EP3962475A1 - Combination therapies comprising apremilast and tyk2 inhibitors - Google Patents

Combination therapies comprising apremilast and tyk2 inhibitors

Info

Publication number
EP3962475A1
EP3962475A1 EP19723291.1A EP19723291A EP3962475A1 EP 3962475 A1 EP3962475 A1 EP 3962475A1 EP 19723291 A EP19723291 A EP 19723291A EP 3962475 A1 EP3962475 A1 EP 3962475A1
Authority
EP
European Patent Office
Prior art keywords
day
substituted
per day
dioxo
methylsulfonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19723291.1A
Other languages
German (de)
English (en)
French (fr)
Inventor
Peter Henry SCHAFER
Robert PLENGE
Mary Adams
Lisa BEEBE
Gilles BUCHWALTER
Tiffany CARR
Te-Chen TZENG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Celgene Corp
Original Assignee
Celgene Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Celgene Corp filed Critical Celgene Corp
Publication of EP3962475A1 publication Critical patent/EP3962475A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • PDE4 phosphodiesterase type 4
  • cAMP cyclic adenosine monophosphate
  • Tyrosine kinase 2 (Tyk2), an intracellular signaling enzyme, activates signal transducer and activator of transcription (STAT)-dependent gene expression and functional responses of IL-12, IL-23, and type I and III interferon receptors.
  • STAT signal transducer and activator of transcription
  • TKIs tyrosine kinase inhibitors
  • BMS-986165 for example, recently showed positive results in phase 2 clinical trials in subjects with moderate to severe plaque psoriasis. See Kim Papp, M.D., Phase 2 Trial of Selective Tyrosine Kinase 2
  • BMS-986165 for example, increased TNF-a and GM-CSF cytokine in whole blood assay, while apremilast inhibited the production of these cytokines. See e.g., Table 5 where the % control for 1 ⁇ M apremilast was 10.7 and the % control for 0.01 ⁇ M BMS-986165 was 143.1 against TNF-a. When administered in combination, however, apremilast corrected the deficiency of BMS- 986165 thereby producing a complementary effect of 13.5% inhibition against TNF-a. See e.g., Table 5. This trend was also established at 0.1 ⁇ M concentrations of BMS-986165 and against cytokine GM-CSF. See e.g., Table 5. These results illustrate the synergistic and complementary pharmacological effects of BMS-986165 and apremilast.
  • BMS-986165 In addition to whole blood assay, the combination of BMS-986165 and apremilast elicit complementary effects against certain pro-inflammatory cytokines in LPS stimulated PBMCs as well. BMS-986165 increased IL-23, IL-12 and TNF-a, while apremilast inhibited the production of these cytokines. See e.g., Table 6 in the Exemplification section. These results further support the advantage of combining BMS-986165 and apremilast in treatment of Th17 related diseases.
  • diseases or disorders responsive to the inhibition of PDE4 in a subject using an effective amount of apremilast, or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor such as BMS-986165.
  • diseases and disorders include e.g., inflammatory diseases such as psoriasis, psoriatic arthritis, and ulcerative colitis.
  • compositions comprising an effective amount of apremilast, or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor such as BMS-986165.
  • FIG. 1 illustrates interleukin-17a (IL-17a) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1b, IL-6 and IL-23 (Th17) stimulated whole blood– TruCulture® tube assay.
  • IL-17a interleukin-17a
  • FIG. 2 illustrates interleukin-17A (IL-17A) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1b, IL-6 and IL-23 (Th17) stimulated whole blood– TruCulture® tube assay.
  • FIG. 3 illustrates interleukin-17F (IL-17F) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1b, IL-6 and IL-23 (Th17) stimulated whole blood– TruCulture® tube assay.
  • FIG. 4 illustrates interleukin-17F (IL-17F) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1b, IL-6 and IL-23 (Th17) stimulated whole blood– TruCulture® tube assay.
  • IL-17F interleukin-17F
  • FIG. 5 illustrates interleukin-22 (IL-22) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1b, IL-6 and IL-23 (Th17) stimulated whole blood– TruCulture® tube assay.
  • IL-22 interleukin-22
  • FIG. 6 illustrates interleukin-22 (IL-22) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1b, IL-6 and IL-23 (Th17) stimulated whole blood– TruCulture® tube assay.
  • IL-22 interleukin-22
  • FIG. 7 illustrates tumor necrosis factor alpha (TNF-a) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti- CD28, IL-1b, IL-6 and IL-23 (Th17) stimulated whole blood– TruCulture® tube assay.
  • TNF-a tumor necrosis factor alpha
  • FIG. 8 illustrates tumor necrosis factor alpha (TNF-a) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-1b, IL-6 and IL-23 (Th17) stimulated whole blood– TruCulture® tube assay.
  • TNF-a tumor necrosis factor alpha
  • FIG. 9 illustrates granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine production (percent of control) by apremilast and BMS-986165 in anti-CD3/anti- CD28 (Th0) or anti-CD3/anti-CD28, IL-1b, IL-6 and IL-23 (Th17) stimulated whole blood– TruCulture® tube assay.
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • FIG. 10 illustrates granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti- CD3/anti-CD28, IL-1b, IL-6 and IL-23 (Th17) stimulated whole blood– TruCulture® tube assay.
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • FIG. 11 illustrates interleukin-23 (IL-23) cytokine production by apremilast in Lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells (PBMCs).
  • LPS Lipopolysaccharide
  • PBMCs peripheral blood mononuclear cells
  • FIG. 12 illustrates interleukin-23 (IL-23) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
  • FIG. 13 illustrates interleukin-12p40 (IL-12p40) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
  • IL-12p40 interleukin-12p40
  • Tyk2i BMS-986165
  • FIG. 14 illustrates interleukin-12p70 (IL-12p70) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
  • FIG. 15 illustrates tumor necrosis factor alpha (TNF-a) cytokine production by apremilast and Tyk2i (B MS-986165) in LPS stimulated PBMCs.
  • TNF-a tumor necrosis factor alpha
  • FIG. 16 illustrates interferon gamma (IFN-g) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
  • IFN-g interferon gamma
  • FIG. 17 illustrates monocyte chemoattractant protein- 1 (MCP-1) cytokine production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
  • a disease or disorder responsive to the inhibition of cyclic nucleotide phosphodiesterase isoenzyme IV comprising administering to a subject an effective amount of N-[2-[(lS)-l-(3-ethoxy- 4-metho xyphenyl)-2-(methylsulfonyl)ethyl]-2, 3-dihydro- 1,3-dioxo- lH-isoindo 1-4- yl] acetamide (apremilast), or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor.
  • PDE4 cyclic nucleotide phosphodiesterase isoenzyme IV
  • 1,3-dioxo- lH-isoindol-4-yl] acetamide (apremilast), or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor, in the manufacture of a medicament for treating a disease or disorder responsive to the inhibition of cyclic nucleotide
  • PDE4 phosphodiesterase isoenzyme IV
  • 1,3-dioxo- lH-isoindol-4-yl] acetamide (apremilast), or a pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2 inhibitor, for use in treating a disease or disorder responsive to the inhibition of cyclic nucleotide phosphodiesterase isoenzyme IV (PDE4).
  • PDE4 cyclic nucleotide phosphodiesterase isoenzyme IV
  • Apremilast has a chiral center designated as (S) in the chemical structure and name.
  • this designation means that apremilast is optically enriched as the (S) enantiomer at this position in an amount of at least 80%, 90%, 95%, 98%, 99%, or 99.9% relative to the corresponding (R) enantiomer.
  • apremilast is referred to herein as being stereomerically or enantiomerically pure at a specified amount, it means that the (S) enantiomer is enriched in that amount.
