Claims for Patent: 7,569,569
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Summary for Patent: 7,569,569
Title: | Pyrrolo[2,3-d]pyrimidine compounds |
Abstract: | A compound of the formula ##STR00001## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, which are inhibitors of the enzyme protein tyrosine kinases such as Janus Kinase 3 and as such are useful therapy as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type 1 diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn\'s disease, Alzheimer\'s disease, Leukemia and other autoimmune diseases. |
Inventor(s): | Blumenkopf; Todd A. (Old Lyme, CT), Flanagan; Mark E. (Gales Ferry, CT), Brown; Matthew F. (Pawcatuck, CT), Changelian; Paul S. (E. Greenwich, CT) |
Assignee: | Pfizer Inc. (New York, NY) |
Application Number: | 10/640,079 |
Patent Claims: | 1. A pharmaceutical composition comprising an effective amount of a compound of the formula ##STR00013## or the pharmaceutically acceptable salt thereof; wherein
R.sup.1 is a group of the formula ##STR00014## wherein m is 0, 1, 2 or 3; n is 0, 1 ,2 or 3; X, B and D are each CR.sup.7R.sup.8; A and E are each CR.sup.7R.sup.8; and R.sup.7 and R.sup.8 are each independently selected from the group consisting of
hydrogen, deuterium, (C.sub.1-C.sub.6)alkyl, amino, hydroxy, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6) alkyl)amino, (C.sub.1-C.sub.6)acylamino, (C.sub.1-C.sub.6)acyl(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)alkoxyacyl,
(C.sub.1-C.sub.6) alkylaminoacyl, ((C.sub.1-C.sub.6)alkyl).sub.2aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl (difluoromethylene), (C.sub.1-C.sub.3) alkyl(difluoromethylene)(C.sub.1-C.sub.3)alkyl,
(C.sub.6-C.sub.10)aryl, (C.sub.5-C.sub.9)heteroaryl, (C.sub.6-C.sub.10) aryl(C.sub.1-C.sub.6) alkyl, (C.sub.5-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.10)aryl(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10) aryl(C.sub.6-C.sub.10)
aryl(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl(C.sub.1-C.sub.6)alkyl, hydroxy (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)acyloxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
piperazinyl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)acylamino(C.sub.1-C.sub.6)alkyl, piperidyl, (C.sub.1-C.sub.6)alkylpiperidyl, (C.sub.6-C.sub.10)aryl (C.sub.1-C.sub.6) alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6) alkylthio(C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.10)arylthio(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylsulfinyl(C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.10)
arylsulfinyl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylsulfonyl(C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.10)arylsulfonyl (C.sub.1-C.sub.6) alkyl, amino(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino (C.sub.1-C.sub.6) alkyl, R.sup.13CO(C.sub.1-C.sub.6)alkyl, R.sup.13CO(C.sub.3-C.sub.10)cycloalkyl, wherein R.sup.13 is R.sup.20O or R.sup.20R.sup.21N wherein R.sup.20 and R.sup.2l are each independently selected from
the group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl and (C.sub.5-C.sub.9)heteroaryl (C.sub.1-C.sub.6)alkyl, R.sup.14, R.sup.14(C.sub.1-C.sub.6)alkyl, R.sup.14(C.sub.3-C.sub.10)cycloalkyl, wherein
R.sup.14 is (C.sub.1-C.sub.6)acylpiperazino, (C.sub.6-C.sub.10) arylpiperazino, (C.sub.5-C.sub.9)heteroarylpiperazino, (C.sub.1-C.sub.6)alkylpiperazino, (C.sub.6-C.sub.10 )aryl (C.sub.1-C.sub.6) alkylpiperazino,
(C.sub.5-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C.sub.1-C.sub.6)alkylpiperidyl, (C.sub.6-C.sub.10)arylpiperidyl, (C.sub.5-C.sub.9) heteroarylpiperidyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylpiperidyl, (C.sub.5-C.sub.9)heteroaryl(C.sub.1-C.sub.6) alkylpiperidyl or (C.sub.1-C.sub.6)acylpiperidyl, or a group of the formula ##STR00015## wherein p is 0, 1, 2 or 3; and Z is hydroxy,
(C.sub.1-C.sub.6)alkoxy or NR.sup.1R.sup.2 wherein R.sup.1 and R.sup.2 are each independently selected from the group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl, piperidyl, (C.sub.1-C.sub.6) alkylpiperidyl, (C.sub.6-C.sub.10)arylpiperidyl,
