WO2017120355A1 - Dihydroquinolines et leurs utilisations - Google Patents

Dihydroquinolines et leurs utilisations Download PDF

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Publication number
WO2017120355A1
WO2017120355A1 PCT/US2017/012358 US2017012358W WO2017120355A1 WO 2017120355 A1 WO2017120355 A1 WO 2017120355A1 US 2017012358 W US2017012358 W US 2017012358W WO 2017120355 A1 WO2017120355 A1 WO 2017120355A1
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WIPO (PCT)
Prior art keywords
alkyl
aryl
mmol
heteroaryl
compound
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PCT/US2017/012358
Other languages
English (en)
Inventor
Eliezer Falb
Victor Piryatinsky
Dvorah Daily
Haifeng Yin
Guoqiang TIAN
Xingnan JIAO
Zhicheng ZHU
Yingjie Li
Lijun LEI
Junsheng Yang
Jinzhong CHEN
Shougang HU
Original Assignee
Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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Application filed by Teva Pharmaceutical Industries Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceutical Industries Ltd.
Publication of WO2017120355A1 publication Critical patent/WO2017120355A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/60—Quinoline or hydrogenated quinoline ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Definitions

  • MS Multiple Sclerosis
  • CIS clinically isolated syndrome
  • CDMS clinically definite multiple sclerosis
  • RRMS relapsing-remitting multiple sclerosis
  • SPMS secondary progressive MS
  • interferon beta 1-a Avonex® and Rebif®
  • interferon beta 1-b Betaseron®
  • glatiramer acetate Copaxone®
  • mitoxantrone Novantrone®
  • natalizumab Tysabri®
  • Fingolimod Gilenya®
  • Immunosuppressants or cytotoxic agents are used in some subjects after failure of conventional therapies. However, the relationship between changes of the immune response induced by these agents and the clinical efficacy in MS is far from settled (EMEA Guideline, 2006) .
  • symptomatic treatment refers to all therapies applied to improve the symptoms caused by the disease (EMEA Guideline, 2006) and treatment of acute relapses with corticosteroids. While steroids do not affect the course of MS over time, they can reduce the duration and severity of attacks in some subjects.
  • Laquinimod (TV-5600) is a synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of Multiple Sclerosis (MS) (Polman, 2005; Sandberg-Wollheim, 2005; Comi et al 2008). Laquinimod and its sodium salt form are described, for example, in U.S. Patent No. 6,077,851. The mechanism of action of laquinimod is not fully understood.
  • Thl T helper 1 cell, produces pro- inflammatory cytokines
  • Th2 T helper 2 cell, produces antiinflammatory cytokines
  • Another study demonstrated (mainly via the NFkB pathway) that laquinimod induced suppression of genes related to antigen presentation and corresponding inflammatory pathways (Gurevich, 2010) .
  • Other suggested potential mechanisms of action include inhibition of leukocyte migration into the CNS, increase of axonal integrity, modulation of cytokine production, and increase in levels of brain- derived neurotrophic factor (BDNF) (Runstrom, 2006; Briick, 2011) .
  • BDNF brain- derived neurotrophic factor
  • Laquinimod showed a favorable safety and tolerability profile in two phase III trials (Results of Phase III BRAVO Trial Reinforce Unique Profile of Laquinimod for Multiple Sclerosis Treatment; Teva Pharma, Active Biotech Post Positive Laquinimod Phase 3 ALLEGRO Results) .
  • Fig. 1 Activity of compounds in MOG EAE Study.
  • Fig. 2 Mean plasma concentration-time profiles of prodrug 53 and parent drug after IV and PO dose of prodrug 53 in male SD rats.
  • Fig. 3 Mean plasma concentration-time profiles of prodrug 5 and parent drug after IV and PO dose of prodrug 5 in male SD rats.
  • Fig. 4 Mean plasma concentration-time profiles of prodrug 69 and parent drug after IV and PO dose of prodrug 69 in male SD rats.
  • Fig. 5 Mean plasma concentration-time profiles of prodrug 54 and parent drug after IV and PO dose of prodrug 54 in male SD rats.
  • the present invention provides compound having the structure:
  • a is absent of present and when present is a bond
  • ⁇ is absent or present and when present is a bond
  • ⁇ is absent or present and when present is a bond
  • X is O, OH, CI, Br, O-Ri, 0-C(0)-R 2 , 0-C(0)-OR 3 , O-C (0) -NR4R5, 0-CH 2 -OR 6 , O-SO2-R7, 0-S0 2 -NR 8 R 9 , O-P (0) (OR10) 2, O-L- ( laquinimod residue), O-L- ( fingolimod residue), O-L- ( cilomilast residue) or O-L- ( D-glucose residue) ,
  • Ri is C2-C12 alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaryl, heterocycloalkyl , alkyl-COOH, alkyl-SCH 3 , alkyl-C0 2 - alkyl, alkyl-NHC (0) -aryl , alkyl-NHC (O) -heteroaryl, alkyl
  • alkyl-NH-alkyl alkyl-C (0) - (N-methylethanolamine) , alkyl-C (0)- (dimethylaminoethanol) , amino acid residue, alkyl- (amino acid residue), alkyl-C (0) -( amino acid residue), alkyl-NH- ( amino acid residue) or -CH ( alkyl-OAc) 2 ;
  • R 2 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C02-alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (0) -NH-indane;
  • R3 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl
  • R.4 and R5 are each, independently, H, alkyl, aminoalkyl, alkenyl, alkynyl, aryl or heteroaryl
  • R6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(O) -alkyl, C(O)- heteroalkyl, C0 2 -alkyl, C (0) -heterocycloalkyl , C (0) NH-alkyl- heterocycloalkyl, C(0)NH-aryl, C (0) (alkyl) 2, C (O) NH-alkyl- N(CH 3 ) (Boc), C0 2 -alkyl-N (CH 3 ) (Boc) , or C (0) -piperazine-C (0) - (amino acid residue) ;
  • R7 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl
  • Rs and R9 are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl;
  • Each Rio is, independently, H or alkyl
  • Y is absent or present and when present is H, CI or alkyl-SCH3,- Z is aryl, heteroaryl or cycloalkyl-aryl ,
  • ⁇ and ⁇ are absent or present and when present are bonds
  • ⁇ and ⁇ are absent or present and when present are bonds
  • R11 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl
  • R12 is H, alkyl, alkenyl, alkynyl,- aryl or heteroaryl, or a pharmaceutically acceptable salt or ester thereof.
  • ⁇ and ⁇ are absent or present and when present are bonds
  • ⁇ is absent or present and when present is a bond
  • Cb is H, OH, alkyl, alkenyl or alkynyl
  • Q is H, OH, alkyl, alkenyl or alkynyl, or a pharmaceutically acceptable salt or ester thereof.
  • the present invention provides compound having the structure:
  • a is absent of present and when present is a bond
  • ⁇ is absent or present and when present is a bond
  • ⁇ is absent or present and when present is a bond
  • X is O, OH, CI, Br, O-Ri, 0-C(0)-R 2 , 0-C(0)-OR 3 , O-C (0) -NR4R5, 0-CH 2 -OR 6 0-S0 2 -R7, 0-S0 2 -NR 8 R 9 , O-P (0) (OR10) 2, O-L- ( laquinimod residue), O-L- (fingolimod residue), O-L- ( cilomilast residue) or O-L- ( D-glucose residue) ,
  • L is present or absent and when present is a chemical linker;
  • Ri is C 2 -C 12 alkyl, alkenyl, alkynyl, hydroxyalkyl , aminoalkyl, alkylaryl, heterocycloalkyl , alkyl-COOH, alkyl-SCH 3 , alkyl-C0 2 - alkyl, alkyl-NHC (0) -aryl, alkyl-NHC (0) -heteroaryl , alkyl-C (0) NH- alkyl-NH-alkyl, alkyl-C (O) - (N-methylethanolamine ) , alkyl-C (0)- (dimethylaminoethanol) , amino acid residue, alkyl- (amino acid residue), alkyl-C (O) - (amino acid residue), alkyl-NH- ( amino acid residue) or -CH ( alkyl-OAc) 2 ;
  • R 2 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C0 2 -alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (0) -NH-indane;
  • R3 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl
  • FU and R 5 are each, independently, H, alkyl, aminoalkyl, alkenyl, alkynyl, aryl or heteroaryl
  • R6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(O) -alkyl, C(O)- heteroalkyl, C0 2 -alkyl, C (O) -heterocycloalkyl, C (0) NH-alkyl- heterocycloalkyl, C(0)NH-aryl, C (O) N (alkyl) 2 , C (0) H-alkyl- N(CH 3 )(Boc), C0 2 -alkyl-N (CH 3 ) (Boc) , or C (O) -piperazine-C (O) - (amino acid residue) ;
  • R ? is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
  • Rg and Rg are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl; and Each Rio is, independently, H or alkyl;
  • Y is absent or present and when present is H, CI or alkyl-SCH 3 ;
  • Z is aryl, heteroaryl or cycloalkyl-aryl
  • Z is heteroaryl or cycloalkyl-aryl.
  • X is CI, Br, O-Ri, 0-C(0)-R 2 , 0-C(0)-OR 3 , O-C (0) -NR4R5, 0-CH 2 - OR 6 , 0-S0 2 -R 7 , 0-S0 2 -NR 8 R9, O-P (0) (OR10) 2, ⁇ O-L- (laquinimod residue), 0-L- (fingolimod residue), 0-L- (cilomilast residue) or 0-L- ( D-glucose residue) ,
  • Ri is C 2 -Ci 2 alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaryl, heterocycloalkyl, alkyl-COOH, alkyl-SCH 3 , alkyl-C0 2 - alkyl, alkyl-NHC (0) -aryl , alkyl-NHC (0) -heteroaryl, alkyl-C (0) H- alkyl-NH-alkyl, alkyl-C (0) - (N-methylethanolamine ) , alkyl-C (O)- (dimethylaminoethanol ) , amino acid residue, alkyl- (amino acid residue), alkyl-C (O) -( amino acid residue), alkyl-NH- ( amino acid residue) or -CH (alkyl-OAc) 2 ;
  • R 2 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C02-alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (O) -NH-indane ;
  • F.3 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
  • R and R5 are each, independently, H, alkyl, aminoalkyl, alkenyl, alkynyl, aryl or heteroaryl;
  • R6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(0) -alkyl, C(0)- heteroalkyl, C0 2 -alkyl, C (0) -heterocycloalkyl, C (0) H-alkyl- heterocycloalkyl, C(0)NH-aryl, C (0) N (alkyl) 2, C (0) NH-alkyl- N(CH 3 ) (Boc), C0 2 -alkyl-N (CH 3 ) (Boc) , or C (0) -piperazine-C (0) - (amino acid residue);
  • Rv is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl
  • Ra and R9 are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl; and Each Rio is, independently, H or alkyl; and
  • Z is aryl, heteroaryl or cycloalkyl-aryl ; or a pharmaceutically acceptable salt or ester thereof.
  • Z is one embodiment, a compound having the structure
  • X is CI, Br, O-Ri, 0-C(0)-R 2/ 0-C(0)-OR 3 , O-C (0) -NR4R5 , 0-CH 2 - OR 6 , O-SO2-R7, 0-S0 2 -NR 8 R 9 , O-P (0) (OR10) 2, O-L- (laquinimod residue), O-L- (fingolimod residue) , O-L- (cilomilast residue) or O-L- ( D-glucose residue) ,
  • L is present or absent and when present is a chemical linker;
  • Ri is C 2 -C 12 alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaryl, heterocycloalkyl, alkyl-COOH, alkyl-SCH 3 , alkyl-C0 2 - alkyl, alkyl-NHC (0) -aryl, alkyl-NHC (0) -heteroaryl , alkyl-C (0) H- alkyl-NH-alkyl, alkyl-C (0) - (N-methylethanolamine ) , alkyl-C (0)-
  • R 2 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C0 2 ⁇ alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (0) -NH-indane ;
  • R3 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl
  • R 4 and R5 are each, independently, H, alkyl, aminoalkyl, alkenyl, alkynyl, aryl or heteroaryl;
  • R6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(0) -alkyl, C(O)- heteroalkyl, C0 2 -alkyl, C (0) -heterocycloalkyl, C (O) NH-alkyl- heterocycloalkyl, C(0)NH-aryl, C (0) (alkyl) 2 , C (0) NH-alkyl- N(CH 3 ) (Boc), C0 2 -alkyl-N (CH 3 ) (Boc) , or C (O) -piperazine-C (0) - (amino acid residue) ;
  • R 7 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl
  • Rs and R9 are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl; and Each Rio is, independently, H or alkyl,
  • A is O-Ri
  • Ri is C 2 -C 12 alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaryl, heterocycloalkyl, alkyl-COOH, alkyl-SCH 3 , alkyl-C0 2 -alkyl, alkyl-NHC (0) -aryl, alkyl-NHC (0) -heteroaryl, alkyl-C (0) H-alkyl-NH- alkyl, alkyl-C (0) - (N-methylethanolamine) , alkyl-C (0)- (dimethylaminoethanol ) , (amino acid residue), alkyl- (amino acid residue) , alkyl-C (0) - (amino acid residue), alkyl-NH- (amino acid residue) or -CH (alkyl-OAc) 2 -
  • Ri is isopropyl, allyl, -CH ( CH3-OAC ) 2
  • A is 0-C(0)-R2.
  • R 2 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C02-alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (0) -NH-indane .
  • H 3 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, C02-alkyl, alkyl-OAc, alkyl-heterocycloalkyl or alkly-C (0) -NH-indane .
  • A is 0-C(0)-OR3, wherein R 4 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl.
  • R3 is methyl, isobutyl, t-butyl or p-nitrophenyl .
  • A is O-C (0) -NR4R5, wherein R,j and R 5 are each, independently, H, alkyl, aminoalkyl, alkenyl, alkynyl, aryl or
  • R4 and R5 are each H, methyl, ethyl or - CH2CH2NHCH3 .
  • A is O-CH2-OR6, wherein R 6 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, hydroxyalkyl, aminoalkyl, alkylaryl, alkyl-OAc, C(O) -alkyl, C (0) -heteroalkyl, C0 2 -alkyl, C(O)- heterocycloalkyl, C (0) H-alkyl-heterocycloalkyl, C(0)NH-aryl,
  • R6 is methyl, butyl, -C(0)0CH3,
  • A is 0-S0 2 -R7 wherein R7 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl.
  • R7 is methyl or p-methylphenyl.
  • A is 0-S0 2 -NRaR9, wherein Re and R9 are each, independently, H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or combine to form a heterocycloalkyl .
  • Re is methyl or ethyl; and Rg is methyl or ethyl; or R 8 and Rg combine to form a morpholino.
  • A is O-P(O) (ORio)2, wherein each Rio is, independently, H or alkyl.
  • each Ri 0 is ethyl.
  • A is O-L- ( laquinimod residue). In some embodiments, A is O-L- ( fingolimod residue). 23 In some embodiments, A is O-L- (cilomilast residue) . In some embodiments, A is O-L- ( D-glucose residue).
  • L is present.
  • L is absent.
  • L is an alkyl, alkyl-C(O), alkyl-NH, alkyl-O, alkyl-C(O) or C (0) -phenyl-C (0) .
  • L is an
  • Z is aryl, heteroaryl or cycloalkyl-aryl , or a pharmaceutically acceptable salt or ester thereof.
  • Z is
  • Z is heteroaryl or cycloalkyl-aryl
  • Z is
  • Y is H, CI or alkyl-SCH 3 ;
  • Z is aryl, heteroaryl or cycloalkyl-aryl , or a pharmaceutically acceptable salt or ester thereof.
  • Z is
  • ⁇ and ⁇ are absent or present and when present are bonds
  • Rii is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl
  • Ri 2 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or a pharmaceutically acceptable salt or ester thereof.
  • Qi is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl
  • Q 2 is H, alkyl, alkenyl, alkynyl, aryl or heteroaryl, or a pharmaceutically acceptable salt or ester thereof.
  • Qi is H , alkyl or aryl
  • Q 2 is H, alkyl or aryl .
  • Qi is H , CH3 or phenyl; and Q2 is H , C3 ⁇ 4 or phenyl.
  • present invention further provides a compound having the structure:
  • ⁇ and ⁇ are absent or present and when present are bonds
  • ⁇ is absent or present and when present is a bond
  • Q3' is H, OH, alkyl, alkenyl or alkynyl
  • Q4 is H, OH, alkyl, alkenyl or alkynyl, or a pharmaceutically acceptable salt or ester thereof. o embodiment, a compound having the structure
  • b is H, OH, alkyl, alkenyl or alkynyl
  • Q4 is H, OH, alkyl, alkenyl or alkynyl, or a pharmaceutically acceptable salt or ester thereof-.
  • Q3 is H or OH; and Q4 is H or OH.
  • Ri is hydroxyalkyl
  • Z is aryl, heteroaryl or cycloalkyl-aryl, or a pharmaceutically acceptable salt or ester the
  • Ri is C 1 -C6 hydroxyalkyl.
  • Z is phenyl
  • a compound having the structure or a pharmaceutically acceptable salt or ester thereof in one embodiment, a compound having the structure:
  • R, and R5 are each an alkyl
  • Z is aryl, heteroaryl or cycloalkyl-aryl, or a pharmaceutically acceptable salt or ester thereof.
  • R4 is Ci-Cs alkyl; and R4 is C1-C6 alkyl In some embodiments, R 4 is methyl; and R is ethyl.
  • Z is phenyl
  • ]3 ⁇ 4 is C (0) N (alkyl ) 2 or C (0) cycloheteroalkyl
  • Z is aryl, heteroaryl or cycloalkyl-aryl , or a pharmaceutically acceptable salt or ester thereof.
  • R6 is C (0) N ( alkyl ) 2, wherein the alkyl is Ci-Ce alkyl.
  • R.6 is C (O) cycloheteroalkyl, wherein the cycloheteroalkyl is a morpholinyl.
  • Z is phenyl. having the structure:
  • the present invention also provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a method of treating subject afflicted with multiple sclerosis comprising administering to the subject an amount of the compound of the present invention.
  • a pharmaceutically acceptable salt or ester of any of the compounds disclosed herein in some embodiments, a pharmaceutically acceptable salt or ester of any of the compounds disclosed herein.
  • the multiple sclerosis is relapsing multiple sclerosis or relapsing-remitting multiple sclerosis.
  • the amount of the compound is effective to reduce a symptom of multiple sclerosis in the subject.
  • the symptom is a MRI-monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, decreased time to confirmed disease progression, decreased time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, deterioration of visual function, fatigue, impaired mobility, cognitive impairment, reduction of brain volume, abnormalities observed in whole Brain MTR histogram, deterioration in general health status, functional status, quality of life, and/or symptom severity on work.
  • the use of the compound for the preparation of a medicament for the treatment of multiple sclerosis is not limited.
  • the use of the compound for the treatment of multiple sclerosis in one embodiment, the use of the compound for the treatment of multiple sclerosis .
  • the compound of the present invention for use in treating a subject afflicted with multiple sclerosis also provides a pharmaceutical composition comprising an amount of the compound of the present invention for use in treating a subject afflicted with multiple sclerosis.
  • the present invention also provides a method of treating a subject afflicted with Crohn's disease comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • the present invention also provides a method of treating a subject afflicted with rheumatoid arthritis comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • the present invention also provides a method of treating a subject afflicted with lupus nephritis or active lupus nephritis comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • the present invention also provides a method of treating a subject afflicted with insulin-dependent diabetes mellitus (IDDM) comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • IDDM insulin-dependent diabetes mellitus
  • the present invention also provides a method of treating a subject afflicted with systemic lupus erythematosus (SLE) comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • SLE systemic lupus erythematosus
  • the present invention also provides a method of treating a subject afflicted with inflammatory bowel disease (IBD) comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • IBD inflammatory bowel disease
  • the present invention also provides a method of treating a subject afflicted with psoriasis comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • the present invention also provides a method of treating a subject afflicted with inflammatory respiratory disorder comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • the present invention also provides a method of treating a subject afflicted with atherosclerosis comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • the present invention also provides a method of treating a subject afflicted with ocular inflammatory disorder comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • the present invention also provides a method of treating a subject suffering from stroke comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subj ect .
  • the present invention also provides a method of treating a subject afflicted with Alzheimer's disease comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • the present invention also provides a method of treating a subject afflicted with BDNF-related disease comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • the present invention also provides a method of treating a subject afflicted with GABA related disorder comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • the present invention also provides a method of treating a subject afflicted with CB1 receptor related disorder comprising administering to the subject an amount of the compound of the present invention so as to thereby treat the subject.
  • the present invention also provides a method for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject, the method comprising administering to the subject the compound of the present invention so as to thereby reduce or inhibit progression of the level of fatigue in the multiple sclerosis subject.
  • the present invention also provides a method of treating a subject afflicted with glaucoma or suffering from retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or of reducing retinal ganglion cell loss, retinal ganglion cell damage or intraocular pressure in a subject, comprising administering to the subject an amount of the compound of the present invention to reduce retinal an ion cell loss or damage, or reduce intraocular pressure in the subject.
  • the present invention provides a method for in vivo delivery of laquinimod to a subject, the method comprising administering to the subject a compound of the present invention so as to thereby deliver laquinimod to the subject.
  • the subject is afflicted with multiple sclerosis.
  • the multiple sclerosis is relapsing multiple sclerosis or relapsing-remitting multiple sclerosis.
  • the in vivo delivery of laquinimod to a subject is effective to reduce a symptom of multiple sclerosis in the subject.
  • the symptom is a MRI-monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, decreased time to confirmed disease progression, decreased time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, deterioration of visual function, fatigue, impaired mobility, cognitive impairment, reduction of brain volume, abnormalities observed in whole Brain MTR histogram, deterioration in general health status, functional status, quality of life, and/or symptom severity on work.
  • the subject is afflicted with Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin- dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage,' or elevated intraocular pressure
  • the in vivo delivery of laquinimod to a subject is effective to reduce a symptom of the Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM) , systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CBl receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure in the subject.
  • the amount of the compound is effective to decrease or inhibit reduction of brain volume in the subject.
  • the amount of the compound is effective to decrease or inhibit reduction of brain volume.
  • the brain volume is measured by percent brain volume change (PBVC) .
  • PBVC percent brain volume change
  • the amount of the compound is effective to increase time to confirmed disease progression.
  • time to confirmed disease progression is increased by 20-60%.
  • the amount of the compound is effective to decrease abnormalities observed in whole Brain MTR histogram.
  • the amount of the compound is effective to decrease abnormalities observed in whole Brain MTR histogram.
  • the accumulation of physical disability is measured by Kurtzke Expanded Disability Status Scale (EDSS) score, or is assessed by the time to confirmed disease progression as measured by EDSS score.
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject had an EDSS score of 0-5.5 at baseline, an EDSS score of 1.5-4.5 at baseline or an EDSS score of 5.5 or greater at baseline.
  • the confirmed disease progression is a 1 point or a 0.5 point increase of the EDSS score.
  • impaired mobility is assessed by the Timed-25 Foot Walk test, the 12-Itern Multiple Sclerosis Walking Scale (MSWS-12) self- report questionnaire, the Ambulation Index (AI), the Six-Minute Walk (6MW) Test or the Lower Extremity Manual Muscle Test (LEMMT) Test.
  • MSWS-12 12-Itern Multiple Sclerosis Walking Scale
  • AI Ambulation Index
  • 6MW Six-Minute Walk
  • LEMMT Lower Extremity Manual Muscle Test
  • the amount of the compound is effective to reduce cognitive impairment.
  • cognitive impairment is assessed by the Symbol Digit Modalities Test (SDMT) score.
  • SDMT Symbol Digit Modalities Test
  • general health status is assessed by the EuroQoL (EQ5D) questionnaire, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC) .
  • EQ5D EuroQoL
  • SGI Subject Global Impression
  • CGIC Clinician Global Impression of Change
  • functional status is measured by the subject's Short-Form General Health survey (SF-36) Subject Reported Questionnaire score .
  • quality of life is assessed by SF-36, EQ5D, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC) .
  • the subject's SF-36 mental component summary score is improved.
  • the subject's SF-36 physical component summary sore (PSC) is improved.
  • fatigue is assessed by the EQ5D, the subject's Modified Fatigue Impact Scale (MFIS) score or the French valid versions of the Fatigue Impact Scale (EMIF-SEP) score.
  • MFIS Modified Fatigue Impact Scale
  • EMIF-SEP French valid versions of the Fatigue Impact Scale
  • symptom severity on work is measured by the work productivity and activities impairment General Health (WPAI-GH) questionnaire .
  • the compound is administered via oral administration. In some embodiments, the compound is administered by inj ection .
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • salicylates slow-acting drugs
  • gold compounds hydroxychloroquine
  • sulfasalazine combinations of slow-acting drugs
  • corticosteroids corticosteroids
  • immunosuppressive drugs immunosuppressive drugs and/or antibodies.
  • the subject is a human patient.
  • the present invention provides the use of the compound of the present invention for the preparation of a medicament for treating multiple sclerosis .
  • the present invention provides the use of the compound of the present invention for treating multiple sclerosis.
  • the present invention provides the use of the compound of the present invention for the preparation of a medicament for treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject.
  • IBD inflammatory bowel disease
  • psoriasis inflammatory respiratory disorder
  • atherosclerosis ocular inflammatory disorder
  • the present invention provides the use of the compound of the present invention for treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM) , systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD), psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF- related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject.
  • IBD inflammatory bowel disease
  • psoriasis inflammatory respiratory disorder
  • atherosclerosis ocular inflammatory disorder
  • stroke Alzheimer's disease
  • the compound of the present invention for use in treating multiple sclerosis .
  • the compound of the present invention for use in treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CBl receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject.
  • IBD inflammatory bowel disease
  • psoriasis inflammatory respiratory disorder
  • atherosclerosis ocular inflammatory disorder
  • stroke Alzheimer's disease
  • a pharmaceutical composition comprising the compound of the present invention for use in treating multiple sclerosis.
  • a pharmaceutical composition comprising the compound of the present invention for use in treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM) , systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD), psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject.
  • the present invention provides the use of the compound of the present invention for the preparation of a medicament for treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject.
  • IBD inflammatory bowel disease
  • psoriasis inflammatory respiratory disorder
  • atherosclerosis ocular inflammatory disorder
  • the present invention provides the use of the compound of the present invention for treating Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM) , systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD), psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF- related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a multiple sclerosis subject.
  • IBD inflammatory bowel disease
  • psoriasis inflammatory respiratory disorder
  • atherosclerosis ocular inflammatory disorder
  • stroke Alzheimer's disease
  • the present invention also provides a package comprising: a) a pharmaceutical composition comprising an amount of the compound of the present invention and a pharmaceutically acceptable carrier and b) instructions for us of the pharmaceutical composition to treat a subject afflicted with multiple sclerosis, Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus ⁇ IDDM) , systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) , psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure, or for reducing or inhibiting progression of the level of fatigue in a
  • the subject invention also provides a process of preparing a medicament prepared for treating a subject afflicted with multiple sclerosis, Crohn's disease, rheumatoid arthritis, lupus nephritis, active lupus nephritis, insulin-dependent diabetes mellitus (IDDM) , systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), psoriasis, inflammatory respiratory disorder, atherosclerosis, ocular inflammatory disorder, stroke, Alzheimer's disease, a BDNF-related disease, a GABA related disorder, a CB1 receptor related disorder, glaucoma, Huntington's disease, retinal ganglion cell loss, retinal ganglion cell damage, or elevated intraocular pressure using an amount of the compound of the present invention, comprising 1) obtaining a pharmaceutical composition comprising an amount of the compound of the present invention and a pharmaceutically acceptable carrier, and 2) packaging the pharmaceutical composition to make the medicament.
  • 2011-0034508 brain-derived neurotrophic factor (BDNF) - related diseases
  • U.S. Application Publication No. 2011-0218179 active lupus nephritis
  • U.S. Application Publication No. 2011-0218203 rheumatoid arthritis
  • U.S. Application Publication No. 2011-0217295 active lupus arthritis
  • U.S. Application Publication No. 2012-0142730 reducing fatigue, improving quality of life, and providing neuroprotection in MS patients
  • U.S. Application Publication No. 2014- 0045886 GABA-mediated disorders
  • U.S. Application Publication No. 2014-0045887 cannabinoid receptor type 1 (cbl) mediated disorders
  • U.S. Application Publication No.2015-0141458 glaucoma
  • BDNF-related disease is a disease in which a patient suffering from the disease has BDNF serum levels which are lower than those of a corresponding healthy individual and/or a disease in which the elevation of BDNF in a patient suffering from the disease can be associated with amelioration of the disease or of symptoms thereof.
  • This application also provides for a method for treating a human subject suffering from a BDNF-related disease selected from the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, depressive disorders, anxiety disorders, retinitis pigmentosa, erectile dysfunction, memory disorders, Rett syndrome, Alzheimer's disease, bipolar disorder and acute mania comprising administering an amount of the compound of the present invention in an amount effective to treat the human subject.
  • a "CBl receptor related disorder” is a disorder in which a patient suffering from the disorder has defective CB1 receptor function. Such disorders include, but are not limited to, attention- deficit/hyperactivity disorder (ADHD), Huntington's Disease, mood disorders, schizophrenia, bipolar disorder and stroke.
  • This application also provides for a method for treating a human subject suffering from a GABA related disorder which includes, but is not limited to, schizophrenia, epilepsy (seizures) , spasticity, stiff-person syndrome (SPS) , premenstrual dysphoric disorder, drug addiction, fertility disorder insomnia, spinocerebellar degeneration, or neuro- Behcet's syndrome.
  • a GABA related disorder which includes, but is not limited to, schizophrenia, epilepsy (seizures) , spasticity, stiff-person syndrome (SPS) , premenstrual dysphoric disorder, drug addiction, fertility disorder insomnia, spinocerebellar degeneration, or neuro- Behcet's syndrome.
  • a “pharmaceutically acceptable carrier” refers to a carrier or excipient that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. It can be a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject.
  • the compound of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • a pharmaceutically acceptable carrier suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the unit can be in a form suitable for oral administration.
  • the compound can be administered alone but is generally mixed with a pharmaceutically acceptable carrier, and co-administered in the form of a tablet or capsule, liposome, or as an agglomerated powder.
  • suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders.
  • Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like.