  • N-[2-[(lS)-l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide that is at least 95% stereomerically pure means that the compound contains greater than or equal to 95% of the (S) enantiomer and 5% or less of the (R) enantiomer.
  • apremilast and a disclosed Tyk2 inhibitor are administered together.
  • apremilast and a disclosed Tyk2 inhibitor are administered at different times on the same day.
  • apremilast and a disclosed Tyk2 inhibitor are administered at different times as separate tablets or capsules.
  • apremilast and a disclosed Tyk2 inhibitor are administered in a fixed dose combination in the same tablet or capsule.
  • treatment refers to reversing, alleviating, or inhibiting the progress of a disease or disorder responsive to the inhibition of PDE4, or one or more symptoms thereof, as described herein.
  • the term“subject” means an animal, such as a mammal, and such as a human.
  • the terms“subject” and“patient” may be used interchangeably.
  • the term“effective amount” or“therapeutically effective amount” refers to an amount of a compound described herein that will elicit a biological or medical response of a subject e.g., a dosage of between 0.001 - 100 mg/kg body weight/day.
  • pharmaceutically acceptable carrier refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which is also safe for human use.
  • compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and crosscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
  • pharmaceutically acceptable salts refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • Suitable pharmaceutically acceptable base addition salts for the compounds described herein include, but are not limited to include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylene diamine, meglumine (N-methylglucamine) and procaine.
  • Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methane sulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
  • inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulf
  • Crystall refers to a solid form of a compound wherein there exists long-range atomic order in the positions of the atoms. The crystalline nature of a solid can be confirmed, for example, by examination of the X-ray powder diffraction pattern.
  • A“single crystalline form” means that the recited compound, i.e., N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, is present as a single crystal or a plurality of crystals in which each crystal has the same crystal form (e.g., crystalline Form B).
  • the crystal form is defined as a specified percentage of one particular single crystalline form of the compound, the remainder is made up of amorphous form and/or crystalline forms other than the one or more particular forms that are specified.
  • a disclosed crystalline form is at least 80% a single crystalline form, at least 90% a single crystalline form, at least 95% a single crystalline form, or at least 99% a single crystalline form by weight. Percent by weight of a particular crystal form is determined by the weight of the particular crystal form divided by the sum weight of the particular crystal, plus the weight of the other crystal forms present plus the weight of amorphous form present multiplied by 100%.
  • amorphous refers to a solid that is present in a non-crystalline state or form.
  • Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering.
  • Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy.
  • the 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation due to factors such as
  • Tyk2 inhibitors used in the disclosed methods and compositions include compounds which block the action of tyrosine kinase 2, a non-receptor tyrosine-protein kinase encoded by the Tyk2 gene.
  • the disclosed Tyk2 inhibitors include, but are not limited to, those described in Xingrui He et al., Expert Opinion on Therapeutics Patents 2019, Vol.
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • Tyk2 inhibitors as part of the third embodiment include those in WO 2008/139161, and WO 2010/055304, the entire contents of each of which are incorporated herein by reference.
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • Tyk2 inhibitors include those in WO 2012/062704, the entire contents of which are incorporated herein by reference.
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formulae:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those described in US 2015/0299139; WO 2015/069310; US 9,505,748; WO 2018/0162889; US 2013/0178478; or WO 2015/123453, the entire contents of each of which are incorporated herein by reference.
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • R 1 is C 1-3 alkyl optionally substituted by 0-7 R 1a ;
  • R 1a at each occurrence is independently hydrogen, deuterium, F, Cl, Br, CF 3 or CN;
  • R 2 is C 1-6 alkyl or-(CH 2 ) r -3-14 membered carbocycle, each group substituted with 0-4 R 2a ;
  • R 3 is C 3-10 cycloalkyl, C 6-10 aryl, or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 3a ;
  • R 3a at each occurrence is independently hydrogen, ⁇ O, halo, OCF 3 , CF 3 , CHF 2 , CN, NO 2 , -(CH 2 ) r OR b , -(CH 2 ) r SR b , -(CH 2 ) r C(O)R b , -(CH 2 ) r C(O)OR b , -(CH 2 ) r OC(O)R b , - (CH 2 ) r NR 11 R 11 , -(CH 2 ) r C(O)NR 11 R 11 , -(CH 2 ) r NR b C(O)R c , -(CH 2 ) r NR b C(O)OR c , - NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 , -NR b S(O) p R c , -S(
  • R 3a together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, S or O said fused ring further substituted by R a1 ;
  • R 4 and R 5 are independently hydrogen, C 1-4 alkyl substituted with 0-1 R f , (CH 2 ) r- phenyl substituted with 0-3 R d , or a -(CH 2 )-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
  • R 11 at each occurrence is independently hydrogen, C 1-4 alkyl substituted with 0-3 R f , CF 3 , C 3-10 cycloalkyl substituted with 0-1 R f , (CH) r -phenyl substituted with 0-3 R d , or - (CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R d ;
  • R a and R a1 at each occurrence are independently hydrogen, F, Cl, Br, OCF 3 , CF 3 , CHF 2 , CN, NO 2 , -(CH 2 ) r OR b , -(CH 2 ) r SR b , -(CH 2 ) r C(O)R b , -(CH 2 ) r C(O)OR b , -(CH 2 ) r OC(O)R b , -(CH 2 ) r NR 11 R 11 , -(CH 2 ) r C(O)NR 11 R 11 , -(CH 2 ) r NR b C(O)R c , -(CH 2 ) r NR b C(O)OR c , - NR b C(O)NR 11 R 11 , -S(O) p NR 11 R 11 , -NR b S(O) p R c ,
  • R b at each occurrence is independently hydrogen, C 1 - 6 alkyl substituted with 0-3 R d , C 1-6 haloalkyl, C 3-6 cycloalkyl substituted with 0-2 R d , or -(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R f or (CH 2 ) r -phenyl substituted with 0-3 R d ;
  • R c is C 1-6 alkyl substituted with 0-3 R f , (CH 2 ) r -C 3-6 cycloalkyl substituted with 0-3 R f , (CH 2 ) r -phenyl substituted with 0-3 R f ; or
  • R d at each occurrence is independently hydrogen, F, Cl, Br, OCF 3 , CF 3 , CN, NO 2 , - OR e , -(CH 2 ) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1-6 alkyl, or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R e at each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 3- 6 cycloalkyl, and (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R f independently at each occurrence is hydrogen, halo, CN, NH 2 , OH, C 3-6 cycloalkyl, CF 3 , O(C 1 - 6 alkyl), or a—(CH 2 ) r -5-7 membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p ;
  • p 0, 1, or 2;
  • r is 0, 1, 2, 3, or 4, wherein additional definitions and specific compounds can be found e.g., in US 2015/0299139, the entire contents of which are incorporated herein by reference.
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • R 1 is C 1-3 alkyl optionally substituted by 0-7 R 1a
  • R 1a at each occurrence is independently hydrogen, deuterium, F, CI, Br, CF 3 or CN;
  • R 2 is C 1-6 alkyl substituted with 0-4 R 2a , C 3-6 cycloalkyl substituted with 0-4 R 2a , C 6-10 aryl substituted with 0-4 R 2a , a 5-14 membered heterocycle containing 1-4
  • heteroatoms selected from N, O, and S, substituted with 0-4 R 2a , NR 6 R 6 or OR b ;
  • R 3 is -(CH 2 ) r -3-14 membered carbocycle substituted 0-5 R 3a ;
