HK1051195B - Pyrrolo(2,3-d)pyrimidine compounds - Google Patents
Pyrrolo(2,3-d)pyrimidine compounds Download PDFInfo
- Publication number
- HK1051195B HK1051195B HK03103456.8A HK03103456A HK1051195B HK 1051195 B HK1051195 B HK 1051195B HK 03103456 A HK03103456 A HK 03103456A HK 1051195 B HK1051195 B HK 1051195B
- Authority
- HK
- Hong Kong
- Prior art keywords
- methyl
- alkyl
- amino
- group
- formula
- Prior art date
Links
Description
Background
The present invention relates to pyrrolo [2, 3-d ] pyrimidine compounds which are inhibitors of protein kinases such as Janus kinase 3 (hereinafter also referred to as JAK3) and are therefore useful as immunosuppressive agents in the treatment of organ transplants, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia and other indications where immunosuppressive effects are desired.
The invention also relates to methods of using such compounds in the treatment of the above-mentioned indications in mammals, especially humans, and to pharmaceutical compositions useful therefor.
JAK3 is a member of the Janus family of protein kinases. Although other members of this family are expressed by essentially all tissues, expression of JAK3 is limited to hematopoietic cells. This is consistent with its essential role in signaling through these multi-chain receptors due to the non-covalent association of JAK3 with the gamma chain common to IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. The XSCID patient population has been identified as severely reduced protein levels of JAK3 or sharing a genetic defect in the gamma chain, suggesting that blocking signaling through the JAK3 pathway should lead to immunosuppression. Animal studies have suggested that JAK3 not only has a major role in the maturation of B and T lymphocytes, but that JAK3 is essential for maintaining T cell function. Modulation of immune activity by this novel mechanism can prove useful in the treatment of T cell proliferative disorders such as graft rejection and autoimmune diseases.
Summary of The Invention
The present invention relates to compounds of the formula or a pharmaceutically acceptable salt thereof;
wherein
R1Is a radical of the formula
Wherein y is 0, 1 or 2;
R4selected from the group consisting of hydrogen, (C)1-C6) Alkyl, (C)1-C6) Alkylsulfonyl group, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, wherein the alkyl, alkenyl and alkynyl are optionally substituted with deuterium, hydroxy, amino, trifluoromethyl, (C)1-C4) Alkoxy group, (C)1-C6) Acyloxy, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino, cyano, nitro, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl or (C)1-C6) Amido substitution; or R4Is (C)3-C10) Cycloalkyl, wherein the cycloalkyl is optionally deuterated, hydroxy, amino, trifluoromethyl, (C)1-C6) Acyloxy, (C)1-C6) Amido, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino, cyano (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl, nitro (C)1-C6) Alkyl or (C)1-C6) Amido substitution;
R5is (C)2-C9) Heterocycloalkyl, wherein the heterocycloalkyl must be substituted with one to five of the following groups: carboxy, cyano, amino, deuterium, hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halo, (C)1-C6) Acyl, (C)1-C6) Alkylamino radical, amino radical (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-NH, (C)1-C6) alkylamino-CO-, (C)2-C6) alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkylamino radical, amino radical (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Acyloxy (C)1-C6) Alkyl, nitro, cyano (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, nitro (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl, (C)1-C6) Amido, (C)1-C6) Amido (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Amido, amino (C)1-C6) Acyl, amino (C)1-C6) Acyl radical (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Acyl group, ((C)1-C6) Alkyl radical)2Amino (C)1-C6) Acyl radical, R15R16N-CO-O-、R15R16N-CO-(C1-C6) Alkyl, (C)1-C6) alkyl-S (O)m、R15R16NS(O)m、R15R16NS(O)m(C1-C6) Alkyl radical, R15S(O)mR16N、R15S(O)mR16N(C1-C6) Alkyl, where m is 0, 1 or 2, R15And R16Each independently selected from hydrogen or (C)1-C6) An alkyl group; or a group of the formula:
wherein a is 0, 1, 2,3 or 4;
b. c, e, f and g are each independently 0 or 1;
