Ligand-therapeutic agent conjugates, silicon-based linkers, and methods for making and using them

Abstract

The present invention relates to ligand-therapeutic agent conjugate compounds, silicon linkers for the conjugate compounds, compositions, methods for making them, and methods for the treatment of cancer using the conjugate compounds. The silicon-based linkers described herein can be used to deliver desired therapeutic agents to particular cells or tissue types targeted by the ligand.

1 . (canceled) 
     
     
         2 . A method of therapeutically treating cancer in a subject in need thereof comprising:
 selecting a cancer subject in need of treatment, and   administering to the selected subject a therapeutically acceptable amount of:   (I) a conjugate compound of formula (I):   
       
         
           
           
               
               
           
         
          wherein 
         L is a cell-targeting ligand; 
         T is a therapeutic agent, with the proviso that T is not CAS Registry No. 115834-23-6 (SF2446A1) or derivatives or analogues thereof; 
         J is a linker group; 
         X is independently selected from the group consisting of:
 (1) a bond; 
 (2) O; 
 
       
       
         
           
           
               
               
           
         
         
           which is independently and optionally substituted from 1 to 2 times with R 8 , wherein the wavy lines indicate point of attachment sites and * is the point of attachment to J and ** is the point of attachment to Si; and 
         
       
       
         
           
           
               
               
           
         
         
           which is independently and optionally substituted from 1 to 2 times with R 8 , wherein the wavy lines indicate point of attachment sites and * is the point of attachment to J and ** is the point of attachment to Si; 
         
         Q is —(CH 2 ) n —, —CH 2 CHR 1 CH 2 —, —CH 2 CR 5 R 6 CH 2 —, —CH 2 CHR 1 CH 2 CH 2 —, —CH 2 CH 2 CHR 1 CH 2 CH 2 —, —CH 2 X 1 CH 2 —, or —CH 2 CH 2 X 1 CH 2 CH 2 —; 
         R 1  is C 1-6  alkyl, aryl, heteroaryl, OR 5 , NR 5 R 6 , or —N(COR 2 )R 7 , each of which is optionally substituted with R 8 ; 
         R 2  is H, C 1-6  alkyl, C 3-6  cycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with R 8 ; 
         R 3  is H, C 1-6  alkyl, C 3-6  cycloalkyl, or —COR 4 , each of which is optionally substituted with R 8 ; 
         R 4  is H, C 1-6  alkyl, or C 3-6  cycloalkyl, each of which is optionally substituted with R 8 ; 
         R 5  is H or C 1-6  alkyl optionally substituted with R 8 ; 
         R 6  is H or C 1-6  alkyl optionally substituted with R 8 ; or 
         R 5  and R 6  are taken together with the nitrogen to which they are attached to form a five- to seven-membered heterocyclic ring, which may be saturated or unsaturated and comprises from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted from 1 to 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, hydroxyl, cyano, oxo, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  alkoxy; 
         R 7  is H, C 1-6  alkyl, C 3-6  cycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with R 8 ; 
         R 8  is H, NO 2 , CN, halogen, oxo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  alkoxyalkyl, C 3-6  cycloalkyl, C 4-7  cycloalkylalkyl, aryl, heteroaryl, COOR 9 , COR 9 , C(O)NR 9 R 10 , COONR 9 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , or OR 9 ; 
         R 9  is H, C 1-6  alkyl, C 3-6  cycloalkyl, aryl, or heteroaryl, wherein the C 1-6  alkyl, C 3-6  cycloalkyl, aryl, or heteroaryl is optionally substituted from 1 to 3 times with halogen, hydroxyl, cyano, oxo, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy; 
         R 10  is H, C 1-6  alkyl, C 3-6  cycloalkyl, aryl, or heteroaryl, wherein the C 1-6  alkyl, C 3-6  cycloalkyl, aryl, or heteroaryl is optionally substituted from 1 to 3 times with halogen, hydroxyl, cyano, oxo, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy; or 
         R 9  and R 10  are taken together with the nitrogen to which they are attached to form a five- to seven-membered heterocyclic ring, which may be saturated or unsaturated and comprises from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted from 1 to 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, hydroxyl, cyano, oxo, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  alkoxy; 
         X 1  is O, S, SO, SO 2 , or NR 3 ; 
         n is 1 to 5; and 
         m is 1 to 8 or
 (II) a conjugate compound of formula (III): 
 
       
       
         
           
           
               
               
           
