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Msg  4164 of 4336  at  9/17/2020 1:26:26 AM  by

JBWIN


Building IP: BMY Patent Application re "TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS HAVING A BENZOTRIAZOLE MOIETY, CONJUGATES THEREOF, AND METHODS AND USES THEREFOR"

 
United States Patent Application20200291028
Kind CodeA1
Poudel; Yam B. ; et al.September 17, 2020

TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS HAVING A BENZOTRIAZOLE MOIETY, CONJUGATES THEREOF, AND METHODS AND USES THEREFOR

Abstract

Compounds having a structure according to formula (I) ##STR00001## where R.sup.1, R.sup.2, and R.sup.3 are as defined herein, are agonists for the Toll-like receptor 7 (TLR7) and can be used as adjuvants for stimulating the immune system. Some such compounds can be used in conjugates for targeted delivery to the organ or tissue of intended action.


Inventors:Poudel; Yam B.; (Fremont, CA) ; Gangwar; Sanjeev; (Foster City, CA) ; Sivaprakasam; Prasanna; (Lawrenceville, NJ) ; Posy; Shoshana L.; (Highland Park, NJ)
Applicant:
NameCityStateCountryType

BRISTOL-MYERS SQUIBB COMPANY

Princeton

NJ

US
Family ID:1000004870060
Appl. No.:16/890765
Filed:June 2, 2020

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
16583869Sep 26, 201910696676
16890765
16103210Aug 14, 201810472361
16583869
62546095Aug 16, 2017

Current U.S. Class:1/1
Current CPC Class:C07D 473/18 20130101; A61P 37/04 20180101
International Class:C07D 473/18 20060101 C07D473/18; A61P 37/04 20060101 A61P037/04

Claims



1. A compound having a structure according to formula (Ia-05) ##STR00049##
Description



CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of allowed application Ser. No. 16/583,869, filed Sep. 26, 2019, which is a continuation of application Ser. No. 16/103,210, filed Aug. 14, 2018, now U.S. Pat. No. 10,472,361; which claims the benefit under 35 U.S.C. .sctn. 119(e) of U.S. Provisional Application Ser. No. 62/546,095, filed Aug. 16, 2017; the disclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] This disclosure relates to Toll-like receptor 7 ("TLR7") agonists and conjugates thereof, and methods for the preparation and use of such agonists and their conjugates.

[0003] Toll-like receptors ("TLRs") are cell-surface receptors that recognize pathogen-associated molecular patterns ("PAMPs"). Activation of a TLR by the binding of a corresponding PAMP signals potential infection by a pathogen and stimulates the immune system to fight the infection. Humans have 11 TLRs, named TLR1 through TLR11.

[0004] The activation of a TLR--with TLR7 being the most studied--by an agonist can have an adjuvant effect on the action of vaccines and immunotherapy agents in treating a variety of conditions other than actual pathogen infection, by stimulating the immune response.

[0005] TLR7 recognizes PAMPs associated with single-stranded RNA viruses. Its activation induces secretion of Type I interferons such as IFN.alpha. and IFN.beta. (Lund et al. 2004). It has two binding sites, one for single stranded RNA ligands such as ssRNA40 (Berghofer et al. 2007) and one for guanosine (Zhang et al. 2016).

[0006] TLR7 can bind to, and be activated by, guanosine-like synthetic agonists such as imiquimod, resiquimod, and gardiquimod, which are based on a 1H-imidazo[4,5-c]quinoline scaffold.

##STR00002##

[0007] Synthetic TLR7 agonists based on a pteridinone molecular scaffold are also known, as exemplified by vesatolimod (Desai et al. 2015), which has been in Phase 2 clinical trials. The potency of vesatolimod is reported to be 100.times. less than that of the corresponding purine-8-one compound, as measured by IFN-.alpha. induction (Roethle et al. 2013).

##STR00003##

[0008] Other synthetic TLR7 agonists are based on a purine-like scaffold, frequently according to formula (A):

##STR00004##

where R, R', and R'' are structural variables, with R'' typically containing an unsubstituted or substituted aromatic or heteroaromatic ring.

[0009] Disclosures of bioactive molecules having a purine-like and their uses in treating conditions such as fibrosis, inflammatory disorders, cancer, or pathogenic infections include: Akinbobuyi et al. 2015b and 2016; Barberis et al. 2012; Carson et al. 2014; Ding et al. 2016, 2017a, and 2017b; Graupe et al. 2015; Hashimoto et al. 2009; Holldack et al. 2012; Isobe et al. 2009a and 2012; Jin et al. 2017a and 2017b; Peterson 2014; Pryde 2010; and Seifert 2015.