  • R 3a or two R 3a , together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, S or O, said fused ring may be further substituted by R a ;
  • R 4 and R 5 are independently hydrogen, C 1-4 alkyl substituted with 0-1 R f ,
  • R 6 and R 11 at each occurrence are independently hydrogen, C 1-4 alkyl substituted with 0-3 R f , CF 3 , C 3-10 cycloalkyl substituted with 0-1 R f , (CH) r -phenyl substituted with 0-3 R d , or -(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4
  • heteroatoms selected from N, O, and S(O) p substituted with 0-3 R d ;
  • R a at each occurrence is hydrogen, F, Cl, Br, OCF 3 , CF 3 , CHF 2 , CN, NO 2 ,
  • R b at each occurrence is hydrogen, C 1-6 alkyl substituted with 0-3 R d ,
  • heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R f , or (CH 2 ) r -phenyl substituted with 0-3 R d ;
  • R C is C 1-6 alkyl substituted with 0-3 R f , (CH 2 ) r -C 3-6 cycloalkyl substituted with 0-3 R f or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R d at each occurrence is independently hydrogen, F, Cl, Br, OCF 3 , CF 3 , CN, NO 2 , OR e , -(CH 2 ) r C(O)R C , NR e R e , -NR e C(O)OR C , C 1-6 alkyl or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R e at each occurrence is independently selected from hydrogen, C 1-6 alkyl,
  • R f independently at each occurrence is hydrogen, halo, CN, NH 2 , OH, C 3-6 cycloalkyl, CF 3 , O(C 1-6 alkyl) or a -(CH 2 ) r -5-7 membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p ;
  • p 0, 1, or 2;
  • r 0,1,2,3, or 4.
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • the disclosed Tyk2 inhibitors may be selected from those having the formula:
  • Y is N or CR 6 ;
  • R 1 is H, C 1-3 alkyl or C 3-6 cycloalkyl, each optionally substituted by 0-7 R 1a ;
  • R 1a at each occurrence is independently hydrogen, deuterium, F, Cl, Br or CN;
  • R 2 is C 1-6 alkyl, -(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R 2a or a 5-14 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 2a (for the sake of clarity, R 2 is intended to include substituted methyl groups such as -C(O)R 2a );
  • R 3 is C 3-10 cycloalkyl, C 6-10 aryl or a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, each group substituted with 0-4 R 3a ;
  • R 3a or two R 3a , together with the atoms to which they are attached, combine to form a fused ring wherein said ring is selected from phenyl and a heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , each fused ring substituted with 0- 3 R a1 ;
  • R 4 and R 5 are independently hydrogen, C 1-4 alkyl substituted with 0-1 R f , (CH 2 ) r- phenyl substituted with 0-3 R d or a -(CH 2 )-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p ;
  • R 6 is hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, OC 1-4 alkyl, CN, NO 2 or OH;
  • R 11 at each occurrence is independently hydrogen, C 1-4 alkyl substituted with 0-3 R f , CF 3 , C 3-10 cycloalkyl substituted with 0-1 R f , (CH) r -phenyl substituted with 0-3 R d or -(CH 2 ) r - 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R d ;
  • R a and R a1 at each occurrence are independently hydrogen, F, Cl, Br, OCF 3 , CF 3 , CHF 2 , CN, NO 2 , -(CH 2 ) r OR b , -(CH 2 ) r SR b , -(CH 2 ) r C(O)R b , -(CH 2 ) r C(O)OR b , -(CH 2 ) r OC(O)R b , -(CH 2 ) r NR 11 R 11 , -(CH 2 ) r C(O)NR 11 R 11 , -(CH 2 ) r NR b C(O)R c , -(CH 2 ) r NR b C(O)OR c , - NR b C(O)NR 11 R 11 , -S(O) p NR“R”, -NR b S(O) p R c , -
  • R b is hydrogen, C 1-6 alkyl substituted with 0-3 R d , C 1-6 haloalkyl, C 3-6 cycloalkyl substituted with 0-2 R d , or -(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R f or (CH 2 ) r -phenyl substituted with 0-3 R d ;
  • R c is C 1-6 alkyl substituted with 0-3 R f , (CH 2 ) r -C 3-6 cycloalkyl substituted with 0-3 R f or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R d at each occurrence is independently hydrogen, F, Cl, Br, OCF 3 , CF 3 , CN, NO 2 , - OR e , -(CH 2 ) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1-6 alkyl or (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R e at each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 3- 6 cycloalkyl and (CH 2 ) r -phenyl substituted with 0-3 R f ;
  • R f independently at each occurrence is hydrogen, halo, CN, NH 2 , OH, C 3-6 cycloalkyl, CF 3 , O(C 1-6 alkyl) or a -(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
  • p 0, 1, or 2;
  • r is 0, 1, 2, 3, or 4, wherein additional definitions and specific compounds are as described in US 9,505,748 and WO 2018/0162889, the entire contents of each of which are incorporated herein by reference.
  • the disclosed Tyk2 inhibitors may be selected from those having the formulae:
  • the Tyk2 inhibitor described herein is 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), having the following chemical structure:
  • the specific dosage and treatment regimen for a disclosed Tyk2 inhibitor to be used in combination with apremilast will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
  • the effective amount of a disclosed Tyk2 inhibitor (e.g., as in any one of the second to thirtieth embodiment) to be used in combination with apremilast ranges from 0.001 to 50 mg/kg body weight/day.
  • the effective amount of a disclosed Tyk2 inhibitor (e.g., as in any one of the second to thirtieth embodiment) to be used in combination with apremilast ranges from about 0.1 mg/day to about 250 mg/day, e.g., from about 0.2 mg/day to about 100 mg./day, about 0.5 mg/ day to about 50 mg/day, and about 1.0 mg to about 24 mg/day.
  • the Tyk2 inhibitor described herein is BMS-986165, or a pharmaceutically acceptable salt thereof, and the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof, ranges from about 0.1 mg/day to about 250 mg/day, about 0.1 mg/day to about 100 mg/day, about 0.1 mg/day to about 50 mg/day, about 0.1 mg/day to about 25 mg/day 0.1 mg/day to about 15 mg/day, about 0.1 mg/day to about 10 mg/day, about 0.5 mg/day to about 15 mg/day, about 0.5 mg/day to about 10 mg/day, about 0.1 mg/day to about 5 mg/day, about 0.5 mg/day to about 5 mg/day, about 1 mg/day to about 25 mg/day, about 2 mg/day to about 14 mg/day, about 2 mg/day to about 12 mg/day, or about 3 mg/day to about 12 mg/day.
  • the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof ranges from about 1 mg/day to about 15 mg/day, about 1 mg/day to about 14 mg/day, about 2 mg/day to about 14 mg/day, about 2 mg/day to about 12 mg/day, or about 3 mg/day to about 12 mg/day.
  • the Tyk2 inhibitor described herein is BMS-986165, or a pharmaceutically acceptable salt thereof, and the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof, is about 0.1 mg/day, about 0.5 mg/day, about 1.0 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day.
  • the effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof is about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day.
  • the effective concentration of BMS-986165, or a pharmaceutically acceptable salt thereof is about 1 nM to about 1 mM (e.g., from about 0.01 mM to about 0.1 pM).
  • apremilast is optically enriched as the (S) enantiomer.
  • the stereomeric purity of apremilast in the methods and compositions described herein is greater than 90%, wherein the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-third embodiments.
  • the stereomeric purity of apremilast in the methods and compositions described herein is greater than 95%, wherein the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- third embodiments.
  • the stereo meric purity of apremilast in the methods and compositions described herein is greater than 97%, wherein the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- third embodiments.
  • the stereo meric purity of apremilast in the methods and compositions described herein is greater than 98%, wherein the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-third embodiments.
  • the stereomeric purity of apremilast in the methods and compositions described herein is greater than 99%, wherein the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-third embodiments.