         
         
            wherein 
         
         L is a cell-targeting ligand; 
         T is a therapeutic agent, with the proviso that T is not CAS Registry No. 115834-23-6 (SF2446A1) or derivatives or analogues thereof; 
         J is a linker group, with the proviso that when X is a bond, J cannot directly bond to the silicon atom with an O, NH, N—CH 3 , S, or carboxyl and forms a hydrolytically stable carbon bond with the silicon atom; 
         X is independently selected from the group consisting of:
 (1) a bond; 
 
       
       
         
           
           
               
               
           
         
         
           which is independently and optionally substituted from 1 to 2 times with R 15 , wherein the wavy lines indicate point of attachment sites and * is the point of attachment to J and ** is the point of attachment to Si; and 
         
       
       
         
           
           
               
               
           
         
         
           which is independently and optionally substituted from 1 to 2 times with R 15 , wherein the wavy lines indicate point of attachment sites and * is the point of attachment to J and ** is the point of attachment to Si; 
         
         R 13  and R 14  are each independently selected from the group consisting of C 1-6  alkyl, C 3-6  cycloalkyl, aryl, and heteroaryl, each of which is optionally substituted with R 16 ; 
         R 15  is H, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  alkoxyalkyl, C 3-6  cycloalkyl, C 4-7  cycloalkylalkyl, CN, halogen, NO 2 , Oxo, aryl, heteroaryl, OR 17 , COOR 17 , COR 17 , CONR 17 R 18 , COONR 17 R 18 , SO 2 R 17 , or SO 2 NR 17 R 18 ; 
         R 16  is H, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxyalkyl, C 3-6  cycloalkyl, C 4-7  cycloalkylalkyl, CN, halogen, NO 2 , OR 17 , NR 17 R 18 , COOR 17 , COR 17 , CONR 17 R 18 , SO 2 R 17 , —SO 2 NR 17 R 18 , aryl, or heteroaryl; 
         R 17  is H, C 1-6  alkyl, C 3-6  cycloalkyl, aryl, or heteroaryl, wherein the C 1-6  alkyl, C 3-6  cycloalkyl, aryl, or heteroaryl is optionally substituted from 1 to 3 times with halogen, hydroxyl, cyano, oxo, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy; 
         R 18  is H, C 1-6  alkyl, C 3-6  cycloalkyl, aryl, or heteroaryl, wherein the C 1-6  alkyl, C 3-6  cycloalkyl, aryl, or heteroaryl is optionally substituted from 1 to 3 times with halogen, hydroxyl, cyano, oxo, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy; or 
         R 17  and R 18  are taken together with the nitrogen to which they are attached to form a five- to seven-membered heterocyclic ring, which may be saturated or unsaturated and comprises from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted from 1 to 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, hydroxyl, cyano, oxo, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  alkoxy; and 
         v is 1 to 8. 
       
     
     
         3 . The method according to  claim 2 , wherein the cancer is selected from the group consisting of carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, esophagus, ovary, prostate, pancreas, liver, skin, stomach, and testes. 
     
     
         4 . The method according to  claim 2 , wherein for the conjugate compound of formula (I) and the conjugate compound of formula (III)
 J is —Z—Y 2 —C(O)—Y 1 —;   Z is   
       
         
           
           
               
               
           
         
          wherein the wavy lines indicate point of attachment sites and * is the point of attachment to L and ** is the point of attachment to Y 2 ; 
         Y 1  is C 1-6  alkylene or —(X 2 —CH 2 —CH 2 ) 1 —, each of which is optionally substituted with R 8 ; 
         Y 2  is C 1-6  alkylene or —(CH 2 CH 2 (X 3 )) q —, each of which is optionally substituted with R 8 ; 
         X 2  is independently selected from the group consisting of:
 (1) a bond; 
 (2) (CH 2 ) k ; 
 (3) O; and 
 (4) NR 12 ; 
 
         X 3  is independently selected from the group consisting of:
 (1) a bond; 
 (2) (CH 2 ) k ; 
 (3) O; and 
 (4) NR 12 ; 
 
         R 11  is H, C 1-6  alkyl, C 1-6  hydroxyalkyl, C 3-6  cycloalkyl, C 4-7  cycloalkylalkyl, aryl, or heteroaryl, each of which is optionally substituted from 1 to 3 times with halogen, hydroxyl, cyano, oxo, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy; 
         R 12  is H, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxyalkyl, C 3-6  cycloalkyl, C 4-7  cycloalkylalkyl, or C 1-6  hydroxyalkyl; 
         k is 1 to 3; 
         1 is 1 to 10; and 
         q is 1 to 10. 
       