[0010] The group R'' can be pyridyl: Bonfanti et al. 2015a and 2015b; Halcomb et al. 2015; Hirota et al. 2000; Isobe et al. 2000, 2002, 2004, 2006, 2009a, 2011, and 2012; Kasibhatla et al. 2007; Koga-Yamakawa et al. 2013; Musmuca et al. 2009; Nakamura 2012; Ogita et al. 2007; and Yu et al. 2013.

[0011] Bonfanti et al. 2015b discloses TLR7 modulators in which the two rings of a purine moiety are spanned by a macrocycle:

##STR00005##

[0012] A TLR7 agonist can be conjugated to a partner molecule, which can be, for example, a phospholipid, a poly(ethylene glycol) ("PEG"), or another TLR (commonly TLR2). Exemplary disclosures include: Carson et al. 2013, 2015, and 2016, Chan et al. 2009 and 2011, Lioux et al. 2016, Maj et al. 2015, Ban et al. 2017; Vemejoul et al. 2014, and Zurawski et al. 2012. Conjugation to an antibody has also been disclosed: Akinbobuyi et al. 2013 and 2015a, and Gadd et al. 2015. A frequent conjugation site is at the R'' group of formula (A).

[0013] TLR7 agonists based on a 5H-pyrrolo[3,2-d]pyrimidine scaffold have also been disclosed. See Cortez et al. 2017a and 2017b, McGowan et al. 2017, and Li et al. 2018.

[0014] Jensen et al. 2015 discloses the use of cationic lipid vehicles for the delivery of TLR7 agonists.

[0015] Some TLR7 agonists, including resiquimod are dual TLR7/TLR8 agonists. See, for example, Beesu et al. 2017; Lioux et al. 2016; and Vemejoul et al. 2014.

[0016] TLR7 agonists based on a 5H-pyrrolo[3,2-d]pyrimidine scaffold have also been disclosed. See Cortez et al. 2017a and 2017b, McGowan et al. 2017, and Li et al. 2018.

[0017] Full citations for the documents cited herein by first author or inventor and year are listed at the end of this specification.

BRIEF SUMMARY OF THE INVENTION

[0018] In one aspect, this specification provides compounds having a structure according to formula (I)

##STR00006##

wherein [0019] R.sup.1 is (C.sub.1-C.sub.5 alkyl)O, (C.sub.1-C.sub.2 alkyl)O(CH.sub.2).sub.2-3O, (C.sub.1-C.sub.5 alkyl)C(.dbd.O)O, (C.sub.1-C.sub.5 alkyl)NH; (C.sub.1-C.sub.2 alkyl)O(CH.sub.2).sub.2-3NH, or (C.sub.1-C.sub.5 alkyl)C(.dbd.O)NH; [0020] R.sup.2 is, independently for each occurrence thereof, H, C.sub.1-C.sub.3 alkyl, halo, O(C.sub.1-C.sub.3 alkyl), CN, or NO.sub.2; [0021] R.sup.3 is H, Me, or (CH.sub.2).sub.xR.sup.4, where the subscript x is 2, 3, or 4; and [0022] R.sup.4 is H, halo, OH, CN, NH.sub.2, NH(C.sub.1-C.sub.5 alkyl), N(C.sub.1-C.sub.5 alkyl).sub.2, NH(C.sub.3-C.sub.6 cycloalkyl), NH(C.sub.4-C.sub.8 bicycloalkyl), NH(C.sub.6-C.sub.10 spirocycloalkyl), N(C.sub.3-C.sub.6 cycloalkyl).sub.2, NH(CH.sub.2).sub.1-3(aryl), N((CH.sub.2).sub.1-3(aryl)).sub.2, a cyclic amine moiety having the structure

##STR00007##

[0022] a 6-membered aromatic or heteroaromatic moiety or a 5-membered heteroaromatic moiety; [0023] wherein [0024] an alkyl, cycloalkyl, bicycloalkyl, spirocycloalkyl, cyclic amine, 6-membered aromatic or heteroaromatic, or 5-membered heteroaromatic moiety is optionally substituted with one or more substituents selected from OH, halo, CN, (C.sub.1-C.sub.3 alkyl), O(C.sub.1-C.sub.3 alkyl), C(.dbd.O)(Me), SO.sub.2(C.sub.1-C.sub.3 alkyl), C(.dbd.O)(Et), NH.sub.2, NH(Me), N(Me).sub.2, NH(Et), N(Et).sub.2, and N(C.sub.1-C.sub.3 alkyl).sub.2; and a cycloalkyl, bicycloalkyl, spirocycloalkyl, or cyclic amine moiety may have a CH.sub.2 group replaced by O, S, NH, N(C.sub.1-C.sub.3 alkyl), or N(Boc).

[0025] Compounds according to formula (I) have activity as TLR7 agonists and consequent and some of them can be conjugated for targeted delivery to a target tissue or organ of intended action. Thus, they can be used in the treatment of conditions amenable to treatment by activation of the immune system.


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