(C.sub.5-C.sub.9)heteroarylpiperidyl, (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6) alkylpiperidyl, (C.sub.5-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylpiperidyl, (C.sub.1-C.sub.6)acylpiperidyl, (C.sub.6-C.sub.10) aryl, (C.sub.5-C.sub.9)heteroaryl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl, (C.sub.5-C.sub.9)heteroaryl (C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.10) aryl(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryl(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6) cycloalkyl(C.sub.1-C.sub.6)alkyl, R.sup.5(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.5)alkyl(CHR.sup.5)(C.sub.1-C.sub.6)alkyl, wherein R.sup.5 hydroxy, (C.sub.1-C.sub.6)acyloxy, (C.sub.1-C.sub.6)alkoxy, piperazino,
(C.sub.1-C.sub.6)acylamino, (C.sub.1-C.sub.6)alkylthio, (C.sub.6-C.sub.10)arylthio, (C.sub.1-C.sub.6)alkylsulfinyl, (C.sub.6-C.sub.10)arylsulfinyl, (C.sub.1-C.sub.6)alkylsulfoxyl, (C.sub.1-C.sub.6) arylsulfoxyl, amino, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2 amino, (C.sub.1-C.sub.6)acylpiperazino, (C.sub.1-C.sub.6)alkylpiperazino, (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylpiperazino, (C.sub.5-C.sub.9)heteroaryl (C.sub.1-C.sub.6) alkylpiperazino, morpholino, thiomorpholino,
piperidino or pyrrolidino, and R.sup.6(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.5)alkyl(CHR.sup.6)(C.sub.1-C.sub.6)alkyl, wherein R.sup.6 is piperidyl, (C.sub.1-C.sub.6)alkylpiperidyl, (C.sub.6-C.sub.10)arylpiperidyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylpiperidyl, (C.sub.5-C.sub.9)heteroarylpiperidyl or(C.sub.5-C.sub.9) heteroaryl(C.sub.1-C.sub.6) alkylpiperidyl; R.sup.2 and R.sup.3 are each independently selected from the group consisting of hydrogen,
deuterium, amino, halo, hydroxy, nitro, carboxy, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.6)alkyl, and (C.sub.1-C.sub.6)alkoxy wherein the alkyl or alkoxy groups are optionally substituted by
one to three groups selected from halo, hydroxy, carboxy, amino (C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino, (C.sub.5-C.sub.9)heteroaryl, (C.sub.2-C.sub.9)heterocycloalkyl, (C.sub.3-C.sub.9)cycloalkyl or
(C.sub.6-C.sub.10) aryl; or R.sup.2 and R.sup.3 are each independently (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)cycloalkoxy, (C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino, (C.sub.6-C.sub.10)arylamino,
(C.sub.1-C.sub.6)alkylthio, (C.sub.6-C.sub.10)arylthio, (C.sub.1-C.sub.6) alkylsulfinyl, (C.sub.6-C.sub.10)arylsulfinyl, (C.sub.1-C.sub.6)alkylsulfonyl, (C.sub.6-C.sub.10)arylsulfonyl, (C.sub.1-C.sub.6) acyl, (C.sub.1-C.sub.6)alkoxy-CO--NH--,
(C.sub.1-C.sub.6)alkylamino-CO--, (C.sub.5-C.sub.9)heteroaryl, (C.sub.2-C.sub.9) heterocycloalkyl or (C.sub.6-C.sub.10)aryl wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted by one to three halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl-CO--NH--, (C.sub.1-C.sub.6)alkoxy-CO--NH--, (C.sub.1-C.sub.6)alkyl-CO--NH--(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6) alkoxy-CO--NH--(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-CO--NH--(C.sub.1-C.sub.6)alkoxy, carboxy,
carboxy(C.sub.1-C.sub.6) alkyl, carboxy(C.sub.1-C.sub.6)alkoxy, benzyloxycarbonyl(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6) alkoxy, (C.sub.6-C.sub.10)aryl, amino, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino, (C.sub.6-C.sub.10) aryl(C.sub.1-C.sub.6)alkoxycarbonylamino, (C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino, (C.sub.1-C.sub.6) alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl, hydroxy, (C.sub.1-C.sub.6) alkoxy, carboxy, carboxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxycarbonyl, (C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6)alkoxy-CO--NH--, (C.sub.1-C.sub.6)alkyl-CO--NH--, cyano, (C.sub.5-C.sub.9) heterocycloalkyl, amino-CO--NH--, (C.sub.1-C.sub.6)alkylamino-CO--NH--, (C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--, (C.sub.6-C.sub.10)arylamino-CO--NH--,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--, (C.sub.1-C.sub.6) alkylamino-CO--NH--(C.sub.1-C.sub.6)alkyl, ((C.sub.1-C.sub.6)alkyl).sub.2amino-CO--NH--(C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.10) arylamino-CO--NH--(C.sub.1-C.sub.6)alkyl,