     
     
         5 . The method according to  claim 2 , wherein for the conjugate compound of formula (I) and the conjugate compound of formula (III)
 J is —Z—Y 3 —;   Z is   
       
         
           
           
               
               
           
         
          wherein the wavy lines indicate point of attachment sites and * is the point of attachment to L and ** is the point of attachment to Y 3 ; 
         Y 3  is selected from the group consisting of C 1-6  alkylene, C 3 -C 8  carbocyclyl, O(CH 2 ) r , arylene, O(CH 2 ) r -arylene, -arylene-(CH 2 ) r —, (CH 2 ) r —(C 3-8  carbocyclyl), —(C 3-8  carbocyclyl)-(CH 2 ) r , C 3-8  heterocyclyl, (CH 2 ) r —(C 3-8  heterocyclyl), —(C 3-8  heterocyclyl)-(CH 2 ) r , —((X 4 )(X 5 )(CH 2 ) r (X 6 )(CH 2 ) r ) s —, and —((X 4 )(X 5 )(CH 2 ) r (X 6 )(X 7 )(CH 2 ) r ) s —, each of which is optionally substituted with R 8 ; 
         X 4 , X 5 , X 6 , and X 7  are each independently selected from the group consisting of a bond, (CH 2 ) k , O, C(O), S, NR 19 , C(O)O, and C(O)NR 19 ; 
         R 11  is H, C 1-6  alkyl, C 1-6  hydroxyalkyl, C 3-6  cycloalkyl, C 4-7  cycloalkylalkyl, aryl, or heteroaryl, each of which is optionally substituted from 1 to 3 times with halogen, hydroxyl, cyano, oxo, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy; 
         R 19  is H, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxyalkyl, C 3-6  cycloalkyl, C 4-7  cycloalkylalkyl, or C 1-6  hydroxyalkyl; 
         each r is 0 to 16; and 
         s is 1 to 10. 
       
     
     
         6 . The method according to  claim 2 , wherein for the conjugate compound of formula (I)
 Q is —(CH 2 ) n — and n is 1 to 5.   
     
     
         7 . The method according to  claim 2 , wherein for the conjugate compound of formula (I) and the conjugate compound of formula (III)
 J further comprises a thiol-containing spacer.   
     
     
         8 . The method according to  claim 2 , wherein for the conjugate compound of formula (I) and the conjugate compound of formula (III)
 L is a protein, a peptide, an amino acid, a receptor ligand, a hormone, or a growth factor.   
     
     
         9 . The method according to  claim 8 , wherein for the conjugate compound of formula (I) and the conjugate compound of formula (III)
 L is selected from the group consisting of an antibody, an antibody fragment, scFv-Fc, minibody, diabody, scFv, folic acid, bombesin, EDG, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-alpha, TFG-beta, VGF, insulin, and insulin-like growth factors I and II.   
     