  • compositions in accordance with the invention may be used but are only representative of the many possible systems envisioned for administering compositions in accordance with the invention.
  • Injectable drug delivery systems include solutions, suspensions, gels, microspheres and polymeric injectables, and can comprise excipients such as solubility-altering agents (e.g., ethanol, propylene glycol and sucrose) and polymers (e.g., polycaprylactones and PLGA's) .
  • solubility-altering agents e.g., ethanol, propylene glycol and sucrose
  • polymers e.g., polycaprylactones and PLGA's
  • injectable drug delivery systems include solutions, suspensions, gels.
  • Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch) , diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc).
  • Implantable systems include rods and discs, and can contain excipients such as PLGA and polycaprylactone .
  • Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc).
  • excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.
  • Transmucosal delivery systems include patches, tablets, suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and enhancers (e.g., propylene glycol, bile salts and amino acids), and other vehicles (e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid) .
  • solubilizers and enhancers e.g., propylene glycol, bile salts and amino acids
  • other vehicles e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid
  • Dermal delivery systems include, for example, aqueous and nonaqueous gels, creams, multiple emulsions, microemulsions , liposomes, ointments, aqueous and nonaqueous solutions, lotions, aerosols, hydrocarbon bases and powders, and can contain excipients such as solubilizers, permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols and amino acids), and hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone ) .
  • the pharmaceutically acceptable carrier is a liposome or a transdermal enhancer.
  • Solutions, suspensions and powders for reconstitutable delivery systems include vehicles such as suspending agents (e.g., gums, zanthans, cellulosics and sugars), humectants (e.g., sorbitol), solubilizers (e.g., ethanol, water, PEG and propylene glycol), surfactants (e.g., sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine) , preservatives and antioxidants (e.g., parabens, vitamins E and C, and ascorbic acid), anti- caking agents, coating agents, and chelating agents (e.g., EDTA) .
  • suspending agents e.g., gums, zanthans, cellulosics and sugars
  • humectants e.g., sorbitol
  • solubilizers e.g., ethanol, water, PEG and propylene glyco
  • an “amount” or “dose” of the compound as measured in milligrams refers to the milligrams of compound present in a preparation, regardless of the form of the preparation.
  • a “dose of 0.6 mg” means the amount of compound in a preparation is 0.6 mg, regardless of the form of the preparation.
  • the weight of the salt form necessary to provide a dose of 0.6 mg would be greater than 0.6 mg due to the presence of the additional salt ion .
  • a “unit dose”, “unit doses” and “unit dosage form ( s ) mean a single drug administration entity/entities.
  • a pharmaceutical composition is “stable” when the composition preserves the physical stability/integrity and/or chemical stability/integrity of the active pharmaceutical ingredient during storage. Furthermore, “stable pharmaceutical composition” is characterized by its level of degradation products not exceeding 5% at 40°C/75%RH after 6 months or 3% at 55°C/75% RH after two weeks, compared to their level in time zero.
  • Efficacy when referring to an amount of the compound refers to the quantity of the compound that is sufficient to yield a desired therapeutic response. Efficacy can be measured by an improvement of a symptom of multiple sclerosis. Such symptoms can include a MRI- monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, time to confirmed disease progression, time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, visual function, fatigue, impaired mobility, cognitive impairment, brain volume, abnormalities observed in whole Brain MTR histogram, general health status, functional status, quality of life, and/or symptom severity on work.
  • an effective amount is an amount that is sufficient to decrease or inhibit reduction of brain volume (optionally brain volume is measured by percent brain volume change (PBVC)), increase time to confirmed disease progression (e.g., by 20-60% or at least 50%), decrease abnormalities observed in whole Brain MTR histogram, decrease the accumulation of physical disability (optionally measured by Kurtzke Expanded Disability Status Scale (EDSS) score, e.g., wherein the accumulation of physical disability is assessed by the time to confirmed disease progression as measured by Kurtzke Expanded Disability Status Scale (EDSS) score), improve impaired mobility (optionally assessed by the Timed-25 Foot Walk test, the 12-Item Multiple Sclerosis Walking Scale ( SWS-12) self-report questionnaire, the Ambulation Index (AI), the Six- Minute Walk (6MW) Test, or the Lower Extremity Manual Muscle Test (LEMMT) Test) , reduce cognitive impairment (optionally assessed by the Symbol Digit Modalities Test (SDMT) score) , improve general health (optionally assessed by the EuroQoL (EQ5D
  • administering to the subject means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject/patient to relieve, cure, or reduce the symptoms associated with a condition, e.g., a pathological condition.
  • the administration can be periodic administration.
  • periodic administration means repeated/recurrent administration separated by a period of time. The period of time between administrations is preferably consistent from time to time. Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times a week and so on, etc.
  • Treating encompasses, e.g., inducing inhibition, regression, or stasis of a disease or disorder, e.g., Relapsing MS (RMS), or alleviating, lessening, suppressing, inhibiting, reducing the severity of, eliminating or substantially eliminating, or ameliorating a symptom of the disease or disorder.
  • Treating as applied to patients presenting CIS can mean delaying the onset of clinically definite multiple sclerosis (CDMS) , delaying the progression to CDMS, reducing the risk of conversion to CDMS, or reducing the frequency of relapse in a patient who experienced a first clinical episode consistent with multiple sclerosis and who has a high risk of developing CDMS.
  • CDMS clinically definite multiple sclerosis
  • “Inhibition" of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.
  • a "symptom" associated with MS or RMS includes any clinical or laboratory manifestation associated with MS or RMS and is not limited to what the subject can feel or observe.
  • Multiple sclerosis is a slowly progressive CNS disease characterized by disseminated patches of demyelination in the brain and spinal cord, resulting in multiple and varied neurologic symptoms and signs, usually with remission and exacerbations.
  • a subject afflicted with multiple sclerosis includes a subject who has been clinically diagnosed to have multiple sclerosis or relapsing multiple sclerosis (RMS) , which includes relapsing-remitting multiple sclerosis (RRMS) and Secondary Progressive multiple sclerosis (SPMS), or is a subject presenting a clinically isolated syndrome (CIS) .
  • RMS relapsing multiple sclerosis
  • RRMS relapsing-remitting multiple sclerosis
  • SPMS Secondary Progressive multiple sclerosis
  • CIS clinically isolated syndrome
  • a subject at "baseline” is as subject prior to administration of the compound.
  • a "patient at risk of developing MS” is a patient presenting any of the known risk factors for MS.
  • the known risk factors for MS include any one of a clinically isolated syndrome (CIS) , a single attack suggestive of MS without a lesion, the presence of a lesion (in any of the CNS, PNS, or myelin sheath) without a clinical attack, environmental factors (geographical location, climate, diet, toxins, sunlight) , genetics (variation of genes encoding HLA-DRBl, IL7R-alpha and IL2R-alpha) , and immunological components (viral infection such as by Epstein-Barr virus, high avidity CD4 + T cells, CD8 + T cells, anti-NF-L, anti-CSF 114 (Glc) ) .
  • CIS Certenically isolated syndrome
  • first clinical event and “first demyelinating event” suggestive of MS, which, for example, presents as an episode of optic neuritis, blurring of vision, diplopia, involuntary rapid eye movement, blindness, loss of balance, tremors, ataxia, vertigo, clumsiness of a limb, lack of co-ordination, weakness of one or more extremity, altered muscle tone, muscle stiffness, spasms, tingling, paraesthesia, burning sensations, muscle pains, facial pain, trigeminal neuralgia, stabbing sharp pains, burning tingling pain, slowing of speech, slurring of words, changes in rhythm of speech, dysphagia, fatigue, bladder problems (including urgency, frequency, incomplete emptying and incontinence) , bowel problems (including constipation and loss of bowel control) , impotence, diminished sexual arousal, loss of
  • Relapse Rate is the number of confirmed relapses per unit time.
  • Annualized relapse rate is the mean value of the number of confirmed relapses of each patient multiplied by 365 and divided by the number of days that patient is on the study drug.
  • “Expanded Disability Status Scale” or “EDSS” is a rating system that is frequently used for classifying and standardizing the condition of people with multiple sclerosis.
  • the score ranges from 0.0 representing a normal neurological exam to 10.0 representing death due to MS.
  • the score is based upon neurological testing and examination of functional systems (FS) , which are areas of the central nervous system which control bodily functions.
  • the functional systems are: Pyramidal (ability to walk), Cerebellar (coordination) , Brain stem (speech and swallowing) , Sensory (touch and pain) , Bowel and bladder functions, Visual, Mental, and Other (includes any other neurological findings due to MS) (Kurtzke JF, 1983) .
  • a “confirmed progression" of EDSS, or “confirmed disease progression” as measured by EDSS score is defined as a 1 point increase from baseline EDSS if baseline EDSS was between 0 and 5.0, or a 0.5 point increase if baseline EDSS was 5.5.
  • the change either 1 point or 0.5 points
  • the change must be sustained for at least 3 months.
  • confirmation of progression cannot be made during a relapse.
  • Adverse event or "AE” means any untoward medical occurrence in a clinical trial subject administered a medicinal product and which does not have a causal relationship with the treatment.
  • An adverse event can therefore be any unfavorable and unintended sign including an abnormal laboratory finding, symptom, or diseases temporally associated with the use of an investigational medicinal product, whether or not considered related to the investigational medicinal product.
  • Gd-enhancing lesion refers to lesions that result from a breakdown of the blood-brain barrier, which appear in contrast studies using gandolinium contrast agents. Gandolinium enhancement provides information as to the age of a lesion, as Gd-enhancing lesions typically occur within a six week period of lesion formation.
  • Magneticization Transfer Imaging or “MTI” is based on the magnetization interaction (through dipolar and/or chemical exchange) between bulk water protons and macromolecular protons. By applying an off resonance radio frequency pulse to the macromolecular protons, the saturation of these protons is then transferred to the bulk water protons. The result is a decrease in signal (the net magnetization of visible protons is reduced) , depending on the magnitude of MT between tissue macromolecules and bulk water.
  • MT or “Magnetization Transfer” refers to the transfer of longitudinal magnetization from the hydrogen nuclei of water that have restricted motion to the hydrogen nuclei of water that moves with many degrees of freedom. With MTI, the presence or absence of macromolecules (e.g. in membranes or brain tissue) can be seen (Mehta, 1996; Grossman, 1994) .
  • Magnetic resonance Resonance Spectroscopy is a specialized technique associated with magnetic resonance imaging (MRI) .
  • MRS Magnetic resonance imaging
  • the MR signal ⁇ produces a spectrum of resonances that correspond to different molecular arrangements of the isotope being “excited”. This signature is used to diagnose . ⁇ certain metabolic disorders, especially those affecting the brain, (Rosen, 2007) as well as to provide information on tumor metabolism (Golder, 2007) .
  • mobility refers to any ability relating to walking, walking speed, gait, strength of leg muscles, leg function and the ability to move with or without assistance. Mobility can be evaluated by one or more of several tests including but not limited to Ambulation Index, Time 25 foot walk, Six-Minute Walk (6MW) , Lower Extremity Manual Muscle Test (LEMMT) and EDSS. Mobility can also be reported by the subject, for example by questionnaires, including but not limited to 12- Item Multiple Sclerosis Walking Scale (MSWS-12) . Impaired Mobility refers to any impairment, difficulty or disability relating to mobility.
  • MSWS-12 12- Item Multiple Sclerosis Walking Scale
  • Tl-weighted MRI image refers to an MR-image that emphasizes Tl contrast by which lesions may be visualized. Abnormal areas in a Tl-weighted MRI image are "hypointense” and appear as dark spots. These spots are generally older lesions.
  • T2-weighted MRI image refers to an MR-image that emphasizes T2 contrast by which lesions may be visualized. T2 lesions represent new inflammatory activity .
  • the "Six-Minute Walk (6MW) Test” is a commonly used test developed to assess exercise capacity in patients with COPD (Guyatt, 1985) . It has been used also to measure mobility in multiple sclerosis patients (Clinical Trials Website) .
  • the "Timed-25 Foot Walk” or “T25-FW” is a quantitative mobility and leg function performance test based on a timed 25-walk. The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the patient has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. Patients may use assistive devices when doing this task.
  • the score for the T25-FW is the average of the two completed trials. This score can be used individually or used as part of the MSFC composite score (National MS Society Website) .
  • Fatigue can be measured by several tests including but not limited to decrease of French valid versions of the Fatigue Impact Scale (EMIF-SEP) score, and European Quality of Life (EuroQoL) Questionnaire (EQ5D) .
  • Other tests including but not limited to Clinician Global Impression of Change (CGIC) and Subject Global Impression (SGI), as well as EQ-5D, can be used to evaluate the general health status and quality of life of MS patients .
  • “Ambulation Index” or , ⁇ " is a rating scale developed by Hauser et al. to assess mobility by evaluating the time and degree of assistance required to walk 25 feet. Scores range from 0 (asymptomatic and fully active) to 10 (bedridden) . The patient is asked to walk a marked 25-foot course as quickly and safely as possible. The examiner records the time and type of assistance (e.g., cane, walker, crutches) needed. (Hauser, 1983) .
  • EQ-5D is a standardized questionnaire instrument for use as a measure of health outcome applicable to a range of health conditions and treatments. It provides a simple descriptive profile and a single index value for health status that can be used in the clinical and economic evaluation of health care as well as population health surveys.
  • EQ-5D was developed by the "EuroQoL” Group which comprises a network of international, multilingual, multidisciplinary researchers, originally from seven centers in England, Finland, the Netherlands, Norway and Sweden. The EQ-5D questionnaire is in the public domain and can be obtained from EuroQoL.
  • SF-36 is a multi-purpose, short-form health survey with 36 questions which yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preference-based health utility index. It is a generic measure, as opposed to one that targets a specific age, disease, or treatment group.
  • the survey is developed by and can be obtained from QualityMetric, Inc. of Buffalo, RI .
  • the compounds used in the method of the present invention may be in a salt form.
  • a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds.
  • the salt is pharmaceutically acceptable.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols.
  • the salts can be made using an organic or inorganic acid.
  • Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium.
  • pharmaceutically acceptable salt in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • Representative salts include the hydrobromide , hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate , and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19) .
  • amino acid residue refers to an amino acid molecule that has lost an “OH” or "H” by becoming covalently bonded to
  • laquinimod residue refers to a laquinimod molecule that has lost an "H” by becoming covalently bonded to another molecule.
  • An example of a laquinimod residue is shown below:
  • fingolimod residue refers ' to a fingolimod molecule that has lost an "H” by becoming covalently bonded to another molecule.
  • Example of fingolimod residues are shown below:
  • cilomilast residue refers to a fingolimod molecule that has lost an "OH” or "H” by becoming covalently bonded to another molecule. Examples of cilomilast residues are shown below:
  • D-glucose residue refers to a D-glucose molecule that has lost an "OH” or "H” by becoming covalently bonded to another molecule.
  • An example of a D-glucose residue is shown below:
  • chemical linker is any organic moiety that links a compound with another compound or drug.
  • the chemical linker can both react with groups on the other compound or drug to link the structures together. It is known in the art how to prepare suitable linkers with suitable groups and react linkers with groups to be linked, as well as to functionalize both the linkers and groups to be linked to cause the desired linkage to occur.
  • the chemical linker may be cleavable non- cleavable or releasable linker.
  • the cleavable linker of the conjugate can be cleaved from the compound by, for example, enzymatic cleavage in vivo, to release the compound of the present invention.
  • the ADC may bind to a cell and become internalized prior to the drug being enzymatically released from the antibody to become activated inside the cell.
  • the chemical linker include, but are not limited to, alkyl linkers, aminoalkyl linkers, terephthalate linkers, peptide linkers, self- immolative linkers, disulfide linkers, thioether linkers, hydrazine linkers, maleimide linkers, hydrophilic linkers or other linkers that are generally known in the art.
  • the chemical linker may also link the compound with a drug.
  • cleaveable linker is intended to mean a moiety that is unstable in vivo.
  • the linker allows for activation of the therapeutic agent by cleaving the agent from the rest of the conjugate.
  • the linker may be cleaved in vivo by the biological environment.
  • the cleavage may come from any process without limitation, e.g., enzymatic, reductive, pH, etc.
  • the cleaveable group may be selected so that activation occurs at the desired site of action, which can be a site in or near the target cells or organs.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci-C n as in “Ci-C n alkyl” is defined to include groups having 1, 2 , n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on.
  • An embodiment can be C1-C20 alkyl, C2-C20 alkyl, C3-C20 alkyl, C4- C20 alkyl and so on.
  • An embodiment can be C1-C30 alkyl, C2-C30 alkyl, C3- C30 alkyl, C4-C30 alkyl and so on.
  • Alkoxy represents an alkyl group as described above attached through an oxygen bridge.
  • Hydroalkyl includes an alkyl where at least one hydrogen is replaced with an -OH.
  • Aminoyalkyl includes an alkyl where at least one hydrogen is replaced with a primary, secondary or tertiary amine or an secondary or tertiary amine is contained within the alkyl chain.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present.
  • C2-C n alkenyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C2-C6 alkenyl means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon- carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a Ce alkenyl, respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl . As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is .indicated.
  • An embodiment can be C2-C12 alkenyl, C3-C 12 alkenyl, C2-C20 alkenyl, C3-C20 alkenyl, C2-C30 alkenyl, or C3-C30 alkenyl.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present.
  • C2 ⁇ C n alkynyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C2-C6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds.
  • Alkynyl groups include ethynyl, propynyl and butynyl.
  • the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • An embodiment can be a C2 ⁇ C n alkynyl .
  • An embodiment can be C2-C12 alkynyl or C3-C12 alkynyl, C2-C20 alkynyl, C3-C20 alkynyl, C2- C30 alkynyl, or C3-C30 alkynyl.
  • heteroalkyl includes both branched and straight-chain saturated aliphatic hydrocarbon groups having at least 1 heteroatom within the chain or branch.
  • cycloalkyl includes cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl) .
  • heterocycloalkyl is intended to mean a 5- to 10- membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of 0, N and S, and includes bicyclic groups.
  • Heterocycl includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl , morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl , tetrahydrothiophenyl , 4- mehtylpiperazinyl and the like.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydro-naphthyl , indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • the substituted aryls included in this invention include substitution at any suitable position with amines, substituted amines, alkylamines, hydroxys and alkylhydroxys , wherein the "alkyl" portion of the alkylamines and alkylhydroxys is a C2-C n alkyl as defined hereinabove.
  • the substituted amines may be substituted with alkyl, alkenyl, alkynl, or aryl groups as hereinabove defined.
  • alkylaryl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an "alkylaryl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group.
  • arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl ) , p-trifluoromethylbenzyl ( 4-trifluoromethyl- phenylmethyl) , 1-phenylethyl , 2-phenylethyl , 3-phenylpropyl, 2- phenylpropyl and the like.
  • heteroaryl represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Bicyclic aromatic heteroaryl groups include but are not limited to phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6- membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from 0, N or S .
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl , benzoxazolyl , carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl , isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • the alkyl, alkenyl, alkynyl, and aryl substituents may be unsubstituted or unsubstituted, unless specifically defined otherwise.
  • a (C 1 -C6) alkyl may be substituted with one or more substituents selected from OH, oxo, halogen, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl, piperidinyl, and so on.
  • alkyl, alkenyl, and alkynyl groups can be further substituted by replacing one or more hydrogen atoms by non-hydrogen groups described herein to the extent possible. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl .
  • substituted means that a given structure has a substituent which can be an alkyl, alkenyl, or aryl group as defined above.
  • the term shall be deemed to include multiple degrees of substitution by a named substitutent .
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • substituent groups include the functional groups described above, and halogens (i.e., F, CI, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n- propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4- trifluoromethylphenylmethoxy) ; heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p- toluenesulfonyl ; nitro, nitrosyl; mercapto; sulfany
  • substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • the substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, heteroalkyl, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl .
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the compounds used in the method of the present invention may be prepared by techniques described in Vogel's Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G.
  • Nl-Boc-Nl-methylethylenediamine (87 mg, 0.5 mmol), 10 (207 mg, 0.5 mmol), EDCI (197 mg, 1.0 mml) and HOBT (135 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) at ambient temperature, and to the solution was added triethylamine (202 mg, 2.0 mmol) . The mixture was stirred overnight at ambient temperature after which it was washed with water (5 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor.
  • 2-Amino-2- ( 4-octylphenethyl) propane-1 , 3-diol (172 mg, 0.5 mmol), 10 (207 mg, 0.5 mmol), EDCI (197 mg, 1.0) and HOBT(135 mg, 1.0 mmol) were dissolved in dichloromethane (20 mL) at ambient temperature.
  • Triethylamine (202 mg, 2.0 mmol) was added, and the mixture was stirred overnight. It was then washed with water (10 mL) , dried with sodium sulfate, and concentrated to dryness on rotavapor.
  • the crude compound (3 g) was dissolved in DCM (15 mL) , TFA (15 mL) was added and the mixture was stirred for 1 h at room temperature, sodium bicarbonate (10%) aqueous solution was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with DCM (15 mL x 2) and the organic phase combined, dried, concentrated and purified by flash chromatography to give the corresponding primary amine (700 mg, 56 % yield for two steps) .
  • Chloromethyl chloroformate (512 mg, 4 mmol) was added to a mixture of Et 3 N (808 mg, 8 mmol) in 5 mL MeOH at 0°C.The mixture was stirred at RT for lh. after which time it was concentrated to afford the chloromethyl methyl carbonate (400 mg, 81 % yield) as colorless oil.
  • a mixture of Laq. 180 mg, 0.5 mmol
  • chloromethyl methyl carbonate 124 mg, 1 mmol
  • CS 2 CO3 326 mg, 1 mmol
  • chloromethyl carbonochloridate (256 mg, 2 mmol) was added drop wise into a mixture of dimethylamine (in 2-Methyl-THF, lmL) and Et3N (202 mg, 2mmol) in THF (5 mL) at 0°C and the resulting mixture was stirred at RT for 2 hours after which the mixture was diluted with EtOAc and washed twice with water. The organic phase was separated, dried (Na2SOi) , filtered, and concentrated to give a residue (200 mg, 73 % yield) which was stirred (137 mg, 1 mmol) with Laq.
  • the dichloromethane layer was washed with water (3 x 20 mL) , dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was treated with ether (5 mL) to give Boc protected 55 (0.3 g, yield 36%) as a white solid which was stirred (0.2 g, 0.33 mmol) in trifluoroacetic acid (3 mL) and dichloromethane (5 mL) for 3 hours at rt., and then concentrated to dryness to leave a residue which was dissolved in dichloromethane (60 mL) and the solution washed with saturated aqueous NaHCC ⁇ solution and then dried, filtered and concentrated to give 55 (145 mg, 87% yield) as a white solid.
  • Nicotinic acid (2.46 g, 20 mmol) , NaHC0 3 (3.16 g, 40 mmol) and BuNCl (0.1 g) were stirred in water (50 mL) and dichloromethane (50 mL) .
  • the mixture was stirred at ambient temperature, and a solution of chloromethyl sulfochloridate (4.95 g, 30 mmol) in dichloromethane (20 mL) was added drop wise and stirred for 2 hours.
  • Nl-methylethane-l , 2-diamine (1.48g, 20 mmol) was dissolved in acetonitrile (50 ml) at ambient temperature.
  • Boc anhydride (2.18g, 10 mmol) and triethylamine (2.02 g, 20 mmol) were added to the mixture which was stirred for 3 hours and then concentrated to dryness on a rotavapor.
  • N-Boc 66 (0.4 g, 63%) as a white solid of which 200 mg (0.25 mmol) were dissolved in DCM (6 mL) and trifluoroacetic acid (3 mL) was added and the mixture was stirred for 2 hours and then concentrated to dryness under vacuum. The residue was treated with ether (10 mL) to give 66 (140 mg, 86%,) as a white solid.
  • Nl , N2-dimethylethane-l , 2-diamine (4.4 g, 50 mmol) and Et 3 N (12 g, 119 mmol) in DCM (100 mL) was added Boc 2 0 (12 g, 55 mmol) drop-wise at 0°C and the mixture was stirred at RT for 12h. and then water (50 mL) were added and the mixture was extracted with DCM (50 mL x 3) .
  • N-Boc 68 (0.4 g, 48 % yield) as a white solid (0.7 mmol) which was dissolved in TFA (2 mL) and DCM (8 mL) and the mixture was stirred at RT for 30 min.
  • EAE Experimental Autoimmune Encephalomyelitis
  • prodrugs were adjusted to ⁇ 5 mg/kg laquinimod dose equivalent based on AUCs of free laquinimod (released from prodrug, see Table 1) exposure :
  • mice of the C57BL/6 strain were obtained from Harlan Animal Breeding Center, Jerusalem, Israel. The body weights of the animals were recorded on the day of delivery. The animals weighed 17-20 g on arrival, and were approximately 9 weeks of age. The mice were allocated to the following treatment groups (15 mice/group, see Table 2) :
  • Plasma stability of 54 and 69 was evaluated in the presence of mouse, rat, dog, monkey and human plasma. Compounds (2 ⁇ ) were incubated in presence of plasma in duplicates for 0, 5, 15, 30, 45 and 60 min at 37 °C. Procaine and Benfluorex were used as reference compounds. Results are summarized in Table 5.
  • Example 5 Pharmacokinetics of prodrug compounds and parent drug in plasma following IV or oral administration of prodrug compounds to male SD rats
  • PK parameters are summarized in Tables 7, 8, 9 and 10 for 53, 5, 69 and 54, respectively.
  • the PK profiles of prodrug and parent drug following a single PO administration of 53, 5, 69 and 54 to rats are presented in Figures 1 to 4, respectively.
  • the PK parameters of the prodrugs and parent drug showed oral bioavailability of the prodrugs (F between 3.18 to 25.8%) with a rapid prodrug to parent drug conversion following administration of the prodrugs to rats.
  • the compound therapy provides a clinically meaningful advantage and is more effective in treating the patient than when laquinimod is administered (at the same dose) in the following manners:
  • the compound is more effective in reducing the decrease in brain volume (determined by the percent brain volume change (PBVC)), in multiple sclerosis patients;
  • the compound is more effective in increasing the time to confirmed disease progression (CDP) , in multiple sclerosis patients, where CDP is defined as a sustained increase in EDSS of >1 point from Baseline for at least 3 months. Progression cannot be confirmed during a relapse;
  • the compound is more effective in reducing abnormalities observed in whole Brain MTR histogram, in multiple sclerosis patients during;
  • the compound is more effective in reducing the number of confirmed relapses and therefore the relapse rate, in multiple sclerosis patients ;
  • the compound is also more effective in reducing the accumulation of physical disability in multiple sclerosis patients, as measured by the time to confirmed progression of EDSS;
  • the compound is more effective in reducing MRI-monitored disease activity in multiple sclerosis patients, as measured by the cumulative number of Tl Gd-enhancing lesions on Tl-weighted images, the cumulative number new Tl hypointense lesions, the cumulative number of new T2 lesions, the cumulative number of new Tl hypointense lesions on Tl-weight images (black holes) , the number of active (new T2 or GdE-Tl) lesions, presence or absence of GdE lesions, change in total volume of Tl Gd-enhancing lesions, change in total volume of T2 lesions, and/or cortical thickness;
  • the compound is more effective in reducing brain atrophy in multiple sclerosis patients
  • the compound is more effective in reducing the frequency of relapses, the frequency of clinical exacerbation, and the risk for confirmed progression in multiple sclerosis patients;
  • the compound is more effective in increasing the time to confirmed relapse in multiple sclerosis patients; 10.
  • the compound is more effective in improving the general health status (as assessed by the EuroQoL (EQ5D) questionnaire) , symptom severity on work (as assessed by the work productivity and activities impairment General Health (WPAI-GH) questionnaire) and quality of life, in multiple sclerosis patients; and/or
  • the compound is more effective in decreasing cerebral dysfunction/cognitive impairment (as assessed by Symbol Digit Modalities Test (SDMT) ) , in multiple sclerosis patients during the double blind study period.
  • SDMT Symbol Digit Modalities Test
  • compounds 5, 53, 54 or 69 are converted to laquinimod in vivo.
  • the analogues of 5, 53, 54 or 69 contained herein are also converted to laquinimod in vivo and act as prodrugs of laquinimod.
  • An amount of any one of the analogues of 5, 53, 54 or 69 contained herein is administered to a subject afflicted with multiple sclerosis. The amount of the compound is effective to treat the subj ect .
  • Disclosed herein is a method for treating a subject, e.g., a human patient, afflicted with multiple sclerosis, e.g., relapsing multiple sclerosis or presenting a CIS, using the compound of the present invention which provides a more efficacious treatment than laquinimod.
  • a subject e.g., a human patient
  • multiple sclerosis e.g., relapsing multiple sclerosis or presenting a CIS
  • the compound of the present invention which provides a more efficacious treatment than laquinimod.
  • laquinimod for multiple sclerosis had been previously suggested in, e.g., U.S. Patent No. 6,077,851.
  • the prodrugs contained herein are particularly effective for the treatment of a subject afflicted with MS or presenting a CIS as compared to laquinimod.

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Abstract

L'invention concerne un composé ou un sel pharmaceutiquement acceptable ou ester de celui-ci. L'invention concerne également une composition pharmaceutique comprenant le composé selon l'invention et un véhicule pharmaceutiquement acceptable. Une méthode destinée à traiter un sujet atteint de sclérose en plaques comprenant l'administration audit sujet d'une quantité du composé selon l'invention est en outre décrite.
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WO2023178107A3 (fr) * 2022-03-14 2023-11-02 The Research Foundation For The State University Of New York Protéines réticulées de manière orthogonale, leurs méthodes de production et leurs utilisations
EP4153576A4 (fr) * 2020-05-21 2024-06-19 Stemsynergy Therapeutics Inc Inhibiteurs de notch et leurs utilisations

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* Cited by examiner, † Cited by third party
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US11478465B2 (en) 2019-12-19 2022-10-25 Active Biotech Ab Compounds for treatment of eye diseases associated with excessive vascularisation
EP4153576A4 (fr) * 2020-05-21 2024-06-19 Stemsynergy Therapeutics Inc Inhibiteurs de notch et leurs utilisations
WO2023178107A3 (fr) * 2022-03-14 2023-11-02 The Research Foundation For The State University Of New York Protéines réticulées de manière orthogonale, leurs méthodes de production et leurs utilisations

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