d is 0, 1, 2 or 3;
x is S (O)nWherein n is 0, 1 or 2; oxygen, carbonyl or-C (═ N-cyano) -;
y is S (O)nWherein n is 0, 1 or 2; or a carbonyl group;
z is carbonyl, C (O), O-, C (O) NR-or S (O)nWherein n is 0, 1 or 2;
R6、R7、R8、R9、R10and R11Each independently selected from hydrogen or (C)1-C6) Alkyl optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C)1-C6) Acyloxy, (C)1-C6) Amido, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino, cyano, nitro, cyano (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl, nitro (C)1-C6) Alkyl or (C)1-C6) Amido substitution;
R12is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halo, (C)1-C6) Acyl, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-NH, (C)1-C6) alkylamino-CO-, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C6) Alkylamino, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Acyloxy (C)1-C6) Alkyl, nitro, cyano (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, nitro (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl, (C)1-C6) Amido, (C)1-C6) Amido (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Amido, amino (C)1-C6) Acyl, amino (C)1-C6) Acyl radical (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Acyl group, ((C)1-C6) Alkyl radical)2Amino (C)1-C6) Acyl radical, R15R16N-CO-O-、R15R16N-CO-(C1-C6) Alkyl radical, R15C(O)NH、R15OC(O)NH、R15NHC(O)NH、(C1-C6) alkyl-S (O)m、(C1-C6) alkyl-S (O)m-(C1-C6) Alkyl radical, R15R16NS(O)m、R15R16NS(O)m(C1-C6) Alkyl radical, R15S(O)mR16N、R15S(O)mR16N(C1-C6) Alkyl, where m is 0, 1 or 2, R15And R16Each independently selected from hydrogen or (C)1-C6) An alkyl group;
R2and R3Each independently selected from hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, trifluoromethyl, trifluoromethoxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)3-C10) Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted with one to three groups selected from halo, hydroxy, carboxy, amino, (C)1-C6) Alkylthio group, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino group, (C)5-C9) Heteroaryl, (C)2-C9) Heterocycloalkyl group, (C)3-C9) Cycloalkyl or (C)6-C10) An aryl group; or R2And R3Each independently is (C)3-C10) Cycloalkyl group, (C)3-C10) Cycloalkoxy, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino group, (C)6-C10) Arylamino, (C)1-C6) Alkylthio group, (C)6-C10) Arylthio group, (C)1-C6) Alkylsulfinyl (C)6-C10) Arylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)6-C10) Arylsulfonyl, (C)1-C6) Acyl, (C)1-C6) alkoxy-CO-NH-, (C)1-C6) alkylamino-CO-, (C)5-C9) Heteroaryl, (C)2-C9) Heterocycloalkyl or (C)6-C10) Aryl, wherein the heteroaryl, heterocycloalkyl and aryl are optionally mono-to trihalogenated, (C)1-C6) Alkyl, (C)1-C6) alkyl-CO-NH-, (C)1-C6) alkoxy-CO-NH-, (C)1-C6) alkyl-CO-NH- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-NH- (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-NH- (C)1-C6) Alkoxy, carboxyl (C)1-C6) Alkyl, carboxyl (C)1-C6) Alkoxy, benzyloxycarbonyl (C)1-C6) Alkoxy group, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkoxy group, (C)6-C10) Aryl, amino (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonylamino group, (C)6-C10) Aryl radical (C)1-C6) Alkoxycarbonylamino group, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino group, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl group, ((C)1-C6) Alkyl radical)2Amino (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, carboxyl (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkyl, (C)1-C6) alkoxy-CO-NH-, (C)1-C6) alkyl-CO-NH-, cyano, (C)5-C9) Heterocycloalkyl, amino-CO-NH-, (C)1-C6) alkylamino-CO-NH- ((C)1-C6) Alkyl radical)2amino-CO-NH-, (C)6-C10) arylamino-CO-NH-, (C)5-C9) heteroarylamino-CO-NH-, (C)1-C6) alkylamino-CO-NH- (C)1-C6) Alkyl group, ((C)1-C6) Alkyl radical)2amino-CO-NH- (C)1-C6) Alkyl, (C)6-C10) arylamino-CO-NH- (C)1-C6) Alkyl, (C)5-C9) Heteroarylamino-CO-NH- (C)1-C6) Alkyl, (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylsulfonylamino group, (C)1-C6) Alkylsulfonamido (C)1-C6) Alkyl, (C)6-C10) Arylsulfonyl, (C)6-C10) Arylsulfonylamino group, (C)6-C10) Arylsulfonylamino (C)1-C6) Alkyl, (C)1-C6) Alkylsulfonylamino group, (C)1-C6) Alkylsulfonamido (C)1-C6) Alkyl, (C)5-C9) Heteroaryl or (C)2-C9) Heterocycloalkyl substituted.
The invention also relates to pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of the invention described above are those which form non-toxic acid addition salts, that is, salts containing pharmaceutically 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 salts (i.e., 1' -methylene-bis (2-hydroxy-3-naphthoate)).
The invention also relates to base addition salts of formula I. Chemical bases which can be used as reagents for preparing pharmaceutically acceptable base salts of acidic compounds of formula I are those which form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from pharmaceutically 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 lower alkanolammonium, and base salts of other pharmaceutically acceptable organic amines.
The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties or combinations thereof.
The term "alkoxy" as used herein includes O-alkyl, wherein "alkyl" is as defined above.
The term "halo" as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.
The compounds of the present invention may contain double bonds. When containing such double bonds, the compounds of the present invention exist in cis and trans configurations and mixtures thereof.
Unless otherwise indicated, the alkyl and alkenyl groups referred to herein, as well as the alkyl portions of other groups referred to herein (e.g., alkoxy), may be straight or branched chain, they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl), or straight or branched chain and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine and iodine.
As used herein (C)2-C9) Heterocycloalkyl means pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxy, benzopyranyl, 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-tetrahydrodiazin-2-yl, 1, 3-tetrahydrodiazin-1-yl, tetrahydroazepine * -yl, piperazinyl, chromanyl, and the like. As will be understood by those of ordinary skill in the art, the (C) is2-C9) The heterocycloalkyl ring being through carbon or sp3The hybrid nitrogen heteroatom is linked.
As used herein (C)2-C9) Heteroaryl means 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, pyrimidinyl, pyrazinyl, pyridazinyl, 1, 2, 4-triazinyl, 1, 2, 3-triazinyl, 1, 3, 5-triazinyl, pyrazolo [3, 4-b ] group]Pyridyl, cinnolinyl, pteridinyl, purinyl, 6, 7-dihydro-5H- [1]Pyridyl, benzo [ b ]]Thienyl, 5, 6, 7, 8-tetrahydroquinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thioindenyl, isothioindenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl, and the like. As will be understood by those of ordinary skill in the art, the (C) is2-C9) The heteroaryl ring being via a carbon atom or sp3The hybrid nitrogen heteroatom is linked.
As used herein (C)6-C10) Aryl means phenyl or naphthyl.
The compounds of formula (I) may be administered alone in a pharmaceutically acceptable dosage form or in combination with one or more additional agents that modulate the immune system or anti-inflammatory agents in a mammal. These agents may include, but are not limited to, cyclosporin A (e.g., Sandimmune * or Neoral *), rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolates (e.g., Cellcept *), azathioprine (e.g., Imuran *), daclizumab (e.g., Zenapax *), OKT3 (e.g., Orthoclone *), AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (e.g., prednisolone or dexamethasone). These agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, according to the same or different dosing regimens, in accordance with standard pharmaceutical practice.
The compounds of the present invention include all conformational isomers, such as cis and trans isomers. The compounds of the invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. The present invention relates to the use of all optical isomers and stereoisomers of the compounds of the invention and mixtures thereof, and all pharmaceutical compositions and methods of treatment which may be employed and which contain them. In this regard, the present invention includes both the E and Z configurations. Tautomers of the compounds of formula I may also exist. The present invention relates to the use of all such tautomers and mixtures thereof.
The invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula I. The invention also encompasses methods of treating or preventing disorders that can be treated or prevented by the inhibition of protein kinases such as Janus kinase 3, comprising administering a prodrug of a compound of formula I. Compounds of formula I having a free amino, amido, hydroxy or carboxy group 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 is covalently bonded via a peptide bond to a free amino, hydroxyl or carboxylic acid group of a compound of formula I. Amino acid residues include the 20 naturally occurring amino acids commonly indicated by three letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug side chain.