     
         10 . The method according to  claim 8 , wherein for the conjugate compound of formula (I) and the conjugate compound of formula (III)
 L is an antibody which binds to one or more tumor-associated antigens or cell-surface receptors selected from (1)-(35):   (1) BMPR1B (bone morphogenetic protein receptor-type IB, Genbank Accession No. NM_001203);   (2) E16 (LAT1, SLC7A5, Genbank Accession No. NM_003486);   (3) STEAP1 (six transmembrane epithelial antigen of prostate, Genbank Accession No. NM_012449);   (4) 0772P (CA125, MUC16, Genbank Accession No. AF361486);   (5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin, Genbank Accession No. NM_005823);   (6)  Napi 3b ( NAPI -3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b, Genbank Accession No. NM_006424);   (7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5bHlog, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B, Genbank Accession No. AB040878);   (8) PSCA hlg (2700050C12Rik, C530008016Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank Accession No. AY358628);   (9) ETBR (Endothelin type B receptor, Genbank Accession No. AY275463);   (10) MSG783 (RNF124, hypotheticalproteinFLJ20315, Genbank Accession No. NM_017763);   (11) STEAP2 (HGNC_8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein, Genbank Accession No. AF455138);   (12) TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4, Genbank Accession No. NM_017636);   (13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor, Genbank Accession No. NP_003203 or NM_003212);   (14) CD21 (CR2 (Complement receptor 2) or C3DR (C3d/Epstein Barr virus receptor) or Hs.73792 Genbank Accession No. M26004);   (15) CD79b (CD79B, CD790, IGb (immunoglobulin-associated beta), B29, Genbank Accession No. NM_000626);   (16) FcRH2 (IFGP4, IRTA4, SPAPlA (SH2 domain containing phosphatase anchor protein 1a), SPAPIB, SPAPIC, Genbank Accession No. NM_030764);   (17) HER2 (Genbank Accession No. M11730);   (18) NCA (Genbank Accession No. M18728);   (19) MDP (Genbank Accession No. BC017023);   (20) IL20Ra (Genbank Accession No. AF184971);   (21) Brevican (Genbank Accession No. AF229053);   (22) Ephb2R (Genbank Accession No. NM_004442);   (23) ASLG659 (Genbank Accession No. AX092328);   (24) PSCA (Genbank Accession No. AJ297436);   (25) GEDA (Genbank Accession No. AY260763);   (26) BAFF-R (B cell-activating factor receptor, BLyS receptor 3, BR3, Genbank Accession No. NP_443177.1);   (27) CD22 (B-cell receptor CD22-B isoform, Genbank Accession No. NP-001762.1);   (28) CD79a (CD79A, CD79α, immunoglobulin-associated alpha, a B cell-specific protein that covalently interacts with Ig beta (CD79B) and forms a complex on the surface with Ig M molecules, transduces a signal involved in B-cell differentiation, Genbank Accession No. NP_001774.1);   (29) CXCR5 (Burkitt's lymphoma receptor 1, a G protein-coupled receptor that is activated by the CXCL13 chemokine, functions in lymphocyte migration and humoral defense, plays a role in HIV −2 infection and perhaps development of AIDS, lymphoma, myeloma, and leukemia, Genbank Accession No. NP_001707.1);   (30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen) that binds peptides and presents them to CD4+ T lymphocytes, Genbank Accession No. NP_002111.1);   (31) P2X5 (Purinergic receptor P2X ligand-gated ion channel 5, an ion channel gated by extracellular ATP, Genbank Accession No. NP_002552.2);   (32) CD72 (B-cell differentiation antigen CD72, Lyb-2, Genbank Accession No. NP_001773.1);   (33) LY64 (Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family, regulates B-cell activation and apoptosis, loss of function is associated with increased disease activity in patients with systemic lupus erythematosis, Genbank Accession No. NP_005573.1);   (34) FCRH1 (Fc receptor-like protein 1, a putative receptor for the immunoglobulin Fc domain that contains C2 type Ig-like and ITAM domains, Genbank Accession No. NP_443170.1); and   (35) IRTA2 (Immunoglobulin superfamily receptor translocation associated 2, a putative immunoreceptor with possible roles in B cell development and lymphomagenesis; deregulation of the gene by translocation occurs in some B cell malignancies, Genbank Accession No. NP_112571.1).   
     
     
         11 . The method according to  claim 8 , wherein for the conjugate compound of formula (I) and the conjugate compound of formula (III)
 L is selected from folic acid and epidermal growth factor.   
     
     
         12 . The method according to  claim 2 , wherein for the conjugate compound of formula (I) and the conjugate compound of formula (III)
 T is a hydroxyl-containing drug moiety.   
     
     
         13 . The method according to  claim 2 , wherein for the conjugate compound of formula (I) and the conjugate compound of formula (III)
 T is an anticancer agent selected from the group consisting of N8-acetyl spermidine, actinomycin, 9-amino camptothecin, aminopterin, anguidine, anthracycline, auristatin, bleomycin, calicheamycin, camptothecin, carminomycin, CC-1065, clofaribine, 1-(2-chloroethyl)-1,2-dimethanesulfonyl hydrazide, cyclopropabenzindol-4-one (CBI), cytarabine, cytosine arabinoside, daunorubicin, dichloromethotrexate, n-(5,5-diacetoxy-pentyl) doxorubicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4-9-diene-2,6-diyne-13-one, difluoronucleosides, doxorubicin, duocarmycin, epirubicin, esperamicin, etoposide, 5-fluorouracil, irinotecan, leurosideine, leurosine, maytansine, melphalan, 6-mercaptopurine, methopterin, methotrexate, mitomycin A, mitomycin C, morpholine-doxorubicin, butyric acid, cisplatin, diacetoxypentyldoxorubicin, maytansinol, capecitabine, leuprolide, bicalutamide, goserelin, 17-AAG, 17-DMAG, des-acetyl vinblastine, nemorubicin, podophyllotoxin, podophyllotoxin derivatives, retinoic acid, saporin, tallysomycin, vinblastine, vincristine, vindesine, taxane, taxol, paclitaxel, taxotere, docetaxel, taxotere retinoic acid, and isomers, salt forms, analogues, and derivatives thereof.   
     
     
         14 . The method according to  claim 2 , wherein the compound of formula (I) has a structure selected from: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method according to  claim 2 , wherein for the conjugate compound of formula (III)
 R 13  and R 14  are each C 1- 6 alkyl or phenyl.   
     
     
         16 . The method according to  claim 2 , wherein the compound of formula (III) has a structure selected from: