WO2008029237A2 - Polythérapies destinées au traitement de l'arthrite rhumatoïde - Google Patents

Polythérapies destinées au traitement de l'arthrite rhumatoïde Download PDF

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Publication number
WO2008029237A2
WO2008029237A2 PCT/IB2007/002468 IB2007002468W WO2008029237A2 WO 2008029237 A2 WO2008029237 A2 WO 2008029237A2 IB 2007002468 W IB2007002468 W IB 2007002468W WO 2008029237 A2 WO2008029237 A2 WO 2008029237A2
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alkyl
methyl
amino
pyrrolo
pyrimidin
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WO2008029237A3 (fr
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Paul Steven Changelian
Samuel Hyman Zwillich
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Pfizer Products Inc
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Pfizer Products Inc
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    • 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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This disclosure relates to pharmaceutical combination therapies for the treatment or prevention of arthritic disorders or conditions in a human, such as rheumatoid arthritis, comprising a Janus Kinase inhibitor such as the presently disclosed pyrrolo[2,3-d]pyrimidine compounds or a pharmaceutically acceptable salt thereof, which are inhibitors of protein kinases, such as the enzyme Janus Kinase 3 (sometimes referred to herein as JAK3) and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof.
  • a Janus Kinase inhibitor such as the presently disclosed pyrrolo[2,3-d]pyrimidine compounds or a pharmaceutically acceptable salt thereof
  • JAK3 Janus Kinase 3
  • This disclosure also relates to methods for the treatment or prevention of such arthritic disorders or conditions and uses of such pharmaceutical combination therapies, and pharmaceutical compositions thereof.
  • JAK3 is a member of the Janus family of protein kinases. Although the other members of this family are expressed by essentially all tissues, JAK3 expression is limited to hematopoietic cells. This is consistent with its essential role in signaling through the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL- 21 by non-covalent association of JAK3 with the gamma chain common to these multichain receptors. SCID patient populations have been identified with severely reduced levels of JAK3 protein or with genetic defects to the common gamma chain, suggesting that immunosuppression should result from blocking signaling through the JAK3 pathway.
  • JAK3 not only plays a critical role in B and T lymphocyte maturation, but that JAK3 is constitutively required to maintain T cell function. Modulation of immune activity through this novel mechanism can prove useful in the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases, such as rheumatoid arthritis.
  • Certain pharmaceutical combination therapies comprising certain Janus kinase inhibitors such as the presently disclosed pyrrolo[2,3-d]pyrimidine compounds are effective for treating or preventing arthritic disorders or conditions in a human, such as arthritis including rheumatoid arthritis.
  • this disclosure relates to a pharmaceutical combination therapy for the treatment or prevention of rheumatoid arthritis in a human comprising a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof.
  • the Janus Kinase inhibitor is a compound of the formula or a pharmaceutically acceptable salt thereof; wherein R 1 is a group of the formula
  • y is 0, 1 or 2;
  • R 4 is selected from the group consisting of hydrogen, (CrC 6 )alkyl, (CrC ⁇ Jalkylsulfonyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 4 )alkoxy, (C r C 6 )acyloxy, (C r C 6 )alkylamino, ((C 1 - C 6 )alkyl) 2 amino, cyano, nitro, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 1 -C 6 )acylamino; or R 4 is (C 3 - C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium, hydroxy, amino
  • R 5 is (C 2 -C 8 )heterocycloalkyl wherein the heterocycloalkyl groups must be substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (CrC 6 )alkyl, (Ci-C 6 )alkoxy, halo, (C 1 -C 6 JaCyI, (C 1 - C 6 )alkylamino, amino(Ci-C 6 )alkyl, (C 1 -C 6 JaIkOXy-CO-NH, (C r C 6 )alkylamino-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (CrC ⁇ alkylamino, amino(C r C 6 )alkyl, hydroxy(C r C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 - C
  • Y is S(O) n wherein n is 0, 1 or 2; or carbonyl;
  • Z is carbonyl, C(O)O-, C(O)NR- or S(O) n wherein n is 0, 1 or 2;
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen or (C r C 6 )alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 - C 6 )acyloxy, (Ci-C 6 )acylamino, (Ci-C 6 )alkylamino, ((Ci-C 6 )alkyl) 2 amino, cyano, cyano ⁇ -C ⁇ alkyl, trifluoromethyl(C r C 6 )alkyl, nitro, nitro(C-
  • R 12 is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (Ci-C 6 )alkyi, trifluoromethyl(C r C 6 )alkyl, (C 1 -C 6 JaIkOXy, halo, (CrC 6 )acyl, (CrC 6 )alkylamino, ((Ci-C 6 )alkyl) 2 amino, amino(CrC 6 )alkyl, (C r C 6 )alkoxy-CO-NH, (C-rCeOalkylamino-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 )alkylamino, hydroxy(Ci-C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyl
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 JaI kynyl, trifluoromethyl, trifluoromethoxy, (C 1 - C 6 )alkyl, (C-rC 6 )alkoxy, (C 3 -Ci 0 )cycloalkyl wherein the alkyl, alkoxy or cycloalkyl groups are optionally substituted by one to three groups selected from halo, hydroxy, carboxy, amino (Ci-C 6 )alkylthio, (C 1 - C 6 )alkylamino, ((CrC ⁇ alkyl ⁇ amino, (C 5 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl, (C 3 -C 9 )cycloalkyl or (C 6
  • the Janus Kinase inhibitor is a compound of the Formula I; or a pharmaceutically acceptable salt thereof; wherein
  • R ⁇ 1 is a group of the formula
  • y is 0, 1 or 2;
  • R 4 is selected from the group consisting of hydrogen, (C ⁇ C 6 )alkyl, (Ci-C 6 )alkylsulfonyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C ⁇ aIkOXy, (C r C 6 )acyloxy, (CrC 6 )alkylamino, ((C 1 - C 6 )alkyl) 2 amino, cyano, nitro, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C-rC ⁇ Jacylamino; or R 4 is (C 3 - C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium, hydroxy, amino
  • R 5 is a piperidinyl substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C 1 - C 6 )alkyl, (C r C 6 )alkoxy, halo, (C r C 6 )acyl, (C r C 6 )alkylamino, amino(Ci-C 6 )alkyl, (C r C 6 )alkoxy-CO-NH, (C-i-CeJalkylamino-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 )alkylamino, amino(C r C 6 )alkyl, hydroxy(C- ⁇ - C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl,
  • Y is S(O) n wherein n is 0, 1 or 2; or carbonyl;
  • Z is carbonyl, C(O)O-, C(O)NR- or S(O) n wherein n is 0, 1 or 2;
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen or (C r C 6 )alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 - C 6 )acyloxy, (C-rC ⁇ acylamino, (C r C 6 )alkylamino, ((C 1 -C 6 )alky)) 2 amino, cyano, cyano(C-
  • R 12 is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (CrC 6 )alkyl, trifluoromethyKC-rC ⁇ alkyl, (C 1 -C 6 JaIkOXy, halo, (CrC 6 )acyl, (Ci-C 6 )alkylamino, ((C-rC 6 )alkyl) 2 amino, amino(C r C 6 )alkyl, (C r C 6 )alkoxy-CO-NH, (C-rC f Oalkylamino-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 1 - C 6 )alkylamino, hydroxy(C 1 -C 6 )alkyl, (C r C 6 )alkoxy(CrC 6 )aikyl, (C 1 -C 6 )acyloxy
  • R 2 and R 3 are each hydrogen.
  • the Janus Kinase inhibitor is a compound of the Formula I;
  • R 1 is a group of the formula
  • R 4 is (C r C 6 )alkyl
  • R 5 is piperidinyl substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C 1 - C 6 )alkyl, (C r C 6 )alkoxy, halo, (CrC 6 )acyl, amino(CrC 6 )alkyl, (C- ⁇ -C 6 )alkoxy-CO-NH, amino(C r C 6 )alkyl, hydroxy(C-p C 6 )alkyl, (C r C 6 )alkoxy(Ci-C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -C 6 )alkyl, nitro, cyano(C r C 6 )alkyl, halo(C 1 -C 6 )alkyl, nitro(C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyKC-i-CeJalkyl, (CrC ⁇ Jacylamin
  • m 0, 1 or 2;
  • R 15 and R 16 are each independently selected from hydrogen or (C r C 6 )alkyl; d Is 1 ;
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen or (Ci-C 6 )alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C-
  • R 12 is cyano, trifluoromethyl, (C r C 6 )alkyl, trifluoromethyKC-i-CeJalkyl, (Ci-C 6 )alkylamino, ((C 1 - C 6 )alkyl) 2 amino, (C 2 -C 6 )alkynyl, cyano(C 1 -C 6 )alkyl, (C r C 6 )alkyl-S(O) m wherein m is 0, 1 or 2; and
  • R 2 and R 3 are each H.
