phosphoric acid di-tert- butyl ester 2-methyl-4-{2-[4-(3-phenoxy-propoxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl- methyl ester (50 mg, 0.089 mmol) in ethanol (5 ml) was added cone. HCI (5 ml). The reaction mixture was stirred at 50°C for 2 hours, then concentrated to dryness. The residue was re-dissolved in AcOEt and precipitated with hexanes. The solid was filtered off, washed with dry ether and dried in vacuo to afford (+/-) mono phosphoric acid mono-{2-amino-2- hydroxymethyl-4-[4-(3-phenoxy-propoxy)-phenyl]-butyl} ester as a colorless powder. ESI+ MS: m/z = 426.4 (M-H)+. By following the procedure of Example 54 but using the appropriate starting materials, the compounds of formula F, wherein R2, Rio and Y are as indicated in Table 6, may be prepared.
Figure imgf000018_0001
Table 6
Figure imgf000018_0002
The compounds of formula I in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. lymphocyte recirculation modulating properties, e.g. as indicated in in vitro and in vivo tests and are therefore indicated for therapy.
A. In vitro
The compounds of formula I have binding affinity to individual human S1P receptors as determined in following assays:
Sphingosine-1 -phosphate (S1P) receptor profiling
Agonist activities of compounds are tested on the human S1P receptors EDG-1 (SIP^, EDG-3 (S1P3), EDG-5 (S1P2), EDG-6 (S1P4) and EDG-8 (S1P5). Functional receptor activation is assessed by quantifying compound induced GTP [γ-35S] binding to membrane protein prepared from transfected CHO or RH7777 cells stably expressing the appropriate human S1P receptor. The assay technology used is SPA (scintillation proximity based assay). Briefly, DMSO dissolved compounds are serially diluted and added to SPA- bead (Amersham-Pharmacia) immobilised S1P receptor expressing membrane protein (10-20 μg/well) in the presence of 50 mM Hepes, 100 mM NaCI, 10 mM MgCI2> 10 μM GDP, 0.1% fat free BSA and 0.2 nM GTP [γ-35S] (1200 Ci/mmol). After incubation in 96 well microtiterplates at RT for 120 min, unbound GTP [γ-35S] is separated by a centrifugation step. Luminescence of SPA beads triggered by membrane bound GTP [γ-35S] is quantified with a TOPcount plate reader (Packard). EC50s are calculated using standard curve fitting software. In this assay, the compounds of formula I have a binding affinity to S1Pι receptor <50 nM.
Figure imgf000019_0001
Agon. = agonist
B. In vivo: Blood Lymphocyte Depletion
A compound of formula I or the vehicle is administered orally by gavage to rats. Tail blood for hematological monitoring is obtained on day -1 to give the baseline individual values, and at 2, 6, 24, 48 and 72 hours after application. In this assay, the compounds of formula I deplete peripheral blood lymphocytes when administered at a dose of 0.03 to 3 mg/kg. For example, following results are obtained: depletion of peripheral blood lymphocytes by more than 50%
Example 1 : 0.03 mg/kg p.o. after 6h, 0.02 mg/kg p.o. after 24h.
Example 3: 0.01 mg/kg p.o. after 6h, <0.03 mg/kg p.o. after 48h.
Example 7: 0.03 mg/kg p.o. after 6h, 0.02 mg/kg p.o. after 48h.
Example 9: 0.2 mg/kg p.o. after 6h, >1 mg/kg p.o. after 48h.
Example 53: 0.1 mg/kg p.o. after 6h, 0.5 mg/kg p.o. after 48h. The compounds of formula I are, therefore, useful in the treatment and/or prevention of diseases or disorders mediated by lymphocytes interactions, e.g. in transplantation, such as acute or chronic rejection of cell, tissue or organ allo- or xenografts or delayed graft function, graft versus host disease, autoimmune diseases, e.g. rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or II and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic rhinitis/conjunctivitis, allergic contact dermatitis, inflammatory diseases optionally with underlying aberrant reactions, e.g. inflammatory bowel disease, Crohn's disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, ischemia/reperfusion injury, e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, traumatic shock, angiogenesis, Alzheimer's disease, cancer, e.g. breast cancer, T cell lymphomas or T cell leukemias, infectious diseases, e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, chronic bacterial infection, or senile dementia. Examples of cell, tissue or solid organ transplants include e.g. pancreatic islets, stem cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus. For the above uses the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired.