Preferred compounds of formula I include those wherein a is 0, b is 1, X is carbonyl, c is 0, d is 0, e is 0, f is 0, g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is carbonyl, c is 0, d is 1, e is 0, f is 0, g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is carbonyl, c is 1, d is 0, e is 0, f is 0, g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is-C (═ N ═ cyano) -, C is 1, d is 0, e is 0, f is 0, and g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 0, c is 0, d is 0, e is 0, f is 0, g is 1, Z is-C (O) -O-.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is S (O)nN is 2, c is 0, d is 0, e is 0, f is 0, g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is S (O)nN is 2, c is 0, d is 2, e is 0, f is 1, g is 1, Z is carbonyl.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is S (O)nN is 2, c is 0, d is 2, e is 0, f is 1, g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is carbonyl, c is 1, d is 0, e is 1, Y is S (O)nN is 2, f is 0, g is 0.
Other preferencesInclude those wherein a is 0, b is 1, X is S (O)nN is 2, c is 1, d is 0, e is 0, f is 0, g is 0.
Other preferred compounds of formula I include those wherein a is 1, b is 1, X is carbonyl, c is 1, d is 0, e is 0, f is 0, g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is S (O)nC is 0, d is 1, e is 1, Y is S (O)nN is 2, f is 0, g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is S (O)nC is 0, d is 1, e is 1, Y is S (O)nN is 2, f is 1, g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is oxygen, c is 0, d is 1, e is 1, Y is S (O)nN is 2, f is 1, g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is oxygen, c is 0, d is 1, e is 1, Y is S (O)nN is 2, f is 0, g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is carbonyl, c is 1, d is 1, e is 1, Y is S (O)nF is 0, g is 0.
Other preferred compounds of formula I include those wherein a is 0, b is 1, X is carbonyl, c is 1, d is 1, e is 1, Y is S (O)nN is 2, f is 1, g is 0.
Other preferred compounds of formula I include those wherein R12Is cyano, trifluoromethyl, (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl, (C)1-C6) Alkylamino group, ((C)1-C6) Alkyl radical)2Amino group, (C)2-C6) Alkynyl, cyano (C)1-C6) Alkyl, (C)1-C6) alkyl-S (O)mWherein m is 0, 1 or 2.
Particularly preferred compounds of formula I include those wherein the compound is selected from the group consisting of:
methyl- [ 4-methyl-1- (propane-1-sulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid methyl ester;
3, 3, 3-trifluoro-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -propan-1-one;
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid dimethylamide;
({ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carbonyl } -amino) -acetic acid ethyl ester;
3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile;
3, 3, 3-trifluoro-1- { 4-methyl-3- [ methyl- (5-methyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -propan-1-one;
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -but-3-yn-1-one;
1- {3- [ (5-chloro-7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -methyl-amino ] -4-methyl-piperidin-1-yl } -propan-1-one;
1- {3- [ (5-fluoro-7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -methyl-amino ] -4-methyl-piperidin-1-yl } -propan-1-one;
n-cyano-4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -N' -propyl-piperidine-1-carboxamidine; and
n-cyano-4, N' -trimethyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxamidine.
The invention also relates to a pharmaceutical composition for (a) treating or preventing a disorder or disease selected from organ transplant rejection, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia, and other autoimmune diseases in a mammal, including a human, or (b) inhibiting a protein kinase or Janus kinase 3(JAK3) in a mammal, including a human, the composition comprising an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, effective for such disorder or disease and a pharmaceutically acceptable carrier.
The present invention also relates to a method of inhibiting protein tyrosine kinase or Janus kinase 3(JAK3) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of treatment or prophylaxis of a disorder or disease selected from organ transplant rejection, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia, and other autoimmune diseases in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat such a disease.
Detailed description of the invention
The following reaction scheme illustrates the preparation of the compounds of the present invention. R in the reaction schemes and subsequent discussion unless otherwise indicated2、R3、R4And R5Is as defined above.
Preparation A
Preparation B
Scheme 1
Scheme 2
Scheme 3
In reaction 1 for preparation A, a pyrimidine compound of formula XXI 4-chloropyrrolo [2, 3-d ] wherein R is hydrogen or a protecting group, such as phenylsulfonyl or benzyl, is converted to a pyrimidine compound of formula XX 4-chloro-5-halopyrrolo [2, 3-d ] wherein Y is chloro, bromo or iodo, i.e., formula XXI is reacted with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide. The reaction mixture is heated to reflux in chloroform for about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, in reaction 1 of preparation A, a pyrimidine of formula XXI 4-chloropyrrolo [2, 3-d ] wherein R is hydrogen is converted to the corresponding pyrimidine of formula XX 4-chloro-5-nitropyrrolo [2, 3-d ] wherein Y is nitro, i.e., formula XXI is reacted with nitric acid in sulfuric acid at a temperature of about-10 ℃ to about 10 ℃, preferably about 0 ℃, for about 5 minutes to about 15 minutes, preferably about 10 minutes. Conversion of a compound of formula XXI, wherein Y is nitro, to the corresponding pyrimidine of formula XX 4-chloro-5-aminopyrrolo [2, 3-d ] wherein Y is amino, i.e. reaction of XXI under various conditions known to the person skilled in the art, such as hydrogenolysis of palladium or stannic (IV) chloride and hydrochloric acid.
In reaction 2 for preparation A, a compound of formula XX 4-chloro-5-halopyrrolo [2, 3-d ] wherein R is hydrogen]Conversion of pyrimidine compounds to R2Is (C)1-C6) Alkyl or benzyl, i.e. treatment of XX with N-butyllithium at a temperature of about-78 ℃ and reaction of the dianionic intermediate formed with an alkyl halide or benzyl halide at a temperature of about-78 ℃ to room temperature, preferably room temperature. Alternatively, the dianion formed is reacted with molecular oxygen to form R2The corresponding compound of formula XIX 4-chloro-5-hydroxypyrrolo [2, 3-d, which is hydroxy]A pyrimidine compound. Conversion of a compound of formula XX wherein Y is bromo or iodo and R is benzenesulfonate to a compound of formula XX wherein R is2Is (C)6-C12) Aryl or vinyl compounds of formula XIX, i.e. XX is treated with N-butyllithium at a temperature of about-78 ℃ and zinc chloride is added at a temperature of about-78 ℃. The corresponding organozinc intermediate thus formed is then reacted with aryl or vinyl iodide in the presence of a catalytic amount of palladium. The reaction mixture is stirred at a temperature of about 50 ℃ to about 80 ℃, preferably about 70 ℃, for about 1 hour to about 3 hours, preferably about 1 hour.
In reaction 3 of preparation A, a compound of formula XIX is converted to the corresponding compound of formula XVI by treatment with N-butyllithium, lithium diisopropylamide or sodium hydride in the presence of a polar aprotic solvent, such as tetrahydrofuran, at a temperature of about-78 ℃. Further reacting the resulting anionic intermediate, (a) if R3Is alkyl or benzyl, with an alkyl halide or benzyl halide at a temperature of about-78 ℃ to room temperature, preferably-78 ℃; (b) if R is3Is an alkoxy group, and is reacted with an aldehyde or ketone at a temperature of about-78 ℃ to room temperature, preferably-78 ℃; (c) is reacted with zinc chloride at a temperature of about-78 c to room temperature, preferably-78 c, and the corresponding organozinc intermediate thus formed is then reacted with aryl or vinyl iodide in the presence of a catalytic amount of palladium. At a temperature of about 50 ℃ to about 80 ℃Preferably about 70 c, and the resulting reaction mixture is stirred for about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, the anion formed is reacted with molecular oxygen to form R3The corresponding compound of formula XVI 4-chloro-6-hydroxypyrrolo [2, 3-d ] which is hydroxy]A pyrimidine compound.
In reaction 1 of preparation B, a pyrimidine compound of formula XXI 4-chloropyrrolo [2, 3-d ] is converted to the corresponding compound of formula XXII according to the procedure described above for reaction 3 of preparation A.
In 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 for reactions 1 and 2 of preparation A.
In reaction 1 of scheme 1, a pyrimidine compound of formula XVII 4-chloropyrrolo [2, 3-d ] is converted to the corresponding compound of formula XVI wherein R is phenylsulfonyl or benzyl, i.e., XVII is treated with benzenesulfonyl chloride, benzyl chloride or benzyl bromide in the presence of a base, such as sodium hydride or potassium carbonate, in a polar aprotic solvent, such as dimethylformamide or tetrahydrofuran. The reaction mixture is stirred at a temperature of about 0 ℃ to about 70 ℃, preferably about 30 ℃, for about 1 hour to about 3 hours, preferably about 2 hours.
In reaction 2 of scheme 1, formula XVI 4-chloropyrrolo [2, 3-d]Conversion of pyrimidine compounds to the corresponding amino-pyrrolo [2, 3-d ] of formula XV4]Pyrimidine compounds, i.e. reaction of XVI with HNR of formula4R5And (3) coupling. The reaction is carried out in an alcoholic solvent, such as tert-butanol, methanol or ethanol, or in other high-boiling organic solvents, such as dimethylformamide, triethylamine, 1, 4-dioxane or 1, 2-dichloroethane, at a temperature of from about 60 ℃ to about 120 ℃, preferably about 80 ℃. Typical reaction times are from about 2 hours to 48 hours, preferably about 16 hours. If R is5Is a nitrogen-containing heterocycloalkyl group, each nitrogen must be protected by a protecting group, such as benzyl. R5The removal of the protecting group is carried out under conditions suitable for the particular protecting group without affecting pyrrolo [2, 3-d]R protecting group on pyrimidine ring. If R is5Protecting groupIs a benzyl group, its removal is carried out in an alcoholic solvent, such as ethanol, in the presence of hydrogen and a catalyst, such as palladium on carbon hydroxide. Can make the generated R5The nitrogen-containing heterocycloalkyl group is reacted with various electrophiles of formula II. For urea formation, electrophiles of formula II, such as isocyanates, carbamates and carbamoyl chlorides, and R of heteroalkyl groups are reacted with R of a heteroalkyl group in the presence of a base, such as sodium or potassium carbonate, in a solvent, such as acetonitrile or dimethylformamide, at a temperature of about 20 ℃ to about 100 ℃5The nitrogen is reacted for about 24 hours to about 72 hours. For amide and sulfonamide formation, electrophiles of formula II, such as acid chlorides and sulfonyl chlorides, are reacted with R of heteroalkyl groups in the presence of a base, such as pyridine, in a solvent, such as methylene chloride, at ambient temperature5The nitrogen is reacted for about 12 hours to about 24 hours. The amide formation may also be carried out by reacting the carboxylic acid with the heteroalkyl group in the presence of a carbodiimide, such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, in a solvent, such as dichloromethane, at ambient temperature for 12-24 hours. With respect to the formation of alkyl groups, electrophiles of formula II, such as α, β -unsaturated amides, acids, nitriles, esters and α -haloamides, are reacted with R of the heteroalkyl group in a solvent, such as methanol, at ambient temperature5The nitrogen is reacted for about 12 hours to about 18 hours. The formation of the alkyl group can also be carried out by reacting the aldehyde 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 about 12 hours to about 18 hours.
In reaction 3 of scheme 1, the protecting group is removed from the compound of formula XV, wherein R is phenylsulfonyl, to give the corresponding compound of formula I, i.e., XV is treated with a base, such as sodium hydroxide or potassium hydroxide, in an alcoholic solvent, such as methanol or ethanol, or in a mixed solvent, such as alcohol/tetrahydrofuran or alcohol/water. The reaction is carried out at room temperature for about 15 minutes to about 1 hour, preferably 30 minutes. The protecting group is removed from the compound of formula XV, wherein R is benzyl, i.e. XV is treated with sodium in ammonia at a temperature of about-78 ℃ for about 15 minutes to about 1 hour.
In reaction 1 of scheme 2, a compound of formula XX 4-chloropyrrolo [2, 3-d ] pyrimidine is converted to the corresponding compound of formula XXIV 4-aminopyrrolo [2, 3-d ] pyrimidine according to the procedure described in reaction 2 of scheme 1 above.