(C.sub.5-C.sub.9)heteroarylamino-CO--NH--(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6) alkylsulfonyl, (C.sub.1-C.sub.6)alkylsulfonylamino, (C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.10)arylsulfonyl,
(C.sub.6-C.sub.10)arylsulfonylamino, (C.sub.6-C.sub.10)arylsulfonylamino(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6)alkylsulfonylamino, (C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl, (C.sub.5-C.sub.9)heteroaryl or
(C.sub.2-C.sub.9)heterocycloalkyl; with the proviso that when R.sup.2 and R.sup.3 are each independently hydrogen or (C.sub.1-C.sub.6) alkyl, R.sub.1 cannot be unsubstituted piperidinyl; and with the proviso that when R.sup.2 and R.sup.3 are each
hydrogen, R.sup.1 cannot be unsubstituted pyrrolidinyl, alone or in combination with one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents, wherein said one or more additional agents is selected from the
group consisting of cyclosporine A, rapamycin, tacrolimus, leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, muromonab-CD3, antithymocyte globulin, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam and anti-inflammatory steroid; and a pharmaceutically acceptable carrier.
2. The pharmaceutical composition of claim 1, wherein R.sup.2 and R.sup.3 of said compound are each independently selected from the group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)cycloalkoxy, (C.sub.2-C.sub.9) heterocycloalkyl, (C.sub.5-C.sub.9)heteroaryl and (C.sub.6-C.sub.10)aryl. 3. The pharmaceutical composition of claim 2, wherein said compound is selected from the group consisting of: 5-Fluoro-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine; 4-Piperidin-1-yl-5-trifluoromethyl-7H-pyrrolo[2,3-d]pyrimidine; N,N-Dimethyl-N'-[3-(4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-ben- zyl]-ethane -1,2-diamine; 2-[(5-m-Tolyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-ethanol; 5-(3-Isopropyl-phenyl)-4-piperidin-1yl7H-pyrrolo[2,3-d]pyrimidine; 5-(3-Methyl-3H-imidazol-4-yl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin- e; 5-(1-Methyl-1H-imidazol-4-yl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimid- ine; 5-(2-Methyl-pyridin-4-yl)-4-piperdin-1-yl-7H-pyrrolo[2,3-d]pyrimidine- ; 5-Chloro-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine; 5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine; 4-Piperidin-1-yl-5-m-tolyl-7H-pyrrolo[2,3-d]pyrimidine; and 4-(3,3-Dimethyl-piperidin-1-yl)-7H-pyrrolo[2,3,-d]pyrimidine, or a pharmaceutically acceptable salt thereof. 4. A method for treating organ transplant rejection or psoriasis in a mammal comprising administering to said mammal the pharmaceutical composition of claim 1. 5. A method for treating organ transplant rejection or psoriasis in a mammal comprising administering to said mammal the pharmaceutical composition of claim 2. 6. A method for treating organ transplant rejection or psoriasis in a mammal comprising administering to said mammal the pharmaceutical composition of claim 3. |
Details for Patent 7,569,569
Applicant | Tradename | Biologic Ingredient | Dosage Form | BLA | Approval Date | Patent No. | Expiredate |
---|---|---|---|---|---|---|---|
Centocor Ortho Biotech Products, L.p. | ORTHOCLONE OKT3 | muromanab-cd3 | Injection | 103463 | 09/14/1992 | ⤷ Try a Trial | 2018-06-19 |
Hoffmann-la Roche Inc. | ZENAPAX | daclizumab | Injection | 103749 | 12/10/1997 | ⤷ Try a Trial | 2018-06-19 |
Biogen Inc. | ZINBRYTA | daclizumab | Injection | 761029 | 05/27/2016 | ⤷ Try a Trial | 2018-06-19 |
>Applicant | >Tradename | >Biologic Ingredient | >Dosage Form | >BLA | >Approval Date | >Patent No. | >Expiredate |
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