  • the stereomeric purity of apremilast in the methods and compositions described herein is greater than 99.5%, wherein the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-third embodiments.
  • the stereomeric purity of apremilast in the methods and compositions described herein is greater than 99.9%, wherein the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-third embodiments.
  • apremilast Polymorphic forms of apremilast are included in the disclosed methods and compositions and include e.g., those described in US 9,018,243, the entire contents of which are incorporated herein by reference.
  • apremilast in the disclosed methods and compositions is a single crystalline form, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-fourth embodiments.
  • apremilast in the disclosed methods and compositions is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 20.7°, and 26.9°, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-fourth embodiments.
  • apremilast in the disclosed methods and compositions is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 15.7°, 18.1°, 20.7°, 24.7°, and 26.9°, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-fourth embodiments.
  • apremilast in the disclosed methods and compositions is a single crystalline Form B characterized by X-ray powder diffraction peaks at 2Q angles selected from 10.1°, 13.5°, 15.7°, 16.3°, 18.1°, 20.7°, 22.5°, 24.7°, 26.2°, 26.9°, and 29.1°, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-fourth embodiments.
  • apremilast in the disclosed methods and compositions is at least 90% single crystalline Form B, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-sixth embodiments.
  • apremilast in the disclosed methods and compositions is at least 95% single crystalline Form B, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-sixth embodiments.
  • apremilast in the disclosed methods and compositions is at least 99% single crystalline Form B, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-sixth embodiments.
  • the specific dosage and treatment regimen of apremilast, or a pharmaceutically acceptable salt thereof, to be used in combination with a disclosed Tyk2 inhibitor will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from about 0.5 mg to about 1000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 10 mg to about 200 mg per day, about 10 mg to about 100 mg per day, about 40 mg to about 100 mg per day, about 20 mg to about 40 mg per day, about 0.1 mg to about 10 mg per day, about 0.5 mg to about 5 mg per day, about 1 mg to about 20 mg per day, and about 1 mg to about 10 mg per day, about 1 mg to about 100 mg per day, about 1 mg to about 80 mg per day, about 5 mg to about 70 mg per day, and about 10 mg to about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from about 10 mg to about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from about 10 mg to about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from about 10 mg to about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from between about 40 mg to between about 100 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from between about 40 mg to between about 100 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from about 4 mg to about 10 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof ranges from between about 4 mg to between about 10 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof is about 1 mg per day, about 2 mg per day, about 3 mg per day, about 4 mg per day, about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per day, about 40 mg per day, about 45 mg per day, about 50 mg per day, about 55 mg per day, or about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-seventh embodiments.
  • the effective amount of apremilast, or the pharmaceutically acceptable salt thereof is about 30 mg per day or about 60 mg per day, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-seventh embodiments.
  • apremilast is administered at a dose of about 30 mg once daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-seventh embodiments.
  • apremilast is administered at a dose of about 30 mg twice daily, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-seventh embodiments.
  • the effective concentration of apremilast is about 100 nM to about 10 ⁇ M (e.g., from about 0.1 ⁇ M to about 1 ⁇ M), wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-seventh embodiments.
  • apremilast is titrated to a dosage of about 30 mg administered twice daily using the following titration schedule:
  • Day 2 about 10 mg in morning and about 10 mg in evening;
  • Day 3 about 10 mg in morning and about 20 mg in evening;
  • Day 4 about 20 mg in morning and about 20 mg in evening;
  • apremilast is titrated to a dosage of between about 40 mg/day to between about 100 mg/day using the following titration schedule:
  • Day 2 about 10 mg in morning and about 10 mg in evening;
  • Day 3 about 10 mg in morning and about 20 mg in evening;
  • Day 4 about 20 mg in morning and about 20 mg in evening;
  • Day 5 about 20 mg in morning and about 30 mg in evening;
  • apremilast is titrated to a dosage of about 20 mg administered twice daily using the following titration schedule:
  • Day 2 about 10 mg in morning and about 10 mg in evening;
  • Day 3 about 10 mg in morning and about 20 mg in evening;
  • Day 4 about 20 mg in morning and about 20 mg in evening;
  • Day 5 about 20 mg in morning and about 30 mg in evening;
  • apremilast is titrated to a dosage of between about 4 mg/day to between about 10 mg/day using the following titration schedule:
  • Day 2 about 1 mg in morning and about 1 mg in evening;
  • Day 3 about 1 mg in morning and about 2 mg in evening;
  • Day 4 about 2 mg in morning and about 2 mg in evening;
  • Day 5 about 2 mg in morning and about 3 mg in evening;
  • apremilast is titrated to a dosage of about 3 mg administered twice daily using the following titration schedule:
  • Day 2 about 1 mg in morning and about 1 mg in evening;
  • Day 3 about 10 mg in morning and about 2 mg in evening;
  • Day 4 about 2 mg in morning and about 2 mg in evening;
  • Day 5 about 2 mg in morning and about 3 mg in evening;
  • compositions comprising a therapeutically effective amount of apremilast, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a Tyk2 inhibitor (e.g., BMS-986165).
  • a Tk2 inhibitor e.g., BMS-986165.
  • compositions comprising a therapeutically effective amount of apremilast, or a pharmaceutically acceptable thereof; and a
  • a Tyk2 inhibitor e.g., BMS-986165
  • a Tyk2 inhibitor for use in treating a disease or disorder responsive to the inhibition of PDE4.
  • a Tyk2 inhibitor e.g., BMS-986165
  • compositions and single unit dosage forms comprising apremilast and a Tyk2 inhibitor (e.g., BMS-986165) alone or together in a fixed dose for administration as described above (e.g., as in any one of the first to thirty-eighth embodiments) is included.
  • Single unit dosage forms of the disclosed methods and compositions are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non- aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suit able for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids)
  • composition, shape, and type of dosage forms of the will typically vary depending on their use.
  • inflammation or a related disorder may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder.
  • apremilast in the disclosed methods and compositions is administered parenterally, transdermally, mucosally, nasally, buccally, sublingually, or orally, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-eighth embodiments.
  • additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty-eighth embodiments.
  • apremilast in the disclosed methods and compositions is administered orally in the form of a tablet or a capsule, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- ninth embodiments.
  • apremilast in the disclosed methods and compositions is formulated as an extended release form, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- ninth embodiments.
  • compositions is formulated as an immediate release form, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to thirty- ninth embodiments.
  • both the apremilast and the Tyk2 inhibitor in the disclosed methods and compositions are administered in fixed dosage combination as a once a day formulation, wherein additional features for apremilast as well as the Tyk2 inhibitor and related features are as described herein e.g., as in any one of the first to forty-second embodiments.
  • Diseases or disorders that are responsive to the inhibition of PDE4 using the methods and compositions disclosed herein include e.g., viral, genetic, inflammatory, allergic, and autoimmune conditions.
  • the disease or disorder responsive to the inhibition of PDE4 is selected from chronic obstructive pulmonary disease, asthma, chronic pulmonary
  • inflammatory disease hyperoxic alveolar injury, inflammatory skin disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, atopic dermatitis, rheumatoid spondylitis, depression, osteoarthritis, contact dermatitis, ankylosing spondylitis, lupus, lupus nephritis, cutaneous lupus erythematosus, systemic lupus
  • the disease or disorder responsive to the inhibition of PDE4 is selected from psoriasis, psoriatic arthritis, contact dermatitis, systemic lupus erythrematosus, cutaneous lupus erythematosus, and ulcerative colitis.
  • the disease or disorder responsive to the inhibition of PDE4 is psoriasis. In another aspect, the disease or disorder responsive to the inhibition of PDE4 is psoriasis and the subject being treated is a candidate for phototherapy or systematic therapy.
  • the disease or disorder responsive to the inhibition of PDE4 is plaque psoriasis.
  • the disease or disorder responsive to the inhibition of PDE4 is plaque psoriasis and the subject being treated is a candidate for phototherapy or systematic therapy.
  • the disease or disorder responsive to the inhibition of PDE4 is moderate to severe plaque psoriasis. In another aspect, the disease or disorder responsive to the inhibition of PDE4 is severe plaque psoriasis and the subject being treated is a candidate for phototherapy or systematic therapy.
  • the disease or disorder responsive to the inhibition of PDE4 is psoriatic arthritis.
  • the disease or disorder responsive to the inhibition of PDE4 is active psoriatic arthritis.
  • the disease or disorder responsive to the inhibition of PDE4 is heart disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin- mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.
  • heart disease such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin- mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.
  • the disease or disorder responsive to the inhibition of PDE4 is HIV, hepatitis, adult respiratory distress syndrome, bone-resorption diseases, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, meningitis, fibrotic disease, cachexia, graft rejection, osteoporosis, multiple sclerosis, and radiation damage.
  • the disease or disorder responsive to the inhibition of PDE4 is cancer of the head, thyroid, neck, eye, skin, mouth, throat, esophagus, cheat, bone, blood, bone marrow, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, adrenal, subcutaneous tissue, lymph nodes, heart, and combinations thereof.
  • the disease or disorder responsive to the inhibition of PDE4 is multiple myeloma, malignant melanoma, malignant glioma, acute lymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute
  • myeloblastic leukemia acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, multiple myeloma and acute, lymphoblastic leukemia, myelogenous leukemia, lymphocytic leukemia, and myelocytic leukemia.
  • the disease or disorder responsive to the inhibition of PDE4 is a solid tumor, such as sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangio sarcoma, lymphangioendotheliosarcoma, syn-ovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary car-cinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,
  • sarcoma such
  • Table 1 Whole blood assay: Study Materials and Reagents.
  • Condition Th0 was a stimulation with
  • Condition Th17 was a stimulation with TruCulture® tubes containing anti-CD3/anti-CD28 plus IL-1b, IL-6 and IL-23.
  • Whole blood was separated into 15 milliliter conical tubes and pre-treated with DMSO, apremilast alone, BMS-986165 alone or BMS-986165 combined with apremilast. Final concentrations were 0.2% DMSO, 1 ⁇ M for apremilast alone, 1 ⁇ M, 0.1 ⁇ M, 0.01 ⁇ M and 0.001 ⁇ M BMS- 986165 alone and in combination with 1 ⁇ M apremilast. Blood was mixed well and then incubated in a 37oC/5%CO 2 incubator for 1 hour.
  • TruCulture® tubes were thawed on the bench top for 30 minutes and then labeled. Plungers were pressed and then broken off. TruCulture® tubes were placed in a rack standing upright such that the plunger side is pointing down in the rack and the tube-cap is pointing up. While blood was incubating with compound Human recombinant IL-6, IL-1b and IL-23 were added to all Th17 tubes in the following concentrations: 120 ng IL-6, 120 ng IL-1b and 150 ng IL-23.
  • PBMCs isolation Whole blood was received through the Celgene Donor program after informed consent and donor
  • Pellets were resuspended in 2%FBS-PBS and filtered through a 40 ⁇ m cell strainer to obtain single-cell suspension. 3ml of RBC lysis buffer were used to eliminate red blood cells in the isolated population. Isolated PBMCs were washed with 2%FBS-PBS and were resuspended in RPMI growth medium containing 10%FBS and antibiotics.
  • PBMCs from 9 healthy donors were isolated and LPS- stimulated ex-vivo for IL-23, IL-12p40, IL-12p70, TNF-a, IFN-g and MCP-1 cytokine analysis.
  • PBMCs were plated in 96 well plate at a density of 200,000 cells per well in 200 ⁇ l of RPMI growth medium containing 10%FBS followed by treatment with DMSO and compounds. Each well received the same amount of DMSO, which is 0.3% v/v as final concentration.
  • Series dilutions of compound treatment was performed according to Table 4 shown below. After two hours of compound treatment, LPS 100 ng/ml as final concentration was used as the stimulator.
  • PBMCs were then incubated in a 37oC/5%CO 2 incubator for 16 hours.
  • BMS-986165 had a similar effect under both stimulation conditions and inhibited 10-25% of IL-17A expression at 0.001-1 ⁇ M.
  • BMS- 986165 When apremilast was combined with BMS- 986165 under Th0 conditions there was synergy seen with 1 ⁇ M BMS-986165 with a 65% reduction in IL-17A. Under Th17 conditions there was synergy with the combination of 1 ⁇ M apremilast and 0.01 ⁇ M, 0.1 ⁇ M and 1 ⁇ M BMS-986165 with inhibition of 24%, 44% and 85% of IL-17A respectively.
  • FIG. 2 shows the picograms per milliliter levels of IL-17A. Levels of IL-17A increased in the Th17 stimulation conditions by 387% compared to the Th0 stimulation. In Th0 conditions apremilast reduced IL-17A levels from 138 pg/mL to
  • BMS-986165 at 1 ⁇ M reduced IL-17A levels to 97 pg/mL.
  • the combination of apremilast with 1 ⁇ M BMS-986165 further reduced IL-17A levels to 24pg/mL with the Th0 stimulation. Under Th17 conditions the stimulation control measured 532 pg/mL and apremilast did not inhibit IL-17A levels.
  • BMS-986165 reduced IL-17A levels to 519 pg/mL at 0.01 ⁇ M, 428 pg/mL at 0.1 ⁇ M and 383 pg/mL at 1 ⁇ M.
  • IL-17F cytokine expression data is in FIG. 3 and FIG. 4. Apremilast inhibited 69% of IL-17F production under Th0 conditions and 49% under Th17 conditions. BMS- 986165 had a similar effect on IL-17F with both the Th0 and Th17 stimulation. There was 31% inhibition at the lowest concentration of 0.001 ⁇ M and a dose response with 34% inhibition at 0.01 ⁇ M, 70% inhibition at 0.1 ⁇ M and 95% inhibition of IL-17F expression at 1 ⁇ M (Th17 results). The combination of 1 ⁇ M apremilast with BMS-986165 under Th0 conditions was partially additive with inhibition ranging from 60% at 0.001 to 95% at 1 ⁇ M.
  • IL-22 cytokine expression data is in FIG. 5 and FIG. 6. Apremilast inhibited 85% of IL-22 cytokine expression under Th0 conditions and 41% under Th17 conditions.
  • BMS-986165 inhibited 16% of IL-22 at 0.01 ⁇ M, 86% at 0.1 ⁇ M and 91% at 1 ⁇ M.
  • BMS-986165 had no effect on IL-22 cytokine expression at 0.001 ⁇ M but inhibited 17% at 0.01 ⁇ M, 60% at 0.1 ⁇ M and 70% at 1 ⁇ M. Under Th0 conditions the combination had similar effects to apremilast alone with ⁇ 90% inhibition at all concentrations of BMS-986165.
  • Th17 The combination under Th17 conditions was synergist at 0.01 ⁇ M with 60% inhibition and at 0.1 ⁇ M with 90% inhibition of IL-22 cytokine expression.
  • the Th0 stimulation control had 1085 pg/mL of IL-22 and the Th17 control was 6524 pg/mL.
  • Apremilast significantly lowered IL-22 levels to 368 pg/mL in the Th0 conditions and 3643 pg/mL in the Th17 conditions.
  • BMS-986165 significantly lowered IL-22 cytokine expression in both stimulation conditions at 0.1 ⁇ M and 1 ⁇ M.
  • TNF-a cytokine expression data is located in FIG. 7 and FIG. 8. Apremilast inhibited 90% of TNF-a levels in Th0 conditions and 94% in Th17 conditions.
  • BMS-986165 increased TNF-a expression by 21% at 0.001 ⁇ M, 43% at 0.01 ⁇ M and 61% at 0.1 ⁇ M.
  • BMS-986165 inhibited 66% of TNF-a cytokine expression.
  • Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) cytokine expression results are in FIG. 9 and FIG. 10.
  • GM-CSF cytokine expression was reduced 80% by apremilast under Th0 conditions and by 66% under Th17 conditions.
  • BMS-986165 increased GM-CSF cytokine expression under both conditions.
  • BMS-986165 increased GM- CSF by 19% at 0.001 ⁇ M, 36% at 0.01 ⁇ M, 110% at 0.1 ⁇ M and 31% at 1 ⁇ M in the Th0 conditions.
  • apremilast 0.1 ⁇ M
  • BMS-986165 increased GM- CSF by 41% at 0.01 ⁇ M, 139% at 0.1 ⁇ M and 104% at 1 ⁇ M. When apremilast was added there was 40-73% inhibition of GM-CSF cytokine expression. Total pg/mL of GM-CSF in the Th0 and Th17 stimulation controls were 409 and 637 respectively. Apremilast significantly inhibited GM-CSF under both stimulation conditions. The increase of GM-CSF by BMS-986165 was significant at 0.1 ⁇ M (both Th0 and Th17) and 1 ⁇ M (Th17). The combination of apremilast and BMS-986165 significantly reduced GM-CSF cytokine levels at all concentrations and under both stimulation conditions.
  • FIG. 11 PBMCs from 9 healthy donors were analyzed for cytokine production in LPS stimulation condition (FIG. 11 to FIG. 17). Results in FIG. 11 and FIG. 12 showed the level of IL-23.
  • FIG. 11 showed that Apremilast decreased IL-23 production in LPS stimulated PBMCs.
  • IL-23 level from DMSO treated LPS stimulated PBMCs was set as 100% (control), cytokine levels were shown as normalized value in % compared to control.
  • FIG. 12 showed that BMS-986165 induces IL-23 level in LPS stimulated PBMCs.
  • BMS-986165 induced a 20 fold increases of IL-23 compared to DMSO group.
  • the combination of apremilast with BMS- 986165 was able to decrease the induction of IL-23 by BMS-986165. With increased level of apremilast, there is significant reduction of IL-23 level.
  • Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS- 986165 alone. There is significant reduction of IL-23 when combining BMS-986165 with low level of apremilast, which is at the concentration of 0.037 ⁇ M (**** p ⁇ 0.001).
  • Results in FIG. 13 showed the normalized level of IL-12p40 compared to DMSO treated LPS stimulated PBMCs group.
  • Apremilast decreased IL-12p40 in a dose dependent manner, whereas BMS-986165 increased it.
  • the combination of BMS-986165 with apremilast significantly decreased the induction of IL-12p40 by BMS-986165.
  • With 1 ⁇ M apremilast the increased IL-12p40 induced by BMS-986165 was 85% inhibited, and almost reached a similar level as Apremilast alone.
  • Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS- 986165 alone. **** p ⁇ 0.001
  • Results in FIG. 14 showed the normalized level of IL-12p70 compared to DMSO treated LPS stimulated PBMCs group. Apremilast decreased IL-12p70 in a dose dependent manner, whereas BMS-986165 increased it. The combination of BMS-986165 with apremilast significantly decreased the induction of IL-12p70 by BMS-986165. In combination treatment, both 0.3 ⁇ M and 1 ⁇ M significantly reduced IL-12p70 level induced by BMS-986165 and have no significant difference compared to apremilast alone. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS-986165 alone. **** p ⁇ 0.001
  • Results in FIG. 15 showed the normalized level of TNF-a compared to DMSO treated LPS stimulated PBMCs group. Apremilast decreased TNF- a level in a dose dependent manner, however, BMS-986165 induced 1.2-1.5 fold increase of TNF-a. The combination of BMS-986165 and apremilast significantly decreased the level of TNF-a. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS-986165 alone. **** p ⁇ 0.001
  • Results in FIG. 16 showed the normalized level of IFN-g compared to DMSO treated LPS stimulated PBMCs group. Both apremilast alone and BMS-986165 alone decreased IFN-g in a dose dependent manner. The combination of BMS-986165 and apremilast has synergistic effect in reducing IFN-g level which significantly decreased IFN- g level compared to single compound treatment. Statistical analysis using ANOVA and Turkey’s multiple comparisons were performed to compare each treatment with BMS- 986165 alone. **** p ⁇ 0.001.
  • Results in FIG. 17 showed the normalized level of MCP-1 compared to DMSO treated LPS stimulated PBMCs group. Both apremilast alone and BMS-986165 alone decreased MCP-1 in a dose dependent manner. The combination of BMS-986165 and
  • Table 5 provides a summary of the cytokine effects of apremilast and BMS-986165 on stimulated whole blood in the Ex-Vivo TruCulture® Assay. Synergistic effects are shown in bold and complementary effects are underlined.
  • BMS-986165 increased TNF-a and GM-CSF production, while apremilast inhibited production of these cytokines.
  • BMS-986165 was combined with apremilast there was a complementary effect on TNF-a and GM-CSF cytokine expression, with apremilast correcting the defect of BMS-986165.
  • These combined effect provide means for treating diseases or disorders responsive to the inhibition of PDE4 such as for the treatment inflammatory diseases (e.g., psoriasis, psoriatic arthritis, and ulcerative colitis).
  • Table 6 provides a summary of the cytokine effects of apremilast and BMS-986165 on LPS stimulated PBMCs. Arrows pointing up indicate induction and arrows pointing down indicate decrease of the production of cytokines.
  • PBMCs from 9 healthy donors were tested in LPS stimulated condition with or without BMS-986165 or apremilast or the combination of both.
  • BMS-986165 treatment alone induced IL-23, IL-12p40, IL-12p70 and TNF-a, whereas apremilast treatment alone decreased these cytokines.
  • BMS-986165 was combined with apremilast, these cytokines were either unchanged or reduced compared to DMSO control group.
  • BMS-986165 Both apremilast and BMS-986165 reduced IFN-g and MCP-1 production, and the combination of both further reduced these two cytokines with a synergistic effect.
  • BMS-986165 inhibits Thl7 lineage cytokines, which provide a means for treating diseases where Thl7 cytokines are implicated in the pathogenesis.
  • the induction of some proinflammatory cytokines, such as IL-23, IL-12 and TNF-a, by BMS-986165 could be a disadvantage in disease treatment.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Indole Compounds (AREA)
  • Medicinal Preparation (AREA)
EP19723291.1A 2019-04-30 2019-04-30 Combination therapies comprising apremilast and tyk2 inhibitors Pending EP3962475A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2019/029772 WO2020222773A1 (en) 2019-04-30 2019-04-30 Combination therapies comprising apremilast and tyk2 inhibitors

Publications (1)

Publication Number Publication Date
EP3962475A1 true EP3962475A1 (en) 2022-03-09

Family

ID=66476870

Family Applications (2)

Application Number Title Priority Date Filing Date
EP19723291.1A Pending EP3962475A1 (en) 2019-04-30 2019-04-30 Combination therapies comprising apremilast and tyk2 inhibitors
EP20725978.9A Pending EP3962476A1 (en) 2019-04-30 2020-04-30 Combination therapies comprising apremilast and tyk2 inhibitors

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP20725978.9A Pending EP3962476A1 (en) 2019-04-30 2020-04-30 Combination therapies comprising apremilast and tyk2 inhibitors

Country Status (14)

Country Link
EP (2) EP3962475A1 (es)
JP (2) JP2022537877A (es)
KR (2) KR20220002488A (es)
CN (2) CN114269336A (es)
AU (2) AU2019443366A1 (es)
BR (2) BR112021021809A2 (es)
CA (2) CA3138473A1 (es)
CL (1) CL2021002847A1 (es)
CO (2) CO2021015622A2 (es)
IL (2) IL287665A (es)
MA (1) MA55799A (es)
MX (2) MX2021013317A (es)
SG (2) SG11202112043PA (es)
WO (2) WO2020222773A1 (es)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG11202112043PA (en) 2019-04-30 2021-11-29 Celgene Corp Combination therapies comprising apremilast and tyk2 inhibitors
TW202246232A (zh) 2021-02-19 2022-12-01 英商蘇多生物科學有限公司 Ｔｙｋ２抑制劑及其用途
AU2022350509A1 (en) * 2021-09-23 2024-04-04 Bristol-Myers Squibb Company Methods of treating hair-loss disorders with tyk2 inhibitors
CA3236262A1 (en) 2021-10-25 2023-05-04 Isaac Marx Tyk2 degraders and uses thereof