  • R 12 is cyano, trifluoromethyl, (Ci-C 6 )alkyl, trifluoromethyl(C r C 6 )alkyl, (C 1 -C 6 )alkylamino, ((Ci-C 6 )alkyl) 2 amino, (C 2 -C 6 )alkynyl, cyano(C r C 6 )alkyl, (C r C 6 )alkyl-S(O) m wherein m is 0, 1 or 2.
  • the Janus Kinase inhibitor is selected from the group consisting of:
  • the Janus Kinase inhibitor is selected from the group consisting of:
  • the Janus Kinase inhibitor is selected from the group consisting of:
  • the Janus Kinase inhibitor is a compound of the formula IA:
  • the Janus Kinase inhibitor is a compound of the formula I:
  • the Janus Kinase inhibitor is a compound of the formula
  • R 1 , A, B, and W are as defined by claim 1 of U.S. Publication No. 2005/0137201 , the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. Publication No. 2005/0137201 , particularly those which are mentioned as being JAK3 inhibitors at Example 173.
  • the Janus Kinase inhibitor is a compound of any one of the formula 500- 511 that is substituted with one or more groups A 0 as defined by U.S. Publication No. 2005/0261253, the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. Publication No. 2005/0261253.
  • the Janus Kinase inhibitor is a compound of the formula I:
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined by claim 1 of U.S. Publication No. 2006/0183906, the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. Publication No. 2006/0183906.
  • the Janus Kinase inhibitor is a compound of the formula I:
  • D 1 , D 2 , D 3 , D 4 , A, and B are as defined by claim 1 of U.S. Publication No. 2006/0106020, the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. Publication No. 2006/0106020.
  • the Janus Kinase inhibitor is a compound mentioned as being a JAK3 kinase inhibitor in WO 2005/105146, particularly at pages 12-17, the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor is a compound of the formula I:
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined by claim 1 of U.S. Publication No. 2004/0214817, the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. Publication No. 2004/0214817, particularly those which are mentioned as being JAK3 inhibitors at Example 9.
  • the Janus Kinase inhibitor is a compound of the formula I:
  • R 1 , R 2 , R 3 , R 4 , R 5 , A and x are as defined by claim 1 of U.S. Publication No. 2006/0122213, the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. Publication No. 2006/0122213, particularly those shown at Tables I and II.
  • the Janus Kinase inhibitor is a compound of the formula I: i
  • R 1 , R 2 , Z 1 , Z 2 , and Z 3 are as defined by claim 1 of U.S. Publication No. 2006/0183761 , the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. Publication No. 2006/0183761 , particularly those shown at Tables I and II.
  • the Janus Kinase inhibitor is a compound of the formula I: (D
  • R 1 , R 3 , R 5 , X 1 , X 2 and X 3 are as defined by claim 1 of U.S. Publication No. 2005/0165029, the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. Publication No. 2005/0165029.
  • the Janus Kinase inhibitor is a compound of the formula I:
  • R 1 , R 2 , R 3 , R 5 , X 1 , and X 2 are as defined by claim 1 of U.S. Publication No. 2005/0187389, the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. Publication No. 2005/0187389.
  • the Janus Kinase inhibitor is a compound of the formula I:
  • R 1 , R 2 , R 3 , R 4 , and Y are as defined by claim 1 of U.S. 6,943,161 , the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. 6,943,161 , particularly those shown at Table I.
  • the Janus Kinase inhibitor is a compound of the formula I:
  • R 1 , R 2 , R 3 , R 4 , X, X 1 , X 2 , and Y are as defined by claim 1 of U.S. Publication No. 2005/0277642, the contents of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. Publication No. 2005/0277642, particularly those shown at Table I.
  • the Janus Kinase inhibitor is a compound of the formula I:
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and X are as defined by U.S. Nos. 6,452,005 and related U.S. Nos. 6,313,129; 6,313,130; 6,177,433; 6,080,747; 6,326,373; 6,080,748 and U.S. Publication Nos. 2004/0192711 and 2005/0187233, the contents all of which are generally and specifically hereby incorporated here by reference for all purposes.
  • the Janus Kinase inhibitor can also be any other compound specifically described in U.S. Nos. 6,452,005 and related U.S. Nos.
  • the Janus Kinase inhibitor is any one of the JAK3 inhibitors shown in Figure 1 of Jack J. Chen, et al., Development of Pyrimidine-Based Inhibitors of Janus Tyrosine Kinase 3. Bioorganic & Medicinal Chemistry Letters (2006), doi.1016/j.bmcl.2006.08.0822.
  • the Janus Kinase inhibitor can also be any other compound specifically described therein, particularly in Tables I and II.
  • the anti-arthritic agent is an NSAID (Non-Steroidal Anti-Inflammatory Drug) or a COX-2 (Cyclo-oxygenase 2) inhibitor selected from the group consisting of acetylsalicylic acid and other salicylates such as choline magnesium trisalicylate, azapropazone, carprofen, celecoxib, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenbufen, fenoprofen, flufenamic acid, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, meloxicam, nabumetone, naproxen, naproxen sodium, oxaprozin, pirprofen, suprofen, salsalate, sulindac, tenoxicam, tiaprofenic acid, and tolmetin.
  • NSAID Non-S
  • the anti-arthritic agent is a glucocorticoid (oral, parenteral and/or intraarticular) selected from the group consisting of hydrocortisone acetate, hydrocortisone tert butyl acetate, dexamethasone acetate, dexamethasone tert butyl acetate, prednisolone, prednisolone acetate, prednisolone tert butyl acetate, prednisone, methylprednisolone methylprednisolone acetate, triamcinolone acetonide, triamcinolone diacetonide, and triamcinolone hexacetonide.
  • glucocorticoids will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • the anti-arthritic agent is a SCE (Small Chemical Entity) DMARD (Disease Modifying Anti-Rheumatic Drug) selected from the group consisting of hydroxychloroquine, chloroquine, dapsone, sulfasalazine, methotrexate, leflunomide, azathioprine, d-penicillamine, cyclosporine A, and gold compounds such as gold sodium thiomalate, aurothioglucose, and auranofin.
  • SCE Mall Chemical Entity
  • DMARD Disease Modifying Anti-Rheumatic Drug
  • the anti-arthritic agent is a biologic DMARD selected from the group consisting of etanercept, infliximab, adalimumab, anakinra, abatacept, rituximab, tocilizumab, and certolizumab pegol.
  • a biologic DMARD selected from the group consisting of etanercept, infliximab, adalimumab, anakinra, abatacept, rituximab, tocilizumab, and certolizumab pegol.
  • the anti-arthritic agent is an analgesic such as acetaminophen.
  • analgesic such as acetaminophen.
  • Other suitable analgesics will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • the anti-arthritic agent is an opioid optionally in combination with acetaminophen selected from the group consisting of morphine, codeine, propoxyphene, hydrocodone, methadone, hydromorphone, oxycodone, fentanyl, buprenorphine, and butorphanol.
  • opioids selected from the group consisting of morphine, codeine, propoxyphene, hydrocodone, methadone, hydromorphone, oxycodone, fentanyl, buprenorphine, and butorphanol.
  • Other suitable opioids will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • this disclosure relates to a method for treating or preventing rheumatoid arthritis in a human comprising co-administering to human a therapeutically effective amount of both a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof, wherein the Janus Kinase inhibitor and the anti-arthritic agents are defined as described herein.
  • this disclosure relates to a pharmaceutical combination therapy for the treatment or prevention of psoriatic arthritis comprising a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof, wherein the Janus Kinase inhibitor and the anti-arthritic agents are defined as described herein.
  • this disclosure relates to a method for treating or preventing psoriatic arthritis in a human comprising co-administering to human a therapeutically effective amount of both a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof, wherein the Janus Kinase inhibitor and the anti-arthritic agents are defined as described herein.
  • this disclosure relates to a pharmaceutical combination therapy for the treatment or prevention of ankylosing spondylitis comprising a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof, wherein the Janus Kinase inhibitor and the anti-arthritic agents are defined as described herein.
  • this disclosure relates to a method for treating or preventing ankylosing spondylitis in a human comprising co-administering to human a therapeutically effective amount of both a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof, wherein the Janus Kinase inhibitor and the anti-arthritic agents are defined as described herein. Additional features and advantages of the pharmaceutical combinations and methods thereof disclosed herein will be apparent from the following detailed description of certain embodiments.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties or combinations thereof.
  • alkoxy includes O-alkyl groups wherein “alkyl” is defined above.
  • halo as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.
  • (C 2 -C 9 )heterocycloalkyl refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1 ,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1- yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1
  • (C 2 -C 9 )heteroaryl refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,3-oxadiazolyl, 1 ,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1 ,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, cinnoliny
  • (C 2 -C 8 )heterocycloalkyl rings is through a carbon atom or a sp 3 hybridized nitrogen heteroatom.
  • (C 6 -C 10 )aryl when used herein refers to phenyl or naphthyl.
  • the term "pharmaceutical combination therapy” or just “combination therapy” as used herein generally refers to the administration of a Janus Kinase inhibitor in combination with one or more anti- arthritic agents disclosed herein.
  • the term “pharmaceutical combination therapy” means the Janus Kinase inhibitor, such as a compound of formula (I), may be administered concomitantly in a pharmaceutically acceptable form with one or more of the anti-arthritic agents disclosed herein: (i) in the same dosage form, e.g., the same tablet or pharmaceutical composition meaning a pharmaceutical composition comprising a Janus Kinase inhibitor, such as a compound of formula (I), one or more anti- arthritic agents disclosed herein, and a pharmaceutically acceptable carrier; (H) in a separate dosage form having the same mode of administration, e.g., a kit comprising a first pharmaceutical composition suitable for oral administration comprising a Janus Kinase inhibitor, such as a compound of formula (I) and a pharmaceutically acceptable carrier
  • kits comprising a first pharmaceutical composition suitable for oral administration comprising a Janus Kinase inhibitor, such as a compound of formula (I) and a pharmaceutically acceptable carrier, a second pharmaceutical composition suitable for oral administration comprising a first anti-arthritic agent disclosed herein and a pharmaceutically acceptable carrier, and a third pharmaceutical composition suitable for parenteral administration comprising a second anti-arthritic agent disclosed herein and a pharmaceutically acceptable carrier.
  • a kit comprising a first pharmaceutical composition suitable for oral administration comprising a Janus Kinase inhibitor, such as a compound of formula (I) and a pharmaceutically acceptable carrier, a second pharmaceutical composition suitable for oral administration comprising a first anti-arthritic agent disclosed herein and a pharmaceutically acceptable carrier, and a third pharmaceutical composition suitable for parenteral administration comprising a second anti-arthritic agent disclosed herein and a pharmaceutically acceptable carrier.
  • the concomitant administration referred to above in the context of a "pharmaceutical combination therapy” means that the pharmaceutical composition comprising a Janus Kinase inhibitor and a pharmaceutical composition(s) comprising the anti-arthritic agent can be administered on the same schedule, i.e., at the same time and day, or on a different schedule, i.e., on different, although not necessarily distinct, schedules.
  • the pharmaceutical composition comprising a Janus Kinase inhibitor and a pharmaceutical composition(s) comprising the anti- arthritic agent may also be referred to herein as "background” or “background administration.”
  • the pharmaceutical composition comprising a Janus Kinase inhibitor may be administered in a certain dosage form twice a day, and the pharmaceutical composition(s) comprising the anti-arthritic agent may be administered once a day, such that the pharmaceutical composition comprising the Janus Kinase inhibitor may but not necessarily be administered at the same time as the pharmaceutical composition(s) comprising the anti-arthritic agent during one of the daily administrations.
  • other suitable variations to "pharmaceutical combination therapy” will be readily apparent to those of skill in the art given the benefit of the present disclosure and are part of the meaning of this term.
  • Janus Kinase inhibitor means a compound(s) that demonstrates an inhibitory effect against one or more Janus Kinases, i.e., one of JAK1 , JAK2, and JAK3, as measured by the Biological Assays disclosed herein.
  • Exemplary Janus Kinase inhibitors include those of Formula I disclosed here.
  • a preferable Janus Kinase inhibitor is 3- ⁇ (3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-amino]-piperidin-1-yl ⁇ -3-oxo-propionitrile or a pharmaceutically acceptable salt thereof.
  • co-administering means the “concomitant” administering of a Janus Kinase inhibitor and one or more an anti-arthritic agents, as the term “concomitant” is used in the definition of "pharmaceutical combination therapy”.
  • this disclosure relates to a pharmaceutical combination therapy for the treatment or prevention of rheumatoid arthritis in a human comprising a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof.
  • the Janus Kinase inhibitor is a compound of the formula
  • R 1 is a group of the formula
  • y is 0, 1 or 2;
  • R 4 is selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, (CrC 6 )alkylsulfonyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 -C 4 JaIkOXy, (C 1 -C 6 JaCyIoXy, (C r C 6 )alkylamino, ((C 1 - C 6 )alkyl) 2 amino, cyano, nitro, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C r C 6 )acylamino; or R 4 is (C 3 - C 10 )cycloalkyl wherein the cycloalkyl group is optionally substituted by deuterium
  • R 5 is (C 2 -Cg)heterocycloalkyl wherein the heterocycloalkyl groups must be substituted by one to five carboxy, cyano, amino, deuterium, hydroxy, (C 1 -C 6 JaIkVl 1 (C 1 -C 6 JaIkOXy, halo, (C 1 -C 6 JaCyI, (C 1 - CeJalkylamino, amino(C r C 6 )alkyl, (C 1 -C 6 JaIkOXy-CO-NH, (CrCeJalkylamino-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C r C 6 )alkylamino, amino(C 1 -C 6 )alkyl, hydroxy(C-i -C 6 JaI kyl, (C 1 -C 6 JaIkOXy(C 1 -C 6 JaIkVl,
  • R 16 are each independently selected from hydrogen or (C r C 6 )alkyl; or a group of the formula
  • Y is S(O) n wherein n is 0, 1 or 2; or carbonyl;
  • Z is carbonyl, C(O)O-, C(O)NR- or S(O) n wherein n is 0, 1 or 2;
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen or (CrC 6 )alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C 1 - C 6 )acyloxy, (CrC ⁇ acylamino, (Ci-C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 amino, cyano, cyano(C 1 -C 6 )alkyl, trifluoromethyKCrCeJalkyl, nitro, nitro(CrC 6 )alkyl or (CrC 6 )acylamino;
  • R 12 is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (Ci-C 6 )alkyl, trifluoromethyl(C ⁇ C 6 )alkyl, (C r C 6 )alkoxy, halo, (CrC ⁇ acyl, (C r C 6 )alkylamino, ((C 1 -C 6 JaIKyI) 2 amino, amino(C 1 -C 6 )alkyl, (CrCeJalkoxy-CO-NH, (CrC ⁇ alkylamino-CO-, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C r C 6 )alkylamino, hydroxy(Ci-C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )acyloxy(C 1 -
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, trifluoromethyl, trifluoromethoxy, (C 1 - C 6 )alkyl, (C-
  • the Janus Kinase inhibitor is selected from the group consisting of:
  • the Janus Kinase inhibitor is 3- ⁇ 4-Methyl-3-[methyl-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-amino]-piperidin-1-yl ⁇ -3-oxo-propionitrile or a pharmaceutically acceptable salt thereof.
  • the Janus Kinase inhibitor is 3- ⁇ (3R,4R)-4-Methyl-3-[methyl-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl ⁇ -3-oxo-propionitrile or a pharmaceutically accpetable salt thereof.
  • the pharmaceutically acceptable salt of 3- ⁇ 4-Methyl-3-[methyl-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl ⁇ -3-oxo-propionitrile and/or 3- ⁇ (3R,4R)-4-Methyl-3- [methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl ⁇ -3-oxo-propionitrile is a citrate salt, such as a mono citrate salt.
  • such compounds are crystalline, as discussed in U.S. Patent No. 6,965,027, the contents of which are hereby incorporated here by reference.
  • the Janus Kinase inhibitors of the present disclosure can be in the form of a pharmaceutically acceptable acid addition salt.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this disclosure are those which form non-toxic acid addition salts, Le., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [Le., 1 ,1'-methylene-bis-(2-hydroxy-3- naphthoate)]salts.
  • the Janus Kinase inhibitors of the present disclosure can be in the form of a pharmaceutically acceptable base addition salt.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • Janus Kinase inhibitors mentioned here are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present disclosure from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this disclosure are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
  • Janus Kinase inhibitors mentioned here are acidic in nature, and are capable of forming base salts with various pharmacologically acceptable cations.
  • examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this disclosure are those which form non-toxic base salts with the acidic compounds of the present disclosure.
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
  • salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • the Janus Kinase inhibitor is a compound specified and/or exemplified in:
  • the Janus Kinase inhibitors of the present disclosure include all conformational isomers (e.g.. cis and trans isomers) and mixtures thereof. Such compounds have asymmetric centers readily apparent to those of skill in the art and therefore exist in different enantiomeric and diastereomeric forms.
  • This disclosure relates to the use of all optical isomers and stereoisomers of such compounds used in the present disclosure, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them. In this regard, this disclosure includes both the E and Z configurations.
  • resolution of racemic mixtures of enantiomers of compounds, used in providing the R 1 substituent of formula I is effected by treating the racemic mixture of the compound of formula HNR 4 R 5 , e.g., a compound of formula III below, with a specific optical isomer of a disubstituted tartaric acid or tartrate in an appropriate solvent such as ethanol with or without water as a co-solvent.
  • the desired enantiomer can be obtained in excess of 90% using such methods disclosed in U.S. Serial No. 10/154,699, the contents of which are hereby incorporated herein by reference for all purposes.
  • Specific resolving agents useful in said resolution include optical isomers of tartaric acid and tartaric acid derivatives such as di-p-toluoyl-L-tartaric acid and (S)-(+)-Andeno acid (pencyphos, (S)-(+)-2-hydroxy-5,5- dimethyl-4-phenyl-1 ,3,2-dioxyphosphorinane-2-oxide) salt.
  • optical isomers of tartaric acid and tartaric acid derivatives such as di-p-toluoyl-L-tartaric acid and (S)-(+)-Andeno acid (pencyphos, (S)-(+)-2-hydroxy-5,5- dimethyl-4-phenyl-1 ,3,2-dioxyphosphorinane-2-oxide) salt.
  • suitable resolving agents potentially useful for resolving such compounds of formula HNR 4 R 5 .
  • the Janus Kinase inhibitors of the present disclosure may also exist as tautomers. This disclosure relates to the use of all such tautomers and mixtures thereof.
  • Interaction between antipodes of the resolving material and specific enantiomer provides a resolution of the racemic mixture whereby a precipitate of the resolving material and enantiomer provides one of the desired stereos pecific materials and wherein the remaining enantiomer in solution can be separately isolated thereby.
  • the stereospecific nature of the resolving nature can be concomitantly selected; e.g. an "L" form of the resolving agent such as a tartrate derivative provides a precipitate of an "R" form of the R 1 substituent and a solution containing the "L” form and vice versa.
  • resolution of the compound of formula III is effected by the steps of: a) mixing a racemic mixture of the compound of formula III in an appropriate solution with a resolving compound, having a defined stereospecificity, for a time sufficient to allow substantial precipitation of a stereospecific isomer of the racemic mixture from the solution; b) depending on the stereospecific form of the compound which is desired, collecting either the precipitate and purifying it or collecting the mother liquor and recrystallizing the enantiomer contained therein.
  • a slurry rather than a solution is formed with the resolution of the present disclosure involving a slurry to slurry conversion.
  • solution encompasses both a solution and a slurry.
  • the temperature at which the resolution and precipitation is effected is preferably ambient temperature and while precipitation time is not restricted for efficiency the time is preferably no more than about four hours.
  • the compound of formula Il is most stable in acid addition salt form such as a hydrochloride salt, rather than a free base form and it is preferred that the racemic compound mixture be accordingly converted prior to resolution.
  • formation of the hydrochloride salt of the compound of formula Il is effected preferably in ethanol with a small amount of toluene as cosolvent.
  • methanol, isopropanol, acetonitrile, or tetrahydrofuran (or mixtures thereof with or without water as a cosolvent) with cosolvents of toluene, ethylacetate, dichloromethane, dichloroethane, or tetrahydrofuran may be used in the salt formation.
  • the HCI salt is particularly preferred since this form provides a superior purification and enriched of other stereoisomers from the prior step.
  • a preferred displacement solvent used in the resolution is ethyl acetate. Toluene, acetonitrile, or heptanes are also useful as solvents.
  • a preferred isolation solvent is acetone.
  • Other solvents useful in this regard include isopropanol, ethanol, methyl ethyl ketone, methyl isopropyl ketone, acetonitrile, and tetrahydrofuran.
  • the solvents may also be used as co-solvents with each other or with water.
  • Preferred resolution compounds include tartaric acid and its derivatives such as toluoyl and benzoyl tartaric acids in stereospecific conformation, as described.
  • Other resolution compounds include stereospecific adeno acid and derivatives thereof.
  • compositions containing prodrugs of_the Janus Kinase inhibitors of the present disclosure such as the compounds of the formula I and the use of such prodrugs in the presently disclosed pharmaceutical combination therapies.
  • Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula I.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-am inobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
  • reaction 1 of Preparation A the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI, wherein R is hydrogen or a protecting group such as benzenesulfonyl or benzyl, is converted to the 4- chloro-5-halopyrrolo[2,3-d]pyrimidine compound of formula XX, wherein Y is chloro, bromo or iodo, by reacting XXI with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide. The reaction mixture is heated to reflux, in chloroform, for a time period between about 1 hour to about 3 hours, preferably about 1 hour.
  • reaction 1 of Preparation A the 4-chloropyrrolo[2,3-d]pyrimidine of formula XXI, wherein R is hydrogen, is converted to the corresponding 4-chloro-5-nitropyrrolo[2,3-d]pyrimidine of formula XX, wherein Y is nitro, by reacting XXI with nitric acid in sulfuric acid at a temperature between about -1O 0 C to about 1O 0 C, preferably about O 0 C, for a time period between about 5 minutes to about 15 minutes, preferably about 10 minutes.
  • reaction 2 of Preparation A the 4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound of formula XX, wherein R is hydrogen, is converted to the corresponding compound of formula XIX, wherein R 2 is (Ci-C 6 )alkyl or benzyl, by treating XX with N-butyllithium, at a temperature of about -78 0 C, and reacting the dianion intermediate so formed with an alkylhalide or benzylhalide at a temperature between about - 78 0 C to room temperature, preferably room temperature.
  • the dianion so formed is reacted with molecular oxygen to form the corresponding 4-chloro-5-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XIX, wherein R 2 is hydroxy.
  • the compound of formula XX, wherein Y is bromine or iodine and R is benzenesulfonate, is converted to the compound of formula XIX, wherein R 2 is (C 6 -C 12 )aryl or vinyl, by treating XX with N-butyllithium, at a temperature of about -78 0 C, followed by the addition of zinc chloride, at a temperature of about -78 0 C.
  • the corresponding organo zinc intermediate so formed is then reacted with aryliodide or vinyl iodide in the presence of a catalytic quantity of palladium.
  • the reaction mixture is stirred at a temperature between about 50 0 C to about 8O 0 C, preferably about 7O 0 C, for a time period between about 1 hour to about 3 hours, preferably about 1 hour.
  • the compound of formula XIX is converted to the corresponding compound of formula XVI by treating XIX with N-butyllithium, lithium diisopropylamine or sodium hydride, at a temperature of about -78 0 C, in the presence of a polar aprotic solvent, such as tetrahydrofuran.
  • a polar aprotic solvent such as tetrahydrofuran.
  • the anionic intermediate so formed is further reacted with (a) alkylhalide or benzylhalide, at a temperature between about -78 0 C to room temperature, preferably -78 0 C, when R 3 is alkyl or benzyl; (b) an aldehyde or ketone, at a temperature between about -78 0 C to room temperature, preferably -78 0 C, when R 3 is alkoxy; and (c) zinc chloride, at a temperature between about -78 0 C to room temperature, preferably - 78 0 C, and the corresponding organozinc intermediate so formed is then reacted with aryliodide or vinyl iodide in the presence of a catalytic quantity of palladium.
  • reaction mixture is stirred at a temperature between about 5O 0 C to about 8O 0 C, preferably about 7O 0 C, for a time period between about 1 hour to about 3 hours, preferably about 1 hour.
  • the anion so formed is reacted with molecular oxygen to form the corresponding 4-chloro-6-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XVI, wherein R 3 is hydroxy.
  • reaction 1 of Preparation B the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI is converted to the corresponding compound of formula XXII, according to the procedure described above in reaction 3 of Preparation A.
  • reaction 2 of Preparation B the compound of formula XXII is converted to the corresponding compound of formula XVI, according to the procedures described above in reactions 1 and 2 of Preparation A.
  • reaction 1 of Scheme 1 the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XVII is converted to the corresponding compound of formula XVI, wherein R is benzenesulfonyl or benzyl, by treating XVII with benzenesulfonyl chloride, benzylchloride or benzylbromide in the presence of a base, such as sodium hydride or potassium carbonate, and a polar aprotic solvent, such as dimethylformamide or tetrahydrofuran.
  • the reaction mixture is stirred at a temperature between about O 0 C to about 70 0 C, preferably about 3O 0 C, for a time period between about 1 hour to about 3 hours, preferably about 2 hours.
  • the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XVI is converted to the corresponding 4-aminopyrrolo[2,3-d]pyrimidine compound of formula XV by coupling XVI with an amine of the formula HNR 4 R 5 .
  • the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XVI is coupled with the enantiomer obtained with the resolution of NHR 4 R 5 , i.e. a single stereoisomer of formula III, to arrive at the corresponding 4-aminopyrrolo[2,3-d]pyrimidine compound of formula XV, which has the same stereochemistry as the resolved reactant of formula NHR 4 R 5 .
  • the coupling reaction 2 in such embodiments proceeds without inversion or loss of stereochemistry and instead proceeds with retention of stereochemistry.
  • the reaction is carried out in an alcohol solvent, such as tert-butanol, methanol or ethanol, or other high boiling organic solvents, such as dimethylformamide, triethylamine, 1,4-dioxane or 1 ,2-dichloroethane, at a temperature between about 60 0 C to about 120 0 C, preferably about 8O 0 C.
  • Typical reaction times are between about 2 hours to about 48 hours, preferably about 16 hours.
  • R 5 is a nitrogen containing heterocycloalkyl group
  • each nitrogen must be protected by a protecting group, such a benzyl.
  • Removal of the R 5 protecting group is carried out under conditions appropriate for that particular protecting group in use which will not affect the R protecting group on the pyrrolo[2,3-d]pyrimidine ring.
  • Removal of the R 5 protecting group, when benzyl, is carried out in an alcohol solvent, such as ethanol, in the presence of hydrogen and a catalyst, such as palladium hydroxide on carbon.
  • the R 5 nitrogen containing heterocycloalkyl group so formed may be further reacted with a variety of different electrophiles of formula II.
  • electrophiles of formula Il such as isocyanates, carbamates and carbamoyl chlorides are reacted with the R 5 nitrogen of the heteroalkyl group in a solvent, such as acetonitrile or dimethylformamide, in the presence of a base, such as sodium or potassium carbonate, at a temperature between about 20 0 C to about 100 0 C for a time period between about 24 hours to about 72 hours.
  • a solvent such as acetonitrile or dimethylformamide
  • electrophiles of formula II such as acylchlorides and sulfonyl chlorides
  • a solvent such as methylene chloride
  • a base such as pyridine
  • Amide formation may also be carried out by reacting a carboxylic acid with the heteroalkyl group in the presence of a carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in a solvent such as methylene chloride at ambient temperatures for 12-24 hours.
  • electrophiles of formula II such as ⁇ , ⁇ -unsaturated amides, acids, nitriles, esters, and ⁇ -halo amides, are reacted with the R 5 nitrogen of the heteroalkyl group in a solvent such as methanol at ambient temperatures for a time period between about 12 hours to about 18 hours.
  • Alkyl formation may also be carried out by reacting aldehydes with the heteroalkyl group in the presence of a reducing agent, such as sodium cyanoborohydride, in a solvent, such as methanol, at ambient temperature for a time period between about 12 hours to about 18 hours.
  • a reducing agent such as sodium cyanoborohydride
  • reaction 3 of Scheme 1 removal of the protecting group from the compound of formula XV, wherein R is benzenesulfonyl, to give the corresponding compound of formula I, is carried out by treating XV with an alkali base, such as sodium hydroxide or potassium hydroxide, in an alcohol solvent, such as methanol or ethanol, or mixed solvents, such as alcohol/tetrahydrofuran or alcohol/water.
  • an alkali base such as sodium hydroxide or potassium hydroxide
  • alcohol solvent such as methanol or ethanol
  • mixed solvents such as alcohol/tetrahydrofuran or alcohol/water.
  • the reaction is carried out at room temperature for a time period between about 15 minutes to about 1 hour, preferably 30 minutes.
  • Removal of the protecting group from the compound of formula XV, wherein R is benzyl is conducted by treating XV with sodium in ammonia at a temperature of about -78 0 C for a time period between about 15 minutes to about 1 hour.
  • reaction 3 of Scheme 2 the compound of formula XXIII is converted to the corresponding compound of formula XV, according to the procedure described above in reaction 3 of Preparation A.
  • reaction 1 of Scheme 3 the compound of formula XVII is converted to the corresponding compound of formula I, according to the procedure described above in reaction 2 of Scheme JL
  • the anti-arthritic agent is an NSAID (Non-Steroidal Anti-Inflammatory Drug) or COX-2 (Cyclo-OXygenase 2) inhibitor selected from the group consisting of acetylsalicylic acid (e.g., Aspirin®) and other salicylates such as choline magnesium trisalicylate (e.g., Trilisate®), azapropazone, carprofen, celecoxib (e.g., Celebrex®, as described in U.S. Patent Nos., 5,466,823; 5,563,165; 5,760,068; 5,972,986); valdecoxib (e.g., Bextra®, as described in U.S.
  • NSAID Non-Steroidal Anti-Inflammatory Drug
  • COX-2 Cyclo-OXygenase 2
  • acetylsalicylic acid e.g., Aspirin®
  • other salicylates such as choline magnesium trisal
  • Patent Nos., 5,601 ,843; 5,698,225 diflunisal (e.g., Dolobid®), etodolac (e.g., Lodine®), fenbufen, fenoprofen (e.g., Nalfon®), flufenamic acid, flurbiprofen (e.g., Ansaid®), ibuprofen (e.g., Advil®), indomethacin (e.g., Indocin®), ketoprofen (e.g., Orudis®), meclofenamate (e.g., Meclomen®), mefenamic acid (e.g., Ponstel®), meloxicam (e.g., Mobic®, as described in U.S.
  • diflunisal e.g., Dolobid®
  • etodolac e.g., Lodine®
  • fenbufen e.g.
  • Patent No. 6,184,220 nabumetone (e.g., Relafen®), naproxen (e.g., Aleve®), naproxen sodium, oxaprozin (e.g., Daypro®), pirprofen, suprofen, salsalate (e.g., Disalcid®, Salflex®), sulindac (e.g., Clinorii®), tenoxicam, tiaprofenic acid, and tolmetin (e.g., Tolectin®).
  • nabumetone e.g., Relafen®
  • naproxen e.g., Aleve®
  • pirprofen pirprofen
  • suprofen salsalate
  • sulindac e.g., Clinorii®
  • tenoxicam tiaprofenic acid
  • tolmetin e.g., Tolectin®
  • the anti-arthritic agent is a glucocorticoid (oral, parenteral and/or intraarticular) selected from the group consisting of hydrocortisone acetate, hydrocortisone tert butyl acetate, dexamethasone acetate, dexamethasone tert butyl acetate, prednisolone, prednisolone acetate, prednisolone tert butyl acetate, prednisone, methylprednisolone methylprednisolone acetate, triamcinolone acetonide, triamcinolone diacetonide, and triamcinolone hexacetonide.
  • glucocorticoids will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • the anti-arthritic agent is a SCE DMARD (Disease Modifying Anti- Rheumatic Drug) selected from the group consisting of hydroxychloroquine (e.g., Plaquenil®), chloroquine, dapsone, sulfasalazine (e.g., Azulfidine®), methotrexate (e.g., Trexall®, Methotrex®), leflunomide (e.g., Arava®), azathioprine (e.g., Imuran®), d-penicillamine (e.g., Cuprimine®), cyclosporine A (e.g., Sandimmune®) and gold compounds including gold sodium thiomalate (e.g., Aurolate), aurothioglucose (e.g., Solganal), and auranofin (e.g., Ridaura®).
  • SCE DMARD Disease Modifying Anti- Rheumatic Drug
  • the anti-arthritic agent is a biologic DMARD selected from the group consisting of etanercept (e.g., Enbrel®), infliximab (e.g., Remicade®), adalimumab (e.g., Humira®), anakinra (e.g., Kineret®), abatacept (e.g., Orencia®), rituximab (e.g., Rituxan®), tocilizumab (e.g., Actemra®), and certolizumab pegol.
  • etanercept e.g., Enbrel®
  • infliximab e.g., Remicade®
  • adalimumab e.g., Humira®
  • anakinra e.g., Kineret®
  • abatacept e.g., Orencia®
  • rituximab e.g
  • the anti-arthritic agent when the anti-arthritic agent is a DMARD, the anti-arthritic agent preferably is methotrexate (sometimes referred to herein as "MTX").
  • methotrexate sometimes referred to herein as "MTX"
  • the anti-arthritic agent is an analgesic, such as acetaminophen (e.g., Tylenol®).
  • analgesic such as acetaminophen (e.g., Tylenol®).
  • suitable analgesics will be readily apparent to those of skill in the art given the benefit of the present disclosure.
  • the anti-arthritic agent is an opioid optionally in combination with acetaminophen selected from the group consisting of morphine, codeine, propoxyphene (e.g., Darvocet®), hydrocodone (e.g., Vicodin®), methadone (e.g., Dolophine®), hydromorphone (e.g., Dilaudid®), oxycodone (e.g., Percocet®), fentanyl, buprenorphine (e.g., Subutex®), and butorphanol (e.g., Stadol®).
  • acetaminophen selected from the group consisting of morphine, codeine, propoxyphene (e.g., Darvocet®), hydrocodone (e.g., Vicodin®), methadone (e.g., Dolophine®), hydromorphone (e.g., Dilaudid®), oxycodone (e.g., Percocet®
  • the anti-arthritic agent administered in the pharmaceutical combination therapies or methods disclosed here is not a DMARD
  • such administration generally may be referred to by those of skill in the art as a monotherapy even though more than one pharmaceutical composition is being administered since the pharmaceutical compositions disclosed here comprising a Janus Kinase inhibitors are considered a DMARD.
  • pharmaceutical combination therapy as used herein also includes such "monotherapies”.
  • compositions of the present disclosure may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the pharmaceutically acceptable carrier can be any such carrier known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro edit. 1985).
  • Pharmaceutical compositions of the compounds presently disclosed may be prepared by conventional means known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable carrier.
  • the compounds presently disclosed may also be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in United States Patent Nos. 3,119,742, 3,492,397, 3,538,214, 4,060,598, and 4,173,626.
  • the active compounds of the disclosure may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous), rectal administration, in a form suitable for administration by inhalation or insufflation, or the active compounds may be formulated for topical administration.
  • parenteral e.g., intravenous, intramuscular or subcutaneous
  • rectal administration in a form suitable for administration by inhalation or insufflation
  • the active compounds may be formulated for topical administration.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (ag., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g.. magnesium stearate, talc or silica); disintegrants (e.g... potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g... lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g.. magnesium stearate, talc or silica
  • disintegrants e.g.. potato starch or
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (exj., lecithin or acacia); non-aqueous vehicles (ex ⁇ , almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents exj., lecithin or acacia
  • non-aqueous vehicles ex ⁇ , almond oil, oily esters or ethyl alcohol
  • preservatives e.g.
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds of the disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the disclosure and a suitable powder base such as lactose or starch.
  • the active compounds of the disclosure may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, exj., in ampules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds of the disclosure may also be formulated in rectal compositions such as suppositories or retention enemas, ejj., containing conventional suppository bases such as cocoa butter or other glycerides.
  • a presently disclosed compound may be formulated as an ointment or cream.
  • the Janus Kinase inhibitors and the anti-arthritic agents are administered in a therapeutically effective amount in the pharmaceutical combination therapies and associated methods disclosed herein, the amount of which is readily apparent to those of skill in the art to achieve the desired pharmacological and/or physiological effect.
  • the Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof (sometimes referred to herein as "the active compounds") is administered in a dose of 0.1 to 1000 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • the dosage level can vary either between one or more dosing regimens or within the same dosing regimen.
  • the dose for the active compounds can be in a range from 1 to 50 mg BID (i.e., twice a day) or from 5 to 20 mg QD (i.e., daily), and preferably 1 mg BID, 2 mg BID, 3 mg BID, 4 mg BID, 5 mg BID, 6 mg BID, 7 mg BID, 8 mg BID, 9 mg BID, lO mg BID, 11 mg BID, 12 mg BID, 13 mg BID, 14 mg BID, 15 mg BID, 20 mg BID, 25 mg BID, or 30 mg BID, and preferably 0.25 mg BID, 0.5 mg BID, 1 mg BID, 5 mg BID, 10 mg BID, 20 mg BID, and more preferably 1 mg BID, 3 mg BID, 5 mg BID, 15 mg, BID, 20 mg QD.
  • the anti-arthritic agent (sometimes referred to herein as just “agent") is administered in a dose of 1 mg to 5 g (i.e., 5000 mg), e.g., 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 750mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg, 2000 mg, or combinations thereof.
  • the agent can be dosed twice a day, daily, weekly, etc. as would be apparent to those of skill in the art, e.g., a prescribed amount.
  • Methotrexate typically is dosed in a weekly amount of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg.
  • the dose of MTX is increased (i.e., titrated up), typically in 2.5 mg increments over time, e.g., from week to week, month to month, etc. depending, of course, on toxicity or lack of tolerability.
  • the dose of MTX is decreased (i.e., titrated down) if the patient has excellent response or if dosed with another agent, such as a biological agent.
  • the dose of MTX is administered in a divided dose, such as 5 mg Q 12 hours x 3 doses on a weekly basis.
  • a divided dose such as 5 mg Q 12 hours x 3 doses on a weekly basis.
  • the active compounds are administered in a dose of 0.25 mg BID, and methotrexate is administered in a dose of 5 mg once weekly. In certain embodiments in the pharmaceutical combination therapies disclosed herein, the active compounds are administered in a dose of 0.25 mg BID, and methotrexate is administered in a dose of 7.5 mg once weekly.
  • the active compounds are administered in a dose of 0.25 mg BID, and methotrexate is administered in a dose of 15 mg once weekly.
  • the active compounds are administered in a dose of 0.5 mg BID, and methotrexate is administered in a dose of 5 mg once weekly.
  • the active compounds are administered in a dose of 0.5 mg BID, and methotrexate is administered in a dose of 7.5 mg once weekly.
  • the active compounds are administered in a dose of 0.5 mg BID, and methotrexate is administered in a dose of 15 mg once weekly.
  • the active compounds are administered in a dose of 1 mg BID, and methotrexate is administered in a dose of 5 mg once weekly.
  • the active compounds are administered in a dose of 1 mg BID, and methotrexate is administered in a dose of 7.5 mg once weekly.
  • the active compounds are administered in a dose of 1 mg BID, and methotrexate is administered in a dose of 15 mg once weekly.
  • the active compounds are administered in a dose of 3 mg BID, and methotrexate is administered in a dose of 5 mg once weekly.
  • the active compounds are administered in a dose of 3 mg BID, and methotrexate is administered in a dose of 7.5 mg once weekly.
  • the active compounds are administered in a dose of 3 mg BID, and methotrexate is administered in a dose of 15 mg once weekly.
  • the active compounds are administered in a dose of 5 mg BID, and methotrexate is administered in a dose of 5 mg once weekly.
  • the active compounds are administered in a dose of 5 mg BID, and methotrexate is administered in a dose of 7.5 mg once weekly. In certain embodiments in the pharmaceutical combination therapies disclosed herein, the active compounds are administered in a dose of 5 mg BID, and methotrexate is administered in a dose of 15 mg once weekly.
  • the active compounds are administered in a dose of 10 mg BID, and methotrexate is administered in a dose of 5 mg once weekly.
  • the active compounds are administered in a dose of 10 mg BID, and methotrexate is administered in a dose of 7.5 mg once weekly.
  • the active compounds are administered in a dose of 10 mg BID, and methotrexate is administered in a dose of 15 mg once weekly.
  • the active compounds are administered in a dose of 15 mg BID, and methotrexate is administered in a dose of 5 mg once weekly.
  • the active compounds are administered in a dose of 15 mg BID, and methotrexate is administered in a dose of 7.5 mg once weekly.
  • the active compounds are administered in a dose of 15 mg BID, and methotrexate is administered in a dose of 15 mg once weekly.
  • the active compounds are administered in a dose of 5 mg QD, and methotrexate is administered in a dose of 5 mg once weekly.
  • the active compounds are administered in a dose of 5 mg QD, and methotrexate is administered in a dose of 7.5 mg once weekly.
  • the active compounds are administered in a dose of 5 mg QD, and methotrexate is administered in a dose of 15 mg once weekly.
  • the active compounds are administered in a dose of 10 mg QD, and methotrexate is administered in a dose of 5 mg once weekly.
  • the active compounds are administered in a dose of 10 mg QD, and methotrexate is administered in a dose of 7.5 mg once weekly.
  • the active compounds are administered in a dose of 10 mg QD, and methotrexate is administered in a dose of 15 mg once weekly. In certain embodiments in the pharmaceutical combination therapies disclosed herein, the active compounds are administered in a dose of 20 mg QD, and methotrexate is administered in a dose of 5 mg once weekly.
  • the active compounds are administered in a dose of 20 mg QD, and methotrexate is administered in a dose of 7.5 mg once weekly.
  • the active compounds are administered in a dose of 20 mg QD, and methotrexate is administered in a dose of 15 mg once weekly.
  • Aerosol formulations in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains 20 ⁇ g to 1000 ⁇ g of the compound of the disclosure.
  • the overall daily dose with an aerosol will be within the range 0.1 mg to 1000 mg.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • the JAK3 kinase assay utilizes a protein expressed in baculovirus-infected SF9 cells (a fusion protein of GST and the catalytic domain of human JAK3) purified by affinity chromatography on glutathione-Sepaharose.
  • the substrate for the reaction is poly-Glutamic acid-Tyrosine (PGT (4:1), Sigma catalog # P0275), coated onto Nunc Maxi Sorp plates at 'lOO ⁇ g/ml overnight at 37°C.
  • kinase buffer 50 mM HEPES, pH 7.3, 125 mM NaCI, 24 mM MgCi2+ 0.2 uM ATP + 1 mM Na orthovanadate.
  • the reaction proceeds for 30 minutes at room temperature and the plates is washed three more times.
  • the level of phosphorylated tyrosine in a given well is quantitated by standard ELISA assay utilizing an anti-phosphotyrosine antibody (ICN PY20, cat. #69-151-1).
  • This screen measures the inhibitory effect of compounds on IL-2 dependent T-CeII blast proliferation in vitro. Since signaling through the IL-2 receptor requires JAK-3, cell active inhibitors of JAK-3 should inhibit IL-2 dependent T-CeII blast proliferation.
  • T-CeIIs are cultured at 1-2 x 10 6 /ml in Media (RPMI + 10% heat-inactivated fetal calf serum (Hyclone Cat # A-1111-L) + 1 % Penicillin/Streptomycin (Gibco)) and induce to proliferate by the addition of 10ug/mi PHA (Murex Diagnostics, Cat # HA 16).
  • cells After 3 days at 37 0 C in 5% CO 2 , cells are washed 3 times in Media, resuspended to a density of 1-2 x 10 6 cells/ml in Media plus 100 Units/ml of human recombinant IL-2 (R&D Systems, Cat # 202-IL). After 1 week the cells are IL-2 dependent and can be maintained for up to 3 weeks by feeding twice weekly with equal volumes of Media + 100 Units/ml of IL-2.
  • IL-2 dependent cells are washed 3 times, resuspended in media and then plated (50,000 cells/well/0.1ml) in a Flat-bottom 96-well microtiter plate (Falcon # 353075). From a10 mM stock of test compound in DMSO, serial 2-fold dilutions of compound are added in triplicate wells starting at 10 uM. After one hour, 10 Units/ml of IL-2 is added to each test well. Plates are then incubated at 37 0 C, 5% CO 2 for 72 hours.
  • the Test Compound is an orally active, moderately selective inhibitor of JAK3 which has demonstrated efficacy in rodent models of inflammatory arthritis and subjects with psoriasis.
  • This study was designed to compare the efficacy, safety, tolerability and effects on health and functional status of 3 dose levels of the Test Compound versus placebo, administered for 6 weeks, with 6 weeks post-dosing follow-up, to subjects with moderate to severe active rheumatoid arthritis ("RA").
  • Subjects were enrolled if they had had an inadequate response to, or had discontinued for unacceptable toxicity, methotrexate or a TNF inhibitor, had discontinued all DMARD or biologic antirheumatic therapies and presented with at least 9 painful / tender joints, 6 swollen joints and evidence of systemic inflammation. They were randomized 1 :1 :1 :1 to placebo, the Test Compound 5 mg BID, 15 mg BID or 30 mg BID. Background NSAIDs, coxibs, low-dose glucocorticoids and analgesics were allowed.
  • Test Compound All 3 dose levels of the Test Compound were highly efficacious, compared to placebo, in the treatment of signs and symptoms of RA, beginning at week 1 and sustained greater than or equal to 6 weeks. Dose levels of 15 mg BID and below also appeared safe and generally well tolerated.
  • Each subject participated for a total of approximately 14 days; and remained under supervision from Day 0 until discharge on Day 9. Subjects were discharged after the last pharmacokinetic blood sample was obtained on Day 9, but were required to return for a follow-up visit which was scheduled before the subject's next weekly MTX dose (approximately Days 11-13).
  • pharmacokinetic parameters were calculated where possible for plasma concentrations of oral dose Test Compound following Study Days 6 & 7.
  • Single dose pharmacokinetic parameters were calculated where possible for plasma concentrations of oral dose MTX following Study Days 1 & 7.
  • the pharmacokinetic parameters were defined as the following: area under the plasma concentration time-curve from time 0 to the last observed time point (last) after dosing [AUC ⁇ ast ], area under the plasma concentration time-curve from time 0 to 12 hours postdose (AUC 12 ); the maximum observed concentration at steady state (C max ); the time to maximum observed concentration at steady state (T max ). Point and interval estimates of the pharmacokinetic parameters [AUC and C max ] were made. For interval estimates, the 90% confidence intervals (Cl) were constructed. The data are presented in graphical and/or tabular form and summarized descriptively.
  • PK Pharmacokinetic
  • the mixed effects model was implemented using SAS Proc Mixed, with REML estimation method, variance-covariance structure of compound symmetry and Satterthwaite degrees of freedom algorithm.
  • Nonparametric analyses were performed on untransformed (raw) PK parameter T max within each analyte.
  • SAS ® /Proc-StatXact 5 ® procedure Paired was used for these analyses. Point estimates of the median differences between treatments (Hodges-Lehmann), and exact 90% Cl around the differences (Lehmann) were constructed.
  • the SAS software program Version 8.2 was used to perform the data summarization and statistical analyses.
  • Steady-state Test Compound 30 mg mean exposure following co-administration with single dose MTX (individualized dosing) was unaffected, compared to that with steady-state Test Compound 30 mg administered alone. All 90% confidence intervals for log-transformed data were wholly within the 80- 125% no effect limit. Similarly, all 90% confidence intervals for both time parameters contained zero.
  • Single dose MTX mean exposure following co-administration with steady state Test Compound 30 mg was decreased by -10% for AUC 24 and -13% for C max compared to that with single dose MTX administered alone. Similarly, AE 24 and Cl rena i were decreased by -21 % and -9% respectively, while CL/F increased by -9% and t
  • Treatment-emergent events were defined as 1) those events that were not present at baseline or during the baseline period and which occurred after treatment with study drug began and 2) events that were present at baseline but increased in severity after treatment with study drug began. If more than one severity was given for any one adverse event for an individual subject, the greatest severity was used in summary tables; missing severities were classified as severe.