In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 0.1 to 50 mg active ingredient.
The compounds of formula I may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form. Pharmaceutical compositions comprising a compound of formula I in free form or in pharmaceutically acceptable salt form in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
The compounds of formula I may be administered in free form or in pharmaceutically acceptable salt form e.g. as indicated above. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
In accordance with the foregoing the present invention further provides:
1.1 A method for preventing or treating disorders or diseases mediated by lymphocytes, e.g. such as indicated above, in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
1.2 A method for preventing or treating acute or chronic transplant rejection or T-cell mediated inflammatory or autoimmune diseases, e.g. as indicated above, in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
2. A compound of formula I, in free form or in a pharmaceutically acceptable salt form for use as a pharmaceutical, e.g. in any of the methods as indicated under 1.1 or 1.2 above.
3. A pharmaceutical composition, e.g. for use in any of the methods as in 1.1 or 1.2 above comprising a compound of formula I in free form or pharmaceutically acceptable salt form in association with a pharmaceutically acceptable diluent or carrier therefor.
4. A compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for use in any of the method as in 1.1 or 1.2 above.
The compounds of formula I may be administered as the sole active ingredient or in conjunction with, e.g. as an adjuvant to, other drugs e.g. immunosuppressive or immunomodulating agents or other anti-inflammatory agents, e.g. for the treatment or prevention of allo- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders, or a chemotherapeutic agent, e.g a malignant cell anti-proliferative agent. For example, the compounds of formula I may be used in combination with a calcineurin inhibitor, e.g. cyclosporin A, FK 506 or ISATχ247; a mTOR inhibitor, e.g. rapamycin, 40-O-(2- hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, TAFA- 93, biolimus 7 or biolimus 9; an ascomycin having immunosuppressive properties, e.g. ABT- 281, ASM981, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40. CD45, CD58, CD80, CD86 or their ligands; other immunomodulatory compounds, e.g. a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or a chemotherapeutic agent, e.g. paclitaxel, gemcitabine, cisplatinum, doxorubicin or 5-fluorouracil; or an anti-infectious agent.
Where the compounds of formula I are administered in conjunction with other immunosuppressive / immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infectious therapy, dosages of the co-administered immunosuppressant, immunomodulatory, anti- inflammatory, chemotherapeutic or anti-infectious compound will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a calcineurin inhibitor, on the specific drug employed, on the condition being treated and so forth. In accordance with the foregoing the present invention provides in a yet further aspect:
5. A method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective non-toxic amount of a compound of formula I and at least a second drug substance, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic drug, e.g. as indicated above.
6. A pharmaceutical combination, e.g. a kit, comprising a) a first agent which is a compound of formula I as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infectious agent. The kit may comprise instructions for its administration.
The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of formula I and a co- agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients.

Claims

CLAIMS 1. A compound of formula I
Figure imgf000024_0001
wherein
Ri is Cι-6alkyl; C1-6alkyl substituted by hydroxy, Cι-2alkoxy or 1 to 6 fluorine atoms; C2.6alkenyl; or C2-6alkynyl; each of X, Y independently is O, CH2, or C=O;
R2 is phenyl; naphthyl; C3.6cycloalkyl; heteroaryl; a heterocyclic residue; phenyl- C1-2alkyl; C3-6cycloalkylC1-2alkyl; heteroarylC^alkyl; heterocyclicC1-2alkyl residue; wherein each may be ring-substituted by 1 to 5 substituents selected from hydroxy, halogen, C1-4alkyl, C1-4alkyl substituted by 1 to 5 fluorine atoms, C3.6cycloalkyl, C1-4alkoxy,
Figure imgf000024_0002
substituted by 1 to 5 fluorine atoms, C3.6cycloalkoxy, Cs-ecycloalkylC^alkyl, cyano, phenyl, and phenyl substituted by hydroxy, halogen, Chalky!, C1-4alkyl substituted by 1 to 5 fluorine atoms, C1- alkoxy, C1-4alkoxy substituted by 1 to 5 fluorine atoms, or cyano;
Ft is Z-X2 wherein Z is CH2, CHF or CF2 and X2 is OH or a residue of formula (a)
Figure imgf000024_0003
wherein Zi is a direct bond, CH2, CHF, CF2 or O, and each of R8 and R9, independently, is H or C1^alkyl optionally substituted by 1 , 2 or 3 halogen atoms; and each of R4 and R5, independently, is H; C1-4alkyl optionally substituted by 1 , 2 or 3 halogen atoms; or acyl; each of R6 and R7, independently, is H; hydroxy; halogen; C1- alkyl; Cι-6cycloalkyl;
C1-4alkoxy; Cι.6cycloalkoxy; C3-6cycloalkylCι-2alkyl; or cyano; and n is 2 or 3; in free form or in salt form.
2. A compound of formula I wherein R2 is phenyl; phenyl substituted by 1 or 2 halogen, Cι-2alkyl or C^alkoxy; cyanophenyl; naphthyl; or benzo[1 ,3]dioxol-5-yl, in free form or in salt form.
3. A compound according to claim 1 or 2 wherein each of R6 and R7, independently, is hydrogen, methoxy, methyl, or chloro in free form or in salt form.
4. A compound according to any preceding claim wherein X is O in free form or in salt form.
5. A compound according to any preceding claim wherein Y is O or S in free form or in salt form.
6. A compound according to any preceding claim wherein R3 is CH2-OH or CH2-OPO3H2.
7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical and for use in the preparation of a medicament.
8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable diluent or carrier therefor.
9. A pharmaceutical combination comprising a compound according to any one of claims 1 to 6, in free form or in pharmaceutically acceptable salt form, and at least one co- agent.
10. A method for preventing or treating disorders or diseases mediated by lymphocytes.and for preventing or treating acute or chronic transplant rejection or T- cell mediated inflammatory or autoimmune diseases in a subject comprising administering to the subject in need thereof an effective amount of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.
PCT/EP2004/004569 2003-04-30 2004-04-29 Amino-propanol derivatives as sphingosine-1-phosphate receptor modulator WO2004096752A1 (en)

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AU2004234066A AU2004234066B2 (en) 2003-04-30 2004-04-29 Amino-propanol derivatives as sphingosine-1-phosphate receptor modulator
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AT04730206T ATE547395T1 (en) 2003-04-30 2004-04-29 AMINOPROPANOL DERIVATIVES AS MODULATORS OF THE SPHINGOSINE-1 PHOSPHATE RECEPTOR
MXPA05011596A MXPA05011596A (en) 2003-04-30 2004-04-29 Amino-propanol derivatives as sphingosine-1-phosphate receptor modulator.
EP04730206A EP1622860B1 (en) 2003-04-30 2004-04-29 AMINO-PROPANOL DERIVATIVES AS SPHINGOSINE-1-PHOSPHATE RECEPTOR MODULATORs
US10/554,556 US7625950B2 (en) 2003-04-30 2004-04-29 Amino-propanol derivatives as sphingosine-1-phosphate receptor modulator
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BRPI0410025-5A BRPI0410025A (en) 2003-04-30 2004-04-29 amino-propanol derivatives as sphingosine-1-phosphate receptor modulator
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US20060211658A1 (en) 2006-09-21
ATE547395T1 (en) 2012-03-15
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BRPI0410025A (en) 2006-04-25
AU2004234066A1 (en) 2004-11-11
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EP1622860B1 (en) 2012-02-29
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