Family Cites Families (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6962940B2 (en) * 2002-03-20 2005-11-08 Celgene Corporation (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
US7893101B2 (en) 2002-03-20 2011-02-22 Celgene Corporation Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof
GB0709031D0 (en) 2007-05-10 2007-06-20 Sareum Ltd Pharmaceutical compounds
GB0820819D0 (en) 2008-11-13 2008-12-24 Sareum Ltd Pharmaceutical compounds
US8367689B2 (en) * 2009-05-06 2013-02-05 Portola Pharmaceuticals, Inc. Inhibitors of JAK
AU2011328237A1 (en) 2010-11-09 2013-05-23 Cellzome Limited Pyridine compounds and aza analogues thereof as TYK2 inhibitors
WO2012149251A1 (en) * 2011-04-28 2012-11-01 Celgene Corporation Methods and compositions using pde4 inhibitors for the treatment and management of autoimmune and inflammatory diseases
UA113750C2 (xx) 2011-12-27 2017-03-10 Склад (+)-2-$1-(3-етокси-4-метоксифеніл)-2-метансульфонілетил]-4-ацетиламіноізоіндолін-1,3-діону
RU2627661C2 (ru) 2012-01-10 2017-08-09 Ф. Хоффманн-Ля Рош Аг Соединения пиридазинамида и их применение в качестве ингибиторов тирозинкиназы селезенки (syk)
EP2832734A4 (en) 2012-03-28 2015-08-26 Takeda Pharmaceutical HETEROCYCLIC CONNECTION
US9296725B2 (en) 2012-05-24 2016-03-29 Cellzome Limited Heterocyclyl pyrimidine analogues as TYK2 inhibitors
UY35126A (es) 2012-11-08 2014-05-30 Bristol Myers Squibb Co Ojo es alfa
EA028052B1 (ru) * 2012-11-08 2017-10-31 Бристол-Майерс Сквибб Компани АЛКИЛАМИДЗАМЕЩЁННЫЕ ПИРИМИДИНОВЫЕ СОЕДИНЕНИЯ, ПРИГОДНЫЕ ДЛЯ МОДУЛЯЦИИ IL-12, IL-23 И/ИЛИ IFNα
WO2014151180A1 (en) * 2013-03-14 2014-09-25 Celgene Corporation Treatment of psoriatic arthritis using apremilast
EP3029031A4 (en) 2013-07-30 2017-01-11 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2015032423A1 (en) 2013-09-03 2015-03-12 Sareum Limited Pharmaceutical compounds
AR094537A1 (es) 2013-11-07 2015-08-12 Bristol Myers Squibb Co COMPUESTOS DE PIRIDILO SUSTITUIDOS CON ALQUILAMIDA ÚTILES COMO MODULADORES DE LAS RESPUESTAS DE IL-12, IL-23 Y/O IFNa
CN105992768B (zh) 2013-12-10 2018-04-20 百时美施贵宝公司 用作IL‑12、IL‑23和/或IFNα响应的调节剂的咪唑并哒嗪化合物
WO2015091584A1 (en) 2013-12-18 2015-06-25 F. Hoffmann-La Roche Ag Thiazolopyridine compounds, compositions and their use as tyk2 kinase inhibitors
WO2015123453A1 (en) 2014-02-14 2015-08-20 Portola Pharmaceuticals, Inc. Pyridazine compounds as jak inhibitors
ES2921874T3 (es) 2014-02-28 2022-09-01 Nimbus Lakshmi Inc Inhibidores de TYK2 y usos de los mismos
EP3157520B1 (en) 2014-06-23 2019-09-04 Celgene Corporation Apremilast for the treatment of a liver disease or a liver function abnormality
US10092541B2 (en) * 2014-08-15 2018-10-09 Celgene Corporation Methods for the treatment of diseases ameliorated by PDE4 inhibition using dosage titration of apremilast
NO2721710T3 (es) 2014-08-21 2018-03-31
WO2016047678A1 (ja) 2014-09-25 2016-03-31 武田薬品工業株式会社 複素環化合物
TWI788655B (zh) 2015-02-27 2023-01-01 美商林伯士拉克許米公司 酪胺酸蛋白質激酶2(tyk2)抑制劑及其用途
EP4327809A3 (en) 2015-09-02 2024-04-17 Takeda Pharmaceutical Company Limited Tyk2 inhibitors and uses thereof
DK3419978T3 (da) 2016-02-24 2020-06-02 Pfizer Pyrazolo[1,5-A]pyrazin-4-yl-derivater som JAK-hæmmere
ES2902995T3 (es) 2016-10-07 2022-03-30 Bristol Myers Squibb Co Compuestos de imidazopiridazina útiles como moduladores de respuestas a IL-12, IL-23 y/o IFN alfa
US10323036B2 (en) 2016-10-14 2019-06-18 Nimbus Lakshmi, Inc. TYK2 inhibitors and uses thereof
WO2018075937A1 (en) 2016-10-21 2018-04-26 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
WO2018081488A1 (en) 2016-10-28 2018-05-03 Bristol-Myers Squibb Company Heterobicyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
CN110191887B (zh) 2016-11-17 2022-02-18 百时美施贵宝公司 IL-12、IL-23和/或IFN-α的咪唑并哒嗪调节剂
GB2562702B (en) 2017-03-06 2022-05-18 Linear Shaped Ltd Frame and linear shaped charge
TW202321243A (zh) * 2017-03-08 2023-06-01 美商林伯士拉克許米公司 Ｔｙｋ２抑制劑之生產方法
SG11202112043PA (en) 2019-04-30 2021-11-29 Celgene Corp Combination therapies comprising apremilast and tyk2 inhibitors

Also Published As

Publication number Publication date
KR20220002489A (ko) 2022-01-06
CL2021002847A1 (es) 2022-07-22
CA3138473A1 (en) 2020-11-05
JP7453251B2 (ja) 2024-03-19
IL287670A (en) 2021-12-01
EP3962476A1 (en) 2022-03-09
IL287665A (en) 2022-07-01
MA55799A (fr) 2022-03-09
AU2020266143A1 (en) 2021-12-02
CN114206333A (zh) 2022-03-18
JP2022537877A (ja) 2022-08-31
MX2021013317A (es) 2022-01-18
CA3138686A1 (en) 2020-11-05
MX2021013318A (es) 2022-01-31
SG11202112018YA (en) 2021-11-29
AU2019443366A1 (en) 2021-12-02
WO2020222773A1 (en) 2020-11-05
KR20220002488A (ko) 2022-01-06
BR112021021809A2 (pt) 2022-01-04
BR112021021826A2 (pt) 2022-01-04
CN114269336A (zh) 2022-04-01
BR112021021826A8 (pt) 2022-06-21
WO2020223431A1 (en) 2020-11-05
CO2021015614A2 (es) 2021-12-10
SG11202112043PA (en) 2021-11-29
JP2022537878A (ja) 2022-08-31
CO2021015622A2 (es) 2022-02-28

Similar Documents

Publication Publication Date Title
US11357775B2 (en) Combination therapies comprising apremilast and Tyk2 inhibitors
EP3962475A1 (en) Combination therapies comprising apremilast and tyk2 inhibitors
RU2316318C2 (ru) Фармацевтическая композиция, включающая ингибитор ренина, блокатор кальциевых каналов и диуретик
JP2006176542A (ja) フェニルエテンスルホンアミド誘導体含有医薬
KR102303052B1 (ko) Jak 저해제를 포함하는 제약 조성물
JP2019537615A (ja) シェーグレン症候群の治療におけるペオニフロリン−６’−ｏ−ベンゼンスルホン酸の使用
JP2022538403A (ja) がんの治療のためのｅｇｆｒ阻害剤
JP6775699B2 (ja) インドール化合物を用いた疼痛又は間質性膀胱炎の治療方法
WO2003065970A2 (en) Treatment of fibromyalgia and related fatigue syndromes using pindolol
US20220009889A1 (en) Polymorphic form of meisoindigo and modified formulation of meisoindigo
WO2020078445A1 (zh) 一种治疗纤维化疾病的药物组合或药物组合物
US20070082903A1 (en) Remedy for rheumatoid arthritis
WO2021224494A1 (en) New treatments of viral infections
AU2016212625B2 (en) Prevention or treatment of uric acid or gout disease
JPH03130218A (ja) 子宮弛緩剤及び膀胱弛緩剤

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20211130

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40071641

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230529

17Q First examination report despatched

Effective date: 20230706

RAP3 Party data changed (applicant data changed or rights of an application transferred)

Owner name: CELGENE CORPORATION