WO2005042529A1 - Improved aza-bridged-bicyclic amino acid derivatives as a4 integrin antagonists - Google Patents
Improved aza-bridged-bicyclic amino acid derivatives as a4 integrin antagonists Download PDFInfo
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- WO2005042529A1 WO2005042529A1 PCT/US2004/036011 US2004036011W WO2005042529A1 WO 2005042529 A1 WO2005042529 A1 WO 2005042529A1 US 2004036011 W US2004036011 W US 2004036011W WO 2005042529 A1 WO2005042529 A1 WO 2005042529A1
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- 0 C*C(*)(*(*)C(C(C1)(C2)CS3*C2*C1C3)=O)C(*)=O Chemical compound C*C(*)(*(*)C(C(C1)(C2)CS3*C2*C1C3)=O)C(*)=O 0.000 description 1
- KSWZLBYCGSMVQV-UHFFFAOYSA-N CC(C)(C)Oc1ccc(CC(C(O)=O)NC(C(CC(C2)O)N2S(c2cccc(F)c2)(=O)=O)=O)cc1 Chemical compound CC(C)(C)Oc1ccc(CC(C(O)=O)NC(C(CC(C2)O)N2S(c2cccc(F)c2)(=O)=O)=O)cc1 KSWZLBYCGSMVQV-UHFFFAOYSA-N 0.000 description 1
- DIKHEYGUGRFKFS-UHFFFAOYSA-N CC(C)CC(C(O)=O)NC(C(Cc1ccccc1C1)N1S(c(cc1OC)ccc1OC)(=O)=O)=O Chemical compound CC(C)CC(C(O)=O)NC(C(Cc1ccccc1C1)N1S(c(cc1OC)ccc1OC)(=O)=O)=O DIKHEYGUGRFKFS-UHFFFAOYSA-N 0.000 description 1
- GMAHSZHZSFQFSN-UHFFFAOYSA-N COC(C(Cc(cc1)ccc1OC(N1CCOCC1)=O)NC(C1NC2CCC1CC2)=O)=O Chemical compound COC(C(Cc(cc1)ccc1OC(N1CCOCC1)=O)NC(C1NC2CCC1CC2)=O)=O GMAHSZHZSFQFSN-UHFFFAOYSA-N 0.000 description 1
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- C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
Definitions
- This invention relates to novel compounds and methods for use in treating integrin mediated disorders. More particularly, this invention relates to novel derivatives of aza-bridged-bicyclic amino acid compounds useful as ⁇ 4 integrin receptor antagonists, methods for treating integrin mediated disorders including, but not limited to, inflammatory, autoimmune and cell-proliferative disorders, methods for preparing the compounds and methods for preparing the intermediates, derivatives and pharmaceutical compositions thereof.
- Integrin receptors are transmembrane, non-covalently linked heterodimers consisting of one ⁇ -chain and one ⁇ -chain. In addition to performing a structural adhesive function, integrin receptors transmit extracellular signals across the plasma membrane.
- the integrin receptor a (also referred to as VLA-4) mediates cell adhesion by binding with either of two protein ligands: vascular cell adhesion molecule-1 (VCAM-1 ) (Osborn, L; et al., Cell, 1989, 59, 1203), or the alternatively-spliced fibronectin variant containing the type III connecting segment (CS-1) (Wayner, E. A.; et al., Cell Biol., 1989, 109, 1321 ).
- VCAM-1 vascular cell adhesion molecule-1
- CS-1 type III connecting segment
- o ⁇ i binds to other primary protein sequences.
- the o ⁇ i integrin receptor recognizes Gln-lle-Asp-Ser (QIDS) in VCAM-1 and lle-Leu-Asp-Val (ILDV) in fibronectin.
- QIDS Gln-lle-Asp-Ser
- ILDV lle-Leu-Asp-Val
- osteopontin ligand interaction with the ⁇ 4 ⁇ receptor may be very important as osteopontin is strongly up-regulated in inflammatory settings, including the inflamed lung.
- the 4 ⁇ integrin receptor is expressed at high levels on mast cells, mononuclear leukocytes, eosinophils, macrophages, and basophils (Adams, S. P.; et al., Ann. Rep. Med. Chem., 1999, 34, 179).
- the binding of 4 ⁇ to cytokine-induced VCAM-1 on high-endothelial venules at sites of inflammation results in leukocyte/endothelium adhesion followed by extravasation into the inflamed tissue (Chuluyan, H. E.; et al., Springer Semin. Immunopathol., 1995, 16, 391).
- the role of mast cells and eosinophils in lung inflammation is well-established.
- VCAM-1 expression on airway endothelial cells seems to play a central role in lung inflammation.
- the ⁇ 4 ⁇ 1 receptor interaction with VCAM-1 also exerts an important effect in stem cell adhesion to bone marrow stromal cells (Simmons, P. J.; et al., Blood, 1992, 80, 388).
- the ⁇ ⁇ 7 integrin is expressed at high levels on lymphocytes and T cells.
- the trafficking of lymphocytes from the vasculature to normal mucosa and lymphoid tissues is mediated by adhesion of mucosal addressing cell adhesion molecule- 1 (MAdCAM-1) with the integrin receptor ⁇ 4 ⁇ 7 .
- MAdCAM-1 mucosal addressing cell adhesion molecule- 1
- MAdCAM-1 an immunoglobulin superfamily adhesion molecule, specifically binds ⁇ 4 ⁇ 7-expressing lymphocytes and participates in the homing of these cells to the mucosal endothelium.
- LDT-based peptides bind to r $7 in a MAdCAM-1/RPMI-8866 cell adhesion assay with IC 50 values in the 1-10 uM range (Shroff, H. N.; et al., Bioorg. Med. Chem. Lett., 1998, 8,
- integrins in general and compelling data for the pathophysiological role of the leukocyte cell adhesion receptor ⁇ 4 ⁇ 1 have spurred interest in the study of ⁇ 4 ⁇ 1 antagonists in vivo.
- the integrin ⁇ 4 ⁇ 1 provides a key co-stimulatory signal supporting cell activation leading to growth factor and cytokine production and mediator release.
- ⁇ 4 ⁇ 1 increases the survival of activated cells by inhibiting apoptosis (Yoshikawa, H.; et al., J. Immunol., 1996, 156, 1832).
- Monoclonal antibodies directed against ⁇ 4 ⁇ 1 or VCAM-1 have been shown to be effective modulators in animal models of chronic inflammatory diseases such as asthma (Laberge, S.; et al., Am. J. Respir. Crit. Care Med., 1995, 151, 822), rheumatoid arthritis (Barbadillo, C; et al., Springer
- BIO-1211 inhibits eosinophilia and airway hyperresponsiveness (Lin, K-C; et al., J. Med. Chem. 1999, 42, 920).
- Pre-treatment of allergic sheep with a 3 mg nebulized dose of BIO-1211 (having an ⁇ 4 ⁇ 1 IC 50 value of 1 nM; 1000- fold selective over ⁇ 4 ⁇ 7) inhibited early and late airway responses following antigen challenge and prevented development of nonspecific airway hyperresponsiveness to carbachol.
- VLA-4 antagonism may also be effective in reducing restenosis following percutaneous coronary interventions.
- Administration of an anti- ⁇ 4 antibody attenuated smooth muscle cell migration associated with electrical injury of rabbit carotid arteries Kerr D, Fingerle J, Harlan JM, Lobb, RR and Lang, F, Mononuclear leukocytes invade rabbit arterial intima during thickening formation via CD-18 and VLA-4-dependent mechanisms and stimulate smooth muscle migration, Circ.
- VCAM-1 expression has been reported on endothelial cells in atherosclerotic lesions in humans (O'Brien KD, Allen MD, McDonald TO, Chait A, Harlan JM, Fishbein D, McCarty J, Ferguson M, Hudkins K, Benjamin CD, et al., Vascular cell adhesion molecule-1 is expressed in human atherosclerotic plaques: implications for the mode of progression of advanced atherosclerosis, J.
- mice Nakahima Y, Raines EW, Plump AS, Breslow JL and Ross R, Upregulation of VCAM-1 and ICAM-1 at atherosclerotic-prone sites on the endothelium of ApoE-deficient mouse, Arterioscler. Thromb. Vase. Biol., 1998, 18, 842-851) and rabbits (llyama K, Hajra L, liyam M, Li,H, DiChura M, Medoff BD and Cybulsky Ml, Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesion and at sites predisposed to lesion formation, Circ.
- a synthetic peptidomimetic of the connecting segment-1 (CS- 1 ) which blocks ⁇ 4 ⁇ on the leukocyte demonstrated reduced leukocyte homing and lipid accumulation in the aortic sinus in both wild type mice and mice with a low density lipoprotein null mutation (LDLR -/-) maintained on a high fat diet (Shih PT, Brennan M-L, Vora DK, Territo MC, Strahl D, Elices
- Antibodies to MAdCAM-1 or integrin ⁇ 4 ⁇ 7 inhibit lymphocyte binding to affinity-purified MAdCAM-1 or MAdCAM-1 transfectants in vitro (Hamann, A.; et al., J. Immunol. 1994, 152, 3282).
- the antibodies also block localization of lymphocytes to Peyer's patches.
- Murine MAdCAM-1 recognizes only ⁇ 4 ⁇ 7 positive human lymphocyte cells lines and 4 ⁇ 7-high memory T cells.
- An in vivo role of ⁇ 4 ⁇ 7 in inflammation has been suggested by increased expression of MAdCAM-1 on HEV-type vessels in the chronically inflamed pancreas of the non-obese mouse (Hanninen, A.C.; et al., J. Clin. Invest.
- R 1 is alkyl, alkenyl, alkynyl, C y , C y -alkyl, C y -alkenyl or C y -alkynyl; wherein alkyl, alkenyl and alkynyl are optionally substituted with R a ; and C y is optionally substituted with R b ;
- R 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl; wherein alkyl, alkenyl and alkynyl are optionally substituted with R a ; and aryl and heteroaryl are optionally substituted with R b ;
- R 3 is hydrogen, alkyl, C y or C y -alkyl; wherein alkyl is optionally substituted with R a ; and C y is optionally substituted with R b ;
- R 4 is hydrogen, alkyl, alken
- R d and R e are independently selected from hydrogen, alkyl, alkenyl, alkynyl, C y and C y -alkyl; wherein alkyl, alkenyl, alkynyl and C y are optionally substituted with R c ; or, R d and R e together with the atoms to which they are attached form a heterocyclic ring of 5-7 members containing 0-2 additional heteroatoms independently selected from N, O and S; R f and
- R 9 are independently selected from hydrogen, alkyl, C y and C y -alkyl; wherein C y is optionally substituted with alkyl; or, R f and R 9 together with the carbon to which they are attached form a ring of 5-7 members containing 0-2 heteroatoms independently selected from N, O and S;
- R h is hydrogen, alkyl, alkenyl, alkynyl, cyano, aryl, aralkyl, heteroaryl, heteroaralkyl or -S0 2 R'; wherein alkyl, alkenyl and alkynyl are optionally substituted with R a ; and aryl and heteroaryl are optionally substituted with R b ;
- R' is alkyl, alkenyl, alkynyl or aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with R c ;
- R k is -OR d ,
- R f R 9 n C(0)N R d R e , -OC(0)R d , CN, C(0)NR d R e , -NR d C(0)R e , -OC(0)NR d R e , -NR d C(0)OR e , -NR d C(0)NR d R e , -CR d (N-OR e ), -CF 3 , oxo, -NR d C(0)NR d S0 2 R i , -NR d S(0) m R e , -OS(O 2 )OR d or -OP(0)(OR d ) 2 ;
- R y is a group selected from R k , alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with
- ring A is a multicyclic bridged cycloalkyl, multicyclic bridged cycloalkenyl or multicyclic bridged heterocyclic group provided the multicyclic bridged heterocyclic group does not contain a lactam and further wherein said multicyclic bridged cycloalkyl, multicyclic bridged cycloalkenyl or multicyclic bridged heterocyclic group is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxy
- R 1 is selected from the group consisting of: (a) -(CH 2 ) ⁇ -Ar- R 5 where R 5 is selected from the group consisting of -0-Z-NR 6 R 6 and -O-Z- R 7 wherein R 6 and R 6 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R 6 and R 6 are joined to form a heterocycle or a substituted heterocycle, R 7 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C(O)- and -SO 2 -, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4; (b) -(CH 2 ) ⁇ -Ar- R 5 where R 5 is selected from the group consisting of -0-Z-NR 6 R 6 and -O-Z-
- R b is selected from the group consisting of R a , C- M oalkyl, C 2 - ⁇ oalkenyl, C 2- ⁇ oalkynyl, aryl C-i.ioalkyl, heteroaryl, Ci-ioalkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from R c ; R c is selected from the group consisting of halogen, amino, carboxy, C 1 .
- R d and R e are independently selected from hydrogen, C ⁇ . 10 alkyl, C -ioalkenyl, C 2 - ⁇ oalkynyl, Cy and Cy-C ⁇ - ⁇ oalkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R c ; or R d and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; R f and R 9 are independently selected from hydrogen, C ⁇ - ⁇ 0 alkyl, Cy and Cy-C M oalkyl; or R a Rf and R a R9 together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2
- R 1 , R 2 and R 3 are as defined above;
- Y is selected from the group consisting of hydrogen, R d , Cy, -OR d , -N0 2 , halogen, -S(0) m R d , -SR d , - S(0) 2 OR d , -S(0) m NR d R e , -NR d R e , -0(CR f R g ) n NR d R e , -C(O)R d , -CH(OH)R d , -C0 2 R d , -C0 2 (CR f R 9 ) n CONR d R e , -OC(0)R d , -CN, C(0)NR d R e , NR d C(O)R e , -OC(0)NR d R e , -NR d C(0)OR e , -NR d C(0)NR
- aza- bridged-bicyclic compounds that are ⁇ 4 integrin receptor antagonists; more particularly, the ⁇ 4 ⁇ and the ⁇ ⁇ 7 integrin receptor. It is also an object of the present invention to provide a process for preparing derivatives of aza- bridged-bicyclic amino acid compounds, compositions, intermediates and derivatives thereof. It is a further object of the invention to provide methods for the treatment of integrin mediated disorders that are ameliorated by inhibition of the ⁇ 4 ⁇ and ⁇ 4 ⁇ 7 integrin receptor including, but not limited to, inflammatory, autoimmune and cell-proliferative disorders.
- Y is selected from the group consisting of hydrogen, -C(0)(CH2)o- 4 Ri8, -C(0)(CH 2 ) q NC(0)R ⁇ , -C( ⁇ CH 2 ) q SR ⁇ , -C(0)(CH 2 ) q SOR ⁇ ; and -C(0)(CH 2 ) q S0 2 R ⁇ ;
- q is an integer from 1 to 8;
- R is selected from the group consisting of hydrogen, R 7 and R 8 ;
- R , R 3 , and R 5 are independently selected from the group consisting of hydrogen and Ci- ⁇ alkyl; wherein C ⁇ -8 alkyl is optionally substituted with one to three substituents independently selected from OH, halogen, C ⁇ -8 alkoxy, carboxy, amino, ⁇ /-(C 1-8 alkyl)amino, N,N-(C- ⁇ .s dialkyl)amino, CF 3 , OCF 3 and R 9 ; provided that R 3 additionally may be a bond when forming a monocyclic ring;
- R is selected from the group consisting of hydrogen, C ⁇ - alkyl and N,N-C ⁇ - 4 glycolamide; wherein C ⁇ _ 4 alkyl is optionally substituted with one to three substituents independently selected from OH, halogen, C -8 alkoxy, carboxy, amino, ⁇ /-(C -8 alkyl)amino, ⁇ /,/V-(C 1-8 dialkyl)amino, CF 3 , OCF 3 and R g ; provided that R 4 additionally may be a bond when forming a monocyclic ring;
- R 3 , and R 4 may form a monocyclic ring; when R 3 and R comprise a bond and C ⁇ -8 alkyl or optionally when both R 3 and R 4 are C ⁇ -8 alkyl, R 3 and R 4 together with the atoms to which each is attached will form a five to seven membered monocyclic ring optionally containing one to two additional heteroatoms independently selected from the group consisting of N, O and S;
- RQ is optionally present and is one to three substituents independently selected from the group consisting of halogen, C ⁇ -8 alkoxy, R 10 , R1 2 , -N(Rn)C(0)-R ⁇ o, -N(R ⁇ )C(0)-R 12 , -N(Rn)S0 2 -R o.
- R 7 , Rg R 10 and R ⁇ are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, benzo-fused heterocyclyl and benzo-fused cycloalkyl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C ⁇ -8 alkyl, C 2 -8alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C ⁇ - 8 alkylcarbonyl, C ⁇ -8 alkoxycarbonyl, carboxyl, aryl, heteroaryl, aryloxy, heteroaryloxy, cycloalkyloxy, heterocycloxy, benzyloxy carbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, amino, /V-(C ⁇ -8 alkyl)amino, ⁇ /, ⁇ /-(C -8 dialkyl)amino, -CF 3 and -OCF 3
- Rs is selected from the group consisting of C h alky!, C 2-8 alkenyl, C 2- 8alkynyl, C . 8 alkoxy and (halo) ⁇ - 3 (C ⁇ . 8 )alkyl; wherein C ⁇ -8 alkyl, C 2 - 8 alkenyl, C 2 . 8 alkynyl and Ci-salkoxy are optionally substituted with one to three substituents independently selected from R ⁇ ;
- R ⁇ 2 , Ri 3 , R 17 and Rig are independently selected from the group consisting of C ⁇ -8 alkyl, C 2 - 8 alkenyl, C 2-8 alkynyl, and (halo) ⁇ -3 (C -8 )alkyl; wherein C ⁇ -8 alkyl, 0 2 -salkenyl and C 2 - 8 alkynyl are optionally substituted with one to three substituents independently selected from R ⁇ 4 ;
- R 11 is selected from the group consisting of hydrogen and C ⁇ -8 alkyl
- Ri 8 is selected from the group consisting of hydroxy, C ⁇ _ 8 alkoxy, C ⁇ -8 alkyloxy O ⁇ -8 alkyl, C ⁇ -8 alkoxycarbonylamino C ⁇ -8 alkyl, amino, amino C ⁇ -8 alkyl, C ⁇ - 8 alkyl amino C ⁇ -8 alkyl, diC ⁇ -8 alkylamino C ⁇ -8 alkyl, benzo-fused heterocyclyl, polycycloalkyl and hydroxy C ⁇ _ 8 alkyl; wherein the benzo-fused heterocyclyl is substituted with C(0)R i9 and C(0)OR ⁇ g;
- A is C ⁇ - alkylene optionally substituted with one to two substituents independently selected from R ⁇ 3 ;
- R 3 when R 3 is C ⁇ _ 8 alkyl, optionally A and R 3 together with the atoms to which each is attached may form a five to seven membered monocyclic ring optionally containing one to two additional heteroatoms independently selected from the group consisting of N, O and S;
- R 4 when R 4 is C ⁇ -8 alkyl, optionally A and R 4 together with the atoms which each is attached may form a five to seven membered monocyclic ring optionally containing one additional heteroatom selected from the group consisting of N, O and S;
- R 5 when R 5 is C ⁇ -8 alkyl, optionally A and R 5 together with the atoms which each is attached may form a three to seven membered monocyclic ring optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S; and,
- B and B 2 are independently selected from the group consisting of C ⁇ - 2 alkylene and C ⁇ alkenylene optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, hydroxy(C -8 )alkyl, hydroxy(C ⁇ - 8 )alkoxy, C ⁇ -8 alkyl, C 2 - 8 alkenyl, C 2 -salkynyl, C ⁇ - 8 alkoxy, carboxyl, amino, ⁇ /-(C ⁇ _ 8 alkyl)amino, ⁇ /,/V-(C ⁇ . 8 dialkyl)amino, -CF 3 and -OCF 3 ;
- An smbodiment of the present invention is directed to aza-bri ⁇ ged- bicyclic compounds having Formula (II):
- Y is selected from the group consisting of hydrogen, C(0)(CH2)o-4R ⁇ ,
- Ri is selected from the group consisting of hydrogen, R 7 and R 8 ;
- R 2 , R 3 , and R are independently selected from the group consisting of a bond, hydrogen and C ⁇ -8 alkyl; wherein C ⁇ -8 alkyl is optionally substituted with one to three substituents independently selected from R 9 ; provided that R 3 , can only be a bond when forming a monocylic ring
- R 4 is selected from the group consisting of hydrogen, and N,N-C ⁇ -4 glycolamide; wherein C ⁇ alkyl is optionally substituted with one to three substituents independently selected from OH, halogen, C ⁇ . 8 alkoxy, carboxy, amino, ⁇ /-(C ⁇ - 8 alkyl)amino, ⁇ /, ⁇ /-(C ⁇ -8 dialkyl)amino, CF 3 , OCF 3 and R g ; provided that R 4 additionally may be a bond when forming a monocyclic ring; wherein R3 and R 4 may form a monocyclic ring: when R 3 and R comprise a bond and C ⁇ -8 alkyl or optionally when both R 3 and R are C ⁇ . 8 alkyl, R 3 and R 4 together with the atoms to which each are attached form a five to seven membered monocyclic ring optionally containing one to two additional heteroatoms independently selected from the group consisting of N, O and S;
- Re is optionally present and is one to three substituents independently selected from the group consisting of halogen, Ci-salkoxy, R 10 , R 12 , -N(R ⁇ )C(0)-R ⁇ o, -N(Rii)C(0)-Ri 2 , -N(Rn)SO 2 -R 10) -N(Rn)SO 2 -R ⁇ 2 , -N(Rn)C(O)-N(Ri 1 ,R 10 ), ⁇ ( ⁇ 1)0(0) ⁇ ( ⁇ 2), -N(Rn)C(0)-N(Ri2,Ri7), -C(O)-N(R ⁇ ,R ⁇ 0- ), -C(0)-N(Rn,R ⁇ 2 ), -C(0)-N(R ⁇ 2 ,R ⁇ 7 ), -OC(0)-N(R ⁇ ,R ⁇ 2 ), -OC(0)-N(R ⁇ 2 ,R ⁇ 7 ), -OC(O)-R ⁇ 0 , -OC(0)-
- R Rg, R 10 and R ⁇ 4 are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl , benzo-fused heterocyclyl and benzo-fused cycloalkyl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C ⁇ -8 alkyl, 0 2 -salkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C ⁇ -8 aikylcarbonyl, C ⁇ -8 alkoxycarbonyl, carboxyl, aryl, heteroaryl, aryloxy, heteroaryloxy, cycloalkyloxy, heterocycloxy, benzyloxy carbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, amino, -(C ⁇ - 8 alkyl)amino, A/,/V-(C ⁇ - 8 dialkyl)amino, -CF 3 and -OC
- R12, R13, Ri7, and Ri are independently selected from the group consisting of d-salkyl, C 2-8 alkenyl, C 2 - 8 alkynyl and (halo) ⁇ . 3 (C ⁇ _ 8 )alkyl; wherein C ⁇ - 8 alkyl, C 2 - 8 alkenyl and C 2 . 8 alkynyl are optionally substituted with one to three substituents independently selected from R ⁇ 4 ;
- R 11 is selected from the group consisting of hydrogen and C ⁇ - 8 alkyl
- R s is selected from the group consisting of hydroxy, Ci-salkoxy, C ⁇ _ 8 alkyloxyCi-salkyl, C ⁇ - 8 alkylcarbonyl aminoC ⁇ -8 alkyl, amino, aminoC ⁇ . 8 alkyl, Ci-salkyl amino C ⁇ -8 alkyl, diC ⁇ - 8 alkylamino C -8 alkyl, benzo-fused heterocyclyl, polycycloalkyl and hydroxy C ⁇ -8 alkyl; wherein the benzo-fused heterocyclyl is substituted with C(0)R ⁇ g and C(0)OR ⁇ ⁇ .
- A is C ⁇ -2 alkylene optionally substituted with one to two substituents independently selected from R ⁇ 3 ; when R 3 is Gvaalkyl, optionally A and R 3 together with the atoms to which each is attached form a five to seven membered monocyclic ring optionally containing one to two additional heteroatoms independently selected from the group consisting of N, O and S; when R 4 is C ⁇ -8 alkyl, optionally A and R 4 together with the atoms to which each is attached form a five to seven membered monocyclic ring optionally containing one additional heteroatom selected from the group consisting of N, O and S;
- R5 is C ⁇ -8 alkyl
- a and R 3 together with the atoms to which each is attached form a three to seven membered monocyclic ring optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S;
- B is selected from the group consisting of C -2 alkylene and C2alkenylene optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, hydroxy(C -8 )alkyl, hydroxy(C ⁇ -8 )alkoxy, C - 8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C ⁇ -8 alkoxy, carboxyl, amino, ⁇ /-(C ⁇ -8 alkyl)amino, ⁇ /, ⁇ /-(C ⁇ - 8 dialkyl)amino, -CF 3 and -OCF 3 ; and,
- n is an integer from 1 to 2;
- An embodiment of the present invention is also directed to a process for preparing the instant aza-bridged-bicyclic compounds, compositions, intermediates and derivatives thereof.
- Another embodiment of the present invention is directed to pharmaceutical compositions comprising the compounds of the present invention.
- the aza-bridged-bicyclic amino acid derivatives of the pres ⁇ it- invention are useful ⁇ 4 integrin receptor antagonists and, more particularly, ⁇ 4 ⁇ and ⁇ 4 ⁇ 7 integrin receptor antagonists.
- a further embodiment of the present invention is directed to a method for the treatment of integrin mediated disorders that are ameliorated by inhibition of the cc 4 ⁇ and ⁇ 4 ⁇ 7 integrin receptor including, but not limited to, inflammatory, autoimmune and cell-proliferative disorders.
- the inflammatory, autoimmune and cell-proliferative disorders include, but are not limited to, inflammation and autoimmunity, asthma and bronchoconstriction, restenosis and atherosclerosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, transplant rejection and multiple sclerosis.
- the preferred embodiments of the aza-bridged-bicyclic compounds of the present invention include those compounds wherein the phenyl group of the phenylalanine amino acid is substituted on the para position with R 6 .
- Preferred embodiments of the instant compounds also include those aza-bridged-bicyclic compounds wherein Re is benzofused heterocyclyl, aryl, arylamido, heteroarylamido, ureido (wherein the terminal amino is dialkyl substituted), aminocarbonyloxy (wherein amino is dialkyl substituted) and aryl(C ⁇ - 8 )alkoxy.
- racemic mixtures have significant activity compared to the resolved diastereomers, the (S,S) diastereomers appear to generally have higher activity than the (R,S) diastereomers.
- the scope of the present invention is intended to encompass all racemic mixtures, enantiomers and diastereomers including, but not limited to, (R/S,S), (R/S,R), (S,R/S), (R,R/S), (S,S), (R,S), (S,R) and (R,R) diastereomers and enantiomers of the compounds of the present invention without limitation.
- Preferred embodiments are those aza-bridged-bicyclic compounds wherein Y is selected from the group consisting of hydrogen, C(0)(CH 2 )o- 4 R ⁇ s, -C(0)(CH 2 ) q NC(0)R ⁇ , -C(0)(CH 2 ) q SR ⁇ , -C(O)(CH 2 ) q S0R ⁇ ; and
- Y is selected from C(0)R ⁇ 8 , -C(O)(0H 2 ) q NC(O)R ⁇ , -C(0)(CH 2 ) q SR 1 , -C(0)(CH ) q SOR ⁇ ; and -C(0)(CH 2 ) q S0 2 R ⁇ wherein q is an integer from 1 to 2
- Y is -C(0)(CH 2 ) q SR ⁇ ,
- R 7 is preferably selected from the group consisting of aryl, heteroaryl, benzo-fused heterocyclyl and benzo-fused cycloalkyl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C ⁇ . 8 alkyl, C 2 . 8 alkenyl, C 2 - 8 alkynyl,
- R 7 is selected from the group consisting of benzo-fused heterocyclyl (e.g. methylenedioxyphenyl), tolyl, phenyl and thienyl.
- Preferred embodiments include those compounds wherein R 2 , R 3 , and R 5 are independently selected from the group consisting of hydrogen and Ci. 4 alkyl. More preferably, R 2 , R3, and R 5 are independently selected from the group consisting of hydrogen and methyl.
- Preferred embodiments of the present invention include compounds wherein R 4 is selected from the group consisting of hydrogen and C ⁇ - 4 alkyl. More preferably, R 4 is independently selected from the group consisting of hydrogen and methyl.
- Preferred embodiments include those compounds wherein R 6 is optionally present and is one to three substituents independently selected from the group consisting of halogen, C ⁇ -8 alkoxy, R 10 , R ⁇ 2 , -N(Rn)C(0)-R ⁇ o, -N(R ⁇ )C(0)-R 12l -N(R ⁇ )S0 2 -R ⁇ o, -N(Rn)C(0)-N(Rn,Ri 2 ), -N(R ⁇ )C(0)-N(Ri2,R ⁇ 7 ), -O0(O)-N(Rn,R ⁇ 2 ), -OC(0)-N(R ⁇ 2 ,R ⁇ 7 ), -OC(O)-R 10 and R ⁇ o-(C -8 )alkoxy.
- R 6 is optionally present and is one to three substituents independently selected from the group consisting of halogen, C ⁇ -4 alkoxy, R 10 , R12, -N(Rn)C(O)-R ⁇ 0 , -N(Rn)C(0)-R ⁇ 2 , -N(R ⁇ )S0 2 -R ⁇ o, -N(Rn)C(0)-N(Rii,Ri 2 ), -N(Rn)C(0)-N(R ⁇ 2 ,Ri7), -OC(0)-N(Rn,R ⁇ 2 ), -OC(0)-N(Ri2,R ⁇ 7 ), -OC(O)-R ⁇ 0 and R 0 -(C ⁇ - 4 )alkoxy.
- Re is one substituent selected from the group consisting of R 10 , -N(R ⁇ )C(O)-R 10 , -N(Rn)C(0)-N(R ⁇ ,R ⁇ 2 ), -N(Rn)C(0)-N(R 12 ,Ri 7 ), • ' OC(0)-N(R ⁇ ,R ⁇ 2 ), -00(0)-N(Ri 2 ,R ⁇ 7 ), -OC(0)-Rfo and R 10 -methoxy.
- R 6 attachment is at the 4 positoin of the phenyl ring of the scaffold.
- R 6 will be -N(Rn)C(0)-R ⁇ o preferably wherein Rn is hydrogen and R 10 is heteroaryl.
- R 8 is selected from the group consisting of dialkyl, C 2- -.alkenyl, C 2-4 alkynyl, C ⁇ -4 alkoxy and (halo) ⁇ _ 3 (C ⁇ -4 )alkyl; wherein C 2-4 alkenyl, C 2- alkynyl and C ⁇ -8 alkoxy are optionally substituted with one to three substituents independently selected from R ⁇ 4 ;
- Preferred embodiments include those compounds wherein R 10 , is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C ⁇ -8 alkyl, C ⁇ -8 alkoxy, C ⁇ -8 alkoxycarbonyl, carboxyl, arylcarbonyl, arylsulfonyl, -CF 3 and -OCF 3 ; wherein cycloalkyl and heterocyclyl are optionally substituted with one to three oxo substituents; and, wherein the aryl portion of the arylcarbonyl substituent is optionally substituted with one to five substituents independently selected from C ⁇ -8 alkoxy.
- R 10 is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C ⁇ - alkyl, C ⁇ - alkoxy, C ⁇ -4 alkoxycarbonyl, carboxyl, arylcarbonyl, arylsulfonyl, -CF 3 and -OCF 3 ; wherein cycloalkyl and heterocyclyl are optionally substituted with one to three oxo substituents; and, wherein the aryl portion of the arylcarbonyl substituent is optionally substituted with one to five substituents independently selected from C -4 alkoxy.
- R 10 is selected from the group consisting of cyclopropyl, 1 ,3-dihydro-2H-isoindolyl, 2-azabicyclo[2.2.2]octyl, piperidinyl, morpholinyl, phenyl, naphthalenyl, thienyl, 1H-pyrrolyl and pyridinyl; wherein cyclopropyl, piperidinyl, morpholinyl, phenyl, naphthalenyl, thienyl, 1H- "p rrolyl and pyridinyl are optionally substituted with one to four substituenis independently selected from the group consisting of chlorine, fluorine, bromine, methyl, isopropyl, f-butyl, methoxy, f-butoxycarbonyl, carboxyl, phenylcarbonyl (wherein the phenyl portion of phenylcarbonyl is optionally substituted with one to two substituent
- R 0 is 3,5 dichloropyridinyl and in a more preferred embodiment R 10 is attached at the 4 position thereof.
- Preferred embodiments include those compounds wherein R ⁇ 2 is selected from the group consisting of C _ 8 alkyl and C 2 - 8 alkynyl optionally substituted on a terminal carbon with R14. More preferably, R12 is selected from the group consisting of C ⁇ -4 alkyl and C 2-4 alkynyl optionally substituted on a terminal carbon with R 14 . Most preferably, R 12 is selected from the group consisting of f-butyl and ethynyl; wherein ethynyl is optionally substituted on a terminal carbon with a substituent R 14 .
- Preferred embodiments include those compounds wherein R ⁇ 4 is preferably aryl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C ⁇ -8 alkyl, C 2- salkenyl, C 2 -salkynyl, C ⁇ -8 alkoxy, C ⁇ .
- Ru is most preferably is selected from the group consisting of phenyl and C ⁇ _
- Preferred embodiments include those compounds wherein Ru is selected from the group consisting of hydrogen and C ⁇ -4 alkyl. More preferably, Ru is hydrogen.
- Preferred embodiments include those compounds wherein R ⁇ 8 is selected from the group consisting of of hydroxy, C ⁇ - alkoxy, amino C - alkyl, C - alkyl amino dialkyl, C ⁇ - alkyl, benzo-fused heterocyclyl, Ciopolycycloalkyl and hydroxy C ⁇ -4 alkyl; wherein the benzofused heterocyclyl is substituted with C(0)R ⁇ g and C(0)OR 9 .
- Preferred embodiments include those compounds wherein Rig is selected from the group consisting of C ⁇ -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and (halo) ⁇ _ 3 (C ⁇ - 4 )alkyl; wherein C ⁇ - alkyl, C 2 -salkenyl and C2- 4 alkynyl are optionally substituted on a terminal carbon with one to three substituents independently selected from Ru;
- Preferred embodiments include those compounds wherein A is selected from the group consisting of methylene and ethylene. Most preferably A is methylene. Preferred embodiments include those compounds wherein B and B 2 are independently selected from the group consisting of C ⁇ _ 2 alkylene and C 2 alkenylene optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, hydroxy(C ⁇ .
- B 1 and B 2 are independently selected from the group consisting of -CH 2 -, -(CH 2 ) 2 - and -(CH) 2 - optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, hydroxy(C ⁇ - 4 )alkyl, hydroxy(C ⁇ - )alkoxy, C ⁇ - alkyl, C2- 4 alkenyl, C 2-4 alkynyl, C -4 alkoxy, carboxyl, amino, ⁇ /-(C ⁇ - alkyl)amino, ⁇ v, ⁇ -(C ⁇ -4 dialkyl)amino, I -GF 3 and -OCF 3 .
- B 1 is selected from the group consisting of -CH2-, -(CH 2 ) 2 - and -(CH)2- optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, hydroxy(C ⁇ -4 )al
- B 1 is selected from the group consisting of -CH 2 -, -(CH 2 ) 2 - and -(CH) 2 -.
- Embodiments of the aza-bridged-bicyclic amino acid compounds of the present invention include those compounds of Formula (HI) shown in Table I of the formula: TABLE I
- Y, Bi, Ri, A and Re are as previously defined and may be selected from the group consisting of:
- Embodiments of the aza-bridged-bicyclic amino acid compounds of the present invention include those compounds of Formula (IN) shown in Table II of the formula: TABLE II
- R 8 , q, A and R 6 are as previously defined and more preferably are selected from the group consisting of:
- the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts.
- the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts" (Ref. International J. Pharm., 1986, 33, 201-217; J. Pharm.Sci., 1997 (Jan), 66, 1, 1).
- Other salts may, however, be useful in the-preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
- organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid.
- Organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, rneglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
- basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, rneglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
- the present invention includes within its scope prodrugs of the compounds of this invention.
- prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound.
- the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
- the compounds may *for ⁇ example, be resolved into their component enantiomers or diasteromers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
- an optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
- the compounds may also be resolved by formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
- crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention.
- some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
- alkyl and alkoxy refers to straight and branched carbon chains having 1 to 8 carbon atoms or any number within this range.
- alkenyl and alkynyl groups include straight and branched chain alkenes and alkynes having 2 to 8 carbon atoms or any number within this range; wherein an alkenyl -chain has " at least one double bond in the chain • and an alkynyl chain has at least one triple bond in the chain.
- Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups.
- phthalimide and saccharin are examples of compounds with oxo substituents.
- cycloalkyl refers to an optionally substituted, stable, saturated or partially saturated monocyclic or bicyclic ring system containing from 3 to 8 ring carbons and preferably 5 to 7 ring carbons.
- examples of such cyclic alkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
- polycycloalkyl refers to an optionally substituted, stable, saturated or partially saturated multicyclic ring system contain from 5 to 10 with at least one carbon bridge between the rings.
- polycyclic alkyl rings include bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2.]octanyl, bicyclo[3.3.0]octanyl, bicyclo[3.2.1]octanyl and adamatanyl.
- benzo-fused cycloalkyl shall mean a bicyclic ring structure wherein one of the rings is a phenyl and the other is a five to six membered cycolalkyl.
- benzo-fused cycloalkyl include but are not limited to indanyl, fluorenyl and the like.
- heterocyclyl refers to an optionally substituted, stable, saturated or partially saturated 5 or 6 membered monocyclic or bicyclic ring systems which consists of carbon atoms and from one to three heteroatoms selected from N, O or S. Examples of heterocyclyl group ⁇ inciude.
- heterocyclyl including 2H-pyrroie,” * 2-pyrrolinyl or 3-pyrrolinyl
- pyrrolidinyl dioxoianyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl or piperazinyl.
- the heterocyclyl group may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure.
- benzo-fused heterocyclyl refers to a heterocycle ring that is fused with a phenyl ring to form a multiple ring system. Examples of which include compounds selected from the group consisting of benzyl[1 ,3]dioxole, 2,3,4,5-tetrahydrobenzo[/]-[1 ,4]oxazepinyl; 3,4.4a,8a- tetrahydro-1H-isoquinolinyl and the like.
- aryl refers to optionally substituted aromatic groups comprising a stable six membered monocyclic or ten membered bicyclic aromatic ring system, which consists of carbon atoms.
- aryl groups include, but are not limited to, phenyl or naphthalenyl.
- heteroaryl as used herein represents a stable five or six membered monocyclic aromatic ring system or a nine or ten membered benzo-fused heteroaromatic ring system which consists of carbon atoms and from one to three heteroatoms selected from N, O or S.
- the heteroaryl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
- arylalkyl means an alkyl group substituted with an aryl group
- arylalkoxy indicates an alkoxy group substituted with an aryl group (e.g., benzyloxy, phenethoxy, etc.).
- aryloxy indicates an oxy group substituted with an aryl group (e.g., phenoxy).
- alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aralkyl, alkylamino) it shall be interpreted as including those limitations given above for "alkyl” and "aryl.”
- Designated numbers of carbon atoms e.g., d -6 ) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
- the aza-bridged-bicyclic amino acid compounds of the present invention are useful ⁇ 4 integrin receptor antagonists and, more particularly, ⁇ 4 ⁇ 1 and ⁇ 4 ⁇ 7 integrin receptor antagonists for treating a variety of integrin mediated disorders that are ameliorated by inhibition of the 4 ⁇ 1 and ⁇ 4 ⁇ 7 integrin receptor including, but not limited to, inflammatory, autoimmune and cell-proliferative disorders.
- Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above.
- a further illustration of the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
- the present invention also provides pharmaceutical compositions comprising one ⁇ f more compound ' s of this Invention in association with a pharmaceutically acceptable carrier.
- An example of the invention is a method for the treatment of integrin mediated disorders in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. Also included in the invention is the use of a compound of Formula (I) for the preparation of a medicament for treating an integrin mediated disorder in a subject in need thereof.
- the method for the treatment of integrin mediated disorders is the method for the treatment of integrin mediated disorders, wherein the therapeutically effective amount of the compound is from about 0.01 mg/kg/day to about 30 mg/kg/day.
- the individual components of the pharmaceutical compositions described herein can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
- the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
- the utility of the compounds to treat integrin mediated disorders can be determined according to the procedures herein.
- the present invention therefore provides a method for the treatment of integrin mediated disorders in a subject in need thereof which comprises administering any of the compounds as defined herein in a quantity effective to inhibit the 4 ⁇ 1 and ⁇ 4 ⁇ 7 integrin receptor including, but not limited to, inflammatory, autoimmune and cell-proliferative disorders.
- a compound of the present invention may be administered by any conventional route of administration including, but not limited to oral, nasal, pulmonary, sublingual, ocular, transdermal, rectal, vaginal and parenteral (i.e. subcutaneous, intramuscular, intradermal, intravenous etc.).
- one or more compounds of Formula (I) or salt thereof as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
- a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
- Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
- any of the usual pharmaceutical media or excipients may be employed.
- suitable carriers and additives include but are not limited to pharmaceutically acceptable wetting agents, dispersants, flocculation agents, thickeners, pH control agents (i.e. buffers), osmotic agents, coloring agents, flavors, fragrances, preservatives (i.e. to control microbial growth, etc.) and a liquid vehicle may be employed. Not all of the components listed above will be required for each liquid dosage form.
- suitable carriers and additives include but are not limited to diluents, granulating agents, lubricants, binders, glidants, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated, gelatin coated, film coated or enteric coated by standard techniques. .
- the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
- the pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg/kg to about 300 mg/kg (preferably from about 0.01 mg/kg to about 100 mg/kg; and, more preferably, from about
- the dosage form will contain a pharmaceutically acceptable carrier containing between from about 0.01 mg to about 100 mg; and, more preferably, from about 5 mg to about 50 mg of the compound, and may be constituted into any form suitable for the mode of administration selected.
- compositions may be varied depending upon the requirement of the subjects, the severity of the condition being treated and the compound being employed.
- the use of either daily administration or post-periodic dosing may be employed.
- these compositions are in unit dosage forms from such as tablets, pills, capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories for administration by oral, intranasal, sublingual, intraocular, transdermal, parenteral, rectal, vaginal, dry powder inhaler or other inhalation or insufflation means.
- the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
- the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, antiadherents and gildants.
- a pharmaceutical carrier e.g. conventional tableting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, antiadherents and gildants.
- Suitable diluents include, but are not limited to, starch (i.e.
- corn, wheat, or potato starch which may be hydrolized), lactose (granulated, spray dried or anhydrous), sucrose, sucrose-based diluents (confectioner's sugar; sucrose plus about 7 to 10 weight percent invert sugar; sucrose plus about 3 weight percent modified dextrins; sucrose plus invert sugar, about 4 weight percent invert sugar, about 0.1 to 0.2 weight percent cornstarch and magnesium stearate), dextrose " , inosltoi, mannitol, sorbit ⁇ l, microcrystalline cellulose (i.-a. !
- AVlCEL TM microcrystalline cellulose available from FMC Corp.
- dicalcium phosphate calcium sulfate dihydrate, calcium lactate trihydrate and the like.
- Suitable binders and adhesives include, but are not limited to acacia gum, guar gum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics (i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like), water soluble or dispersible binders (i.e. alginic acid and salts thereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e.
- TYLOSE TM available from Hoechst Celanese
- polyethylene glycol polysaccharide acids
- bentonites polyvinylpyrrolidone
- polymethacrylates polymethacrylates and pregelatinized starch
- Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium starch glycolates, pregelatinized starches, clays (magnesium aluminum silicate), celluloses (such as crosslinked sodium carboxymethylcellulose and microcrystalline cellulose), alginates, pregelatinized starches (i.e. corn starch, etc.), gums (i.e.
- Suitable lubricants and antiadherents include, but are not limited to, stearates (magnesium, calcium and sodium), stearic acid, talc waxes, stearowet, boric acid, sodium chloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate and the like.
- Suitable gildants include, but are not limited to, talc, comstarch, silica (i.e. CAB-O-SIL TM silica available from Cabot, SYLOID TM silica available from W.R. Grace/Davison, and AEROSIL TM silica available from Degussa) and the like.
- silica i.e. CAB-O-SIL TM silica available from Cabot, SYLOID TM silica available from W.R. Grace/Davison, and AEROSIL TM silica available from Degussa
- Sweeteners and flavorants may be added to chewable solid dosage forms to improve the palatability of the oral dosage form. Additionally, colorants and coatings may be added or applied to the solid dosage form for ease of identification of the drug or for aesthetic purposes.
- These carriers are formulated with the pharmaceutical active to provide an accurate, appropriate dose of the pharmaceutical active with a therapeutic release profile.
- these carriers are mixed with the pharmaceutical active to form a solid preformulatiori ? composition containing a homogeneous mixture of the pharmaceutical active of the present invention, or a pharmaceutically acceptable salt thereof.
- the preformulation will be formed by one of three common methods: (a) wet granulation, (b) dry granulation and (c) dry blending.
- wet granulation it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
- This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.1 mg to about 500 mg of the active ingredient of the present invention.
- the tablets or pills containing the novel compositions may also be formulated in multilayer tablets or pills to provide a sustained or provide dual-release products.
- a dual release tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric materials such as shellac, cellulose acetate (i.e.
- Sustained release tablets may also be made by film coating or wet granulation using slightly soluble or insoluble substances in solution (which for a wet granulation acts as the binding agents) or low melting solids a molten form (which in a wet granulation may incorporate the active ingredient).
- These materials include natural and synthetic polymers waxes, hydrogenated oils, fatty acids and alcohols (i.e.
- liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, but are not limited to aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- Suitable suspending agents for aqueous suspensions include synthetic and natural gums such as, acacia, agar, alginate (i.e. propylene alginate, sodium alginate and the like), guar, karaya, locust bean, pectin, tragacanth, and xanthan gum, cellulosics such as sooium carDoxymethyiceiiuiose, metnyiceiiuiose, ny ⁇ roxymetnyiceiiuiose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose, and combinations thereof, synthetic polymers such as polyvinyl pyrrolidone, carbomer (i.e.
- Suitable surfactants include but are not limited to sodium docusate, sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxamer 188, polyoxamer 235 and combinations thereof.
- Suitable deflocculating or dispersing agent include pharmaceutical grade lecithins.
- Suitable flocculating agent include but are not limited to simple neutral electrolytes (i.e.
- Suitable preservatives include but are not limited to parabens (i.e. methyl, ethyl, t?-propyl and n-butyl), sorbic acid, thimerosal, quaternary ammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate, phenylethanol and the like.
- liquid vehicles that may be used in liquid pharmaceutical dosage forms, however, the liquid vehicle that is used in a particular dosage form must be compatible with the suspending agent(s).
- nonpoiar liquid vehicles such as fatty- esters and oils liquid vehicles are best used with suspending agents such as low HLB (Hydrophile-Lipophile Balance) surfactants, stearalkonium hectorite, water insoluble resins, water insoluble film forming polymers and the like.
- suspending agents such as low HLB (Hydrophile-Lipophile Balance) surfactants, stearalkonium hectorite, water insoluble resins, water insoluble film forming polymers and the like.
- polar liquids such as water, alcohols, polyols and glycols are best used with suspending agents such as higher HLB surfactants, clays silicates, gums, water soluble cellulosics, water soluble polymers and the like.
- sterile suspensions and solutions are desired.
- Liquid forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
- Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is ⁇ esire ⁇ .
- compounds of the present invention can be administered in an intranasal dosage form via topical use of suitable intranasal vehicles or via transdermal skin patches, the composition of which are well known to those of ordinary skill in that art.
- transdermal delivery system the administration of a therapeutic dose will, of course, be continuous rather than intermittent throughout the dosage regimen.
- Compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, multilamellar vesicles and the like.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, phosphatidylcholines and the like.
- Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
- the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
- Such polymers can include, but are not limited to polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy- ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palrnitcyi residue.
- the compounds of the present inventioir may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, to homopolymers and copolymers (which means polymers containing two or more chemically distinguishable repeating units) of lactide (which includes lactic acid d-, I- and meso lactide), glycolide (including glycolic acid), ⁇ -caprolactone, p-dioxanone (1 ,4-dioxan- 2-one), trimethylene carbonate (1 ,3-dioxan-2-one), alkyl derivatives of trimethylene carbonate, ⁇ -valerolactone, ⁇ -butyrolactone, ⁇ -butyrolactone, ⁇ - decalactone, hydroxybutyrate, hydroxy val erate, 1 ,4-dioxepan-2-one (including its dimer 1 ,5,8, 12-tetraoxacyclotetradecane-7,14-
- lactide
- Compounds of this invention may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever treatment of integrin mediated disorders is required for a subject in need thereof.
- the daily dose of a pharmaceutical composition of the present invention may be varied over a wide range from about 0.7 mg to about 21 ,000 mg per adult human per day; preferably, the dose will be in the range of from about 0.7 mg to about 7000 mg per adult human per day; most preferably the dose will be in the range of from about 0.7 mg to about 2100 mg per adult human per day.
- the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
- An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day.
- the range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day; and, most preferably, from about 0.01 mg/kg to about 30 mg/kg of body weight per day.
- a compound of the present " invention may be- administered in ⁇ a-s.ng! ⁇ daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily.
- Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level.
- Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
- Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and are illustrated more particularly in the schemes that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the art.
- amino ester Compound A1 is protected with a conventional amino protecting group to give Compound A2, which is saponified under basic conditions to yield carboxylic acid Compound A3.
- Compound A3 is condensed with Compound A4 in the presence of an appropriate coupling agent, base, and solvent.
- An appropriate coupling agent may include, and is not limited to, EDAC hydrochloride, DIC, EDC, DCC or HATU; an appropriate base may include but is not limited to, DIEA; and an appropriate solvent may include, but is not limited to, DCM or DMF.
- R A may be selected from the group consisting of -R 10 . -R12, -N(Rn,R ⁇ o), -N(Rn,R ⁇ 2 ), and -N(R ⁇ 2 ,R ⁇ 7 )- Sulfamides could be made by analogues procedures.
- Compound A7 is deprotected under acidic conditions to provide the resultant amino Compound A8 which is then acylated by several methods:
- Compound A8 may be condensed with carboxylic acids in the presence of an appropriate coupling agent, base, and solvent.
- R B may be selected from the group consisting of -(CH 2 )o- 4 Ri 8 ,-(CH 2 ) q NC(0)R 1 , -(CH 2 ) q SR ⁇ , - (CH 2 ) q SOR ⁇ ; and -(CH 2 ) q S0 2 R ⁇ .
- Compounds of the present invention were made in the presence of HOBt, EDC, NMM in DCM; similarly, Compound A8 may be condensed with an appropriate acid chloride to provide Compound
- Scheme B describes the preparation of compounds of the present invention in which substituents of the phenyl group are attached through an oxygen atom.
- Compound A3 is coupled with Compound B1 in the presence of an appropriate coupling agent, base, and solvent, as described in Scheme A. If B1 is to be substituted with only -O-R ⁇ 0 or R ⁇ o-C _ 8 alkoxy B1 the appropriate substituted phenyl group may be used as a starting material and the acylation step skipped.
- the hydroxyl group of Compound B2 is acylated with acid chloride.
- the Rc group is an acylated group listed in RQ selected from the group consisting of -Rin. -Ri?. -NfR-M.Rin). -N(R;H ,RIA and -N(R ⁇ ? ,R ⁇ 7 ).
- Rg is as defined in Scheme A.
- Other compounds of the present invention having a variety of substituents attached to the oxygen atom may be made by reacting Compound B2 with a variety of acid chlorides.
- Compound B3 is deprotected using hydrogenation to provide the resultant amino Compound B4 which is acylated by several methods: Compound B4 may be condensed with carboxylic acids in the presence of an appropriate coupling agent, base, and solvent. Compounds of the present invention were made in the presence of HOBt, EDC, NMM in DCM; similarly, Compound B4 may be condensed with an appropriate acid chloride to provide Compound B5. The ester of Compound B5 is saponified under basic conditions to yield Compound B6.
- Amino ester Compound 1a (5.90 g, 0.0322 mol) was dissolved in dry DCM (100 mL) containing TEA (9.43 mL, 0.067 mol) and the solution was cooled in an ice bath.
- Benzyl chloroformate Compound 1b (4.83 mL, 0. 338 mol) was added dropwise over a 45 min period.
- the reaction was stirred for 2 h at 0 ° C, after which time the reaction was warmed to rt and stirred an additional 18h.
- the reaction mixture was washed with 0.1 N HCI, 5% NaHCOs, and water before being dried (MgS0 4 ) and concentrated to a viscous oil.
- the compounds of the present invention are ⁇ 4 ⁇ 1 and ⁇ 4 ⁇ 7 integrin receptor antagonists useful in treating integrin mediated disorders including, but not limited to, inflammatory, autoimmune and cell-proliferative disorders.
- Ramos Cell Adhesion Assay ( ⁇ 4 ⁇ Mediated Adhesion / VCAM-1) Immulon 96 well plates (Dynex) were coated with 100 ⁇ L recombinant hVCAM-1 at 4.0 ⁇ g/mL in 0.05 M NaC0 3 buffer pH 9.0 overnight at 4° C (R&D Systems). Plates were washed 3 times in PBS with 1 % BSA and blocked for 1 h @ room temperature in this buffer. PBS was removed and compounds to be tested (50 ⁇ L) were added at 2X concentration.
- Ramos cells (50 ⁇ L at 2 X 10 6 /mL) labeled with 5 ⁇ M Calcein AM (Molecular Probes) for 1 h at 37 ° C, were added to each well and allowed to adhere for 1 h at room temperature. Plates were washed 3 X in PBS + 1 % BSA and cells were lysed for 15 minutes in 100 ⁇ L of 1 M Tris pH 8.0 with 1 % SDS. The plate was read at 485 nm excitation and 530 nm emission.
- Immulon 96 well plates (Dynex) were coated with 100 ⁇ L recombinant hVCAM-1 at 4.0 ⁇ g/mL in 0.05 M NaC0 3 buffer pH 9.0 overnight at 4° C (R&D Systems). Plates were washed 3 times in PBS with 1 % BSA and blocked for 1 h @ room temperature in this buffer. PBS was removed and compounds to be tested (50 ⁇ L) were added at 2X concentration.
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Abstract
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Priority Applications (5)
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EP04817486A EP1680419A1 (en) | 2003-10-31 | 2004-10-28 | Improved aza-bridged-bicyclic amino acid derivatives as a4 integrin antagonists |
AU2004285025A AU2004285025A1 (en) | 2003-10-31 | 2004-10-28 | Improved aza-bridged-bicyclic amino acid derivatives as a4 integrin antagonists |
CA002543438A CA2543438A1 (en) | 2003-10-31 | 2004-10-28 | Improved aza-bridged-bicyclic amino acid derivatives as a4 integrin antagonists |
JP2006538306A JP2007509969A (en) | 2003-10-31 | 2004-10-28 | Aza-bridged bicyclic amino acid derivatives improved as A4 integrin antagonists |
BRPI0416102-5A BRPI0416102A (en) | 2003-10-31 | 2004-10-28 | aza-linked bicyclic amino acid derivatives enhanced as alpha4 integrin antagonists |
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US51657403P | 2003-10-31 | 2003-10-31 | |
US60/516,574 | 2003-10-31 |
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PCT/US2004/036011 WO2005042529A1 (en) | 2003-10-31 | 2004-10-28 | Improved aza-bridged-bicyclic amino acid derivatives as a4 integrin antagonists |
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Country | Link |
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US (1) | US20050176755A1 (en) |
EP (1) | EP1680419A1 (en) |
JP (1) | JP2007509969A (en) |
KR (1) | KR20070012319A (en) |
CN (1) | CN1902197A (en) |
AR (1) | AR046570A1 (en) |
AU (1) | AU2004285025A1 (en) |
BR (1) | BRPI0416102A (en) |
CA (1) | CA2543438A1 (en) |
TW (1) | TW200528441A (en) |
WO (1) | WO2005042529A1 (en) |
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WO2006096807A1 (en) * | 2005-03-08 | 2006-09-14 | Janssen Pharmaceutica N.V. | Aza-bridged-bicyclic amino acid derivatives as alpha 4 integrin antagonists |
WO2020092401A1 (en) * | 2018-10-30 | 2020-05-07 | Gilead Sciences, Inc. | COMPOUNDS FOR INHIBITION OF ALPHA 4β7 INTEGRIN |
US11116760B2 (en) | 2018-10-30 | 2021-09-14 | Gilead Sciences, Inc. | Quinoline derivatives |
US11174256B2 (en) | 2018-10-30 | 2021-11-16 | Gilead Sciences, Inc. | Imidazopyridine derivatives |
US11224600B2 (en) | 2018-10-30 | 2022-01-18 | Gilead Sciences, Inc. | Compounds for inhibition of alpha 4 beta 7 integrin |
US11578069B2 (en) | 2019-08-14 | 2023-02-14 | Gilead Sciences, Inc. | Compounds for inhibition of α4 β7 integrin |
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SG10201401836RA (en) * | 2009-04-27 | 2014-10-30 | Elan Pharm Inc | Pyridinone antagonists of alpha-4 integrins |
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Also Published As
Publication number | Publication date |
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CA2543438A1 (en) | 2005-05-12 |
TW200528441A (en) | 2005-09-01 |
US20050176755A1 (en) | 2005-08-11 |
KR20070012319A (en) | 2007-01-25 |
AU2004285025A1 (en) | 2005-05-12 |
EP1680419A1 (en) | 2006-07-19 |
BRPI0416102A (en) | 2007-01-02 |
AR046570A1 (en) | 2005-12-14 |
CN1902197A (en) | 2007-01-24 |
JP2007509969A (en) | 2007-04-19 |
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