  • the same Subject experienced a greater than 30 msec increase from baseline in both QTcB and QTcF (-46 & -33 msec respectively) while receiving MTX SD on Day 1.
  • the same Subject also experienced a greater than 30 msec increase from baseline in both QTcB (-37 msec) while receiving Test Compound (30 mg q12h) on Day 3.
  • Test Compound co-administration reduces MTX AUC 24 by - 10% and C max ⁇ 13% compared to that with single dose MTX administered alone.
  • Steady state exposure of Test Compound (30 mg) in a pharmaceutical combination therapy with single dose MTX was unaffected, compared to steady state Test Compound (30 mg) administered alone.
  • Single dose exposure of MTX in a pharmaceutical combination therapy with steady state Test Compound (30 mg) was decreased by -10% for AUC 24 and -13% for C max , compared to MTX administered alone.
  • Treatments of steady state Test Compound (30 mg) and single dose MTX administered alone as well as administered in a pharmaceutical combination therapy were generally very well tolerated.
  • LRMS Low Resolution Mass Spectra
  • LRMS Low Resolution Mass Spectra
  • APCI Atmospheric Pressure Chemical Ionization
  • Room or ambient temperature refers to 20- 25°C.
  • Triacetoxy sodium borohydride (4.9 grams, 23 mmol) was added and the new mixture stirred at room temperature in a sealed tube for 24 h, at which time, the reaction was quenched upon addition of 1 N sodium hydroxide (50 mL). The reaction mixture was then extracted 3 x 80 ml_ with ether, the combined ether layers dried over sodium sulfate (Na2SO 4 ) and concentrated to dryness in vacuo affording 1.7 grams (69%) of the title compound as a white solid. LRMS: 219.1 (M+1 ).
  • Example 34-35 and 47 were prepared by a method analogous to that described in Example 33.
  • the title compounds for Examples 36-46 and 48-57 are prepared by a method analogous to that described in Example 33.

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Abstract

La présente invention concerne des polythérapies destinées au traitement ou à la prévention de l'arthrite chez un humain, telle que l'arthrite rhumatoïde. Lesdites polythérapies comprennent un inhibiteur de la Janus Kinase ou un sel pharmaceutiquement acceptable de celui-ci, et au moins un agent anti-arthritique ou un sel pharmaceutiquement acceptable de celui-ci. La présente invention concerne également certains procédés destinés au traitement ou à la prévention de l'arthrite chez un humain, telle que l'arthrite rhumatoïde. Lesdits procédés comprennent l'administration combinée, à un humain, d'un inhibiteur de la Janus Kinase ou d'un sel pharmaceutiquement acceptable de celui-ci, et d'au moins un agent anti-arthritique ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/IB2007/002468 2006-09-05 2007-08-24 Polythérapies destinées au traitement de l'arthrite rhumatoïde Ceased WO2008029237A2 (fr)

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WO2011097087A1 (fr) * 2010-02-05 2011-08-11 Pfizer Inc. Composés d'urée à base de pyrrolo[2,3-d]pyrimidine à titre d'inhibiteurs de jak
US8299084B2 (en) 2009-04-20 2012-10-30 Auspex Pharmaceuticals, Inc. Piperidine inhibitors of Janus kinase 3
CN102875555A (zh) * 2012-09-27 2013-01-16 同济大学 一种JAK抑制剂Tofacitinib的合成方法
US8461328B2 (en) 2010-01-12 2013-06-11 Genentech, Inc. Tricyclic heterocyclic compounds, compositions and methods of use thereof
US8609647B2 (en) 2009-07-31 2013-12-17 Japan Tobacco Inc. Nitrogen-containing spirocyclic compounds and pharmaceutical uses thereof
CN103819474A (zh) * 2013-11-04 2014-05-28 湖南华腾制药有限公司 一种托法替尼的制备方法
CN106146517A (zh) * 2016-06-20 2016-11-23 山东大学 一种枸橼酸托法替尼的合成方法
EP2994454A4 (fr) * 2013-12-09 2016-12-21 Unichem Lab Ltd Procede ameliore pour la preparation de (3r,4r)-(1-benzyl-4-methylpiperidin-3yl)-methylamine
CN107602569A (zh) * 2017-10-23 2018-01-19 上海博悦生物科技有限公司 一种新型吡咯并[2,3‑d]嘧啶化合物及其合成方法和用途
CN114835631A (zh) * 2021-02-01 2022-08-02 重庆恩联生物科技有限公司 顺式-1-苄基-4-甲基-3-甲氨基-哌啶双盐酸盐的制备方法

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AU2016208906B2 (en) * 2015-01-20 2018-07-12 Wuxi Fortune Pharmaceutical Co., Ltd JAK inhibitor
CN105237463B (zh) * 2015-10-09 2017-10-10 刘卫国 一种(3r,4r)‑(1‑苄基‑4‑甲基哌啶‑3‑基)甲胺‑l‑二对甲苯甲酰酒石酸盐的制备方法

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EA006227B1 (ru) * 1999-12-10 2005-10-27 Пфайзер Продактс Инк. СОЕДИНЕНИЯ ПИРРОЛО[2,3-d]ПИРИМИДИНА
EA006153B1 (ru) * 2000-06-26 2005-10-27 Пфайзер Продактс Инк. СОЕДИНЕНИЯ ПИРРОЛО[2,3-d]ПИРИМИДИНА В КАЧЕСТВЕ ИММУНОДЕПРЕССАНТОВ
CA2545192A1 (fr) * 2003-11-25 2005-06-09 Pfizer Products Inc. Methode de traitement de l'atherosclerose

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US9856261B2 (en) 2009-04-20 2018-01-02 Auspex Pharmaceuticals, Inc. Piperidine inhibitors of Janus kinase 3
US8299084B2 (en) 2009-04-20 2012-10-30 Auspex Pharmaceuticals, Inc. Piperidine inhibitors of Janus kinase 3
US8962638B2 (en) 2009-04-20 2015-02-24 Auspex Pharmaceuticals, Inc. Piperidine inhibitors of janus kinase 3
US9493469B2 (en) 2009-04-20 2016-11-15 Auspex Pharmaceuticals, Inc. Piperidine inhibitors of Janus kinase 3
US8609647B2 (en) 2009-07-31 2013-12-17 Japan Tobacco Inc. Nitrogen-containing spirocyclic compounds and pharmaceutical uses thereof
US8461328B2 (en) 2010-01-12 2013-06-11 Genentech, Inc. Tricyclic heterocyclic compounds, compositions and methods of use thereof
CN102822177A (zh) * 2010-02-05 2012-12-12 美国辉瑞有限公司 吡咯并[2,3-d]嘧啶脲化合物
WO2011097087A1 (fr) * 2010-02-05 2011-08-11 Pfizer Inc. Composés d'urée à base de pyrrolo[2,3-d]pyrimidine à titre d'inhibiteurs de jak
CN102875555A (zh) * 2012-09-27 2013-01-16 同济大学 一种JAK抑制剂Tofacitinib的合成方法
CN103819474A (zh) * 2013-11-04 2014-05-28 湖南华腾制药有限公司 一种托法替尼的制备方法
EP2994454A4 (fr) * 2013-12-09 2016-12-21 Unichem Lab Ltd Procede ameliore pour la preparation de (3r,4r)-(1-benzyl-4-methylpiperidin-3yl)-methylamine
CN106146517A (zh) * 2016-06-20 2016-11-23 山东大学 一种枸橼酸托法替尼的合成方法
CN107602569A (zh) * 2017-10-23 2018-01-19 上海博悦生物科技有限公司 一种新型吡咯并[2,3‑d]嘧啶化合物及其合成方法和用途
CN114835631A (zh) * 2021-02-01 2022-08-02 重庆恩联生物科技有限公司 顺式-1-苄基-4-甲基-3-甲氨基-哌啶双盐酸盐的制备方法
CN114835631B (zh) * 2021-02-01 2024-02-13 重庆恩联生物科技有限公司 顺式-1-苄基-4-甲基-3-甲氨基-哌啶双盐酸盐的制备方法

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