In reaction 2 of scheme 2, a compound of formula XXIV 4-aminopyrrolo [2, 3-d ] wherein R is benzenesulfonate and Z is bromine or iodine]Conversion of pyrimidine compounds to the corresponding compounds of formula XXIII, i.e. XXIV (a) if R2Is aryl, and is reacted with an arylboronic acid in an aprotic solvent, such as tetrahydrofuran or dioxane, in the presence of a catalytic amount of palladium (O) at a temperature of about 50 ℃ to about 100 ℃, preferably about 70 ℃, for about 2 hours to about 48 hours, preferably about 12 hours; (b) if R is2Is an alkynyl group, with an alkyne in the presence of a catalytic amount of copper (I) iodide and palladium (O) in a polar solvent, such as dimethylformamide, at room temperature for about 1 hour to about 5 hours, preferably about 3 hours; (c) if R is2Is vinyl or styryl, and is reacted with an olefin or styrene in the presence of a catalytic amount of palladium, in dimethylformamide, dioxane or tetrahydrofuran, at a temperature of about 80 ℃ to about 100 ℃, preferably about 100 ℃, for about 2 hours to about 48 hours, preferably about 48 hours.
In reaction 3 of scheme 2, a compound of formula XXIII is converted to the corresponding compound of formula XV following the procedure described above for reaction 3 of preparation A.
In 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 1.
The basic compounds of the present invention 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 necessary in practice to initially isolate a pharmaceutically unacceptable salt of a compound of the invention from the reaction mixture and then simply convert the latter to the free base compound by treatment with a basic agent, followed by conversion of the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of the present invention are readily prepared by treating the base compound with substantially equivalent amounts of the selected inorganic or organic acid in an aqueous solvent medium or a suitable organic solvent, such as methanol or ethanol. Careful evaporation of the solvent readily affords the desired solid salt. The desired acid salt may also be precipitated from a solution of the free base in an organic solvent, i.e. by adding a suitable inorganic or organic acid to the solution.
The acidic compounds of the present invention are capable of forming base salts with various pharmaceutically acceptable cations. Examples of such salts include the salts of alkali or alkaline earth metals, specifically the sodium and potassium salts. These salts are prepared by conventional techniques. Chemical bases used as reagents for preparing the pharmaceutically acceptable base salts of the present invention are those that form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from pharmaceutically acceptable cations such as sodium, potassium, calcium, magnesium, and the like. These salts can be readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may be prepared by mixing a solution of the acidic compound in a lower alkanol together with the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as described above. In both processes, it is preferred to employ stoichiometric amounts of reagents in order to ensure complete reaction and to maximize the yield of the desired end product.
The compositions of the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the present invention may be formulated for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation. The active compounds of the present invention may also be formulated in sustained release dosage forms.
For oral administration, the pharmaceutical composition may take the form of, for example, tablets or capsules formulated by conventional means with pharmaceutically acceptable excipients, for example, binders (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethyl cellulose), fillers (for example, lactose, microcrystalline cellulose or calcium phosphate), lubricants (for example, magnesium stearate, talc or silicon dioxide), disintegrants (for example, potato starch or sodium starch glycolate) or wetting agents (for example, sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may, for example, take the form of solutions, syrups or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (for example sorbitol syrup, methyl cellulose or hydrogenated edible fats), emulsifying agents (for example lecithin or acacia), non-aqueous vehicles (for example almond oil, oily esters or ethanol) and preservatives (for example methyl or propyl p-hydroxybenzoate).
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the present invention 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, e.g., in ampoules 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 formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The active compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are suitably delivered in the form of a solution or suspension from a pump spray container which is squeezed or sucked by the patient, or as an aerosol from a pressurised container or nebuliser, using a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by a valve providing metered release. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base, for example, lactose or starch.
The recommended dose of the compounds of the invention for oral, parenteral or buccal administration to the average adult for the treatment of the above-mentioned diseases (e.g. rheumatoid arthritis) is 0.1 to 1000mg of active ingredient per unit dose, which may be administered, for example, in 1 to 4 divided doses per day.
Aerosols for the treatment of the above-mentioned diseases in the average adult (e.g. asthma) are preferably arranged so that each metered dose or "puff" of aerosol contains from 20 μ g to 1000 μ g of a compound of the invention. The total daily dose of the aerosol will be in the range 0.1mg to 1000 mg. Administration may be, for example, several times daily, e.g. 2,3, 4 or 8 times, each time, e.g. 1, 2 or 3 doses.
The compounds of formula (I) may be administered alone in a pharmaceutically acceptable dosage form or in combination with one or more additional agents that modulate the immune system or anti-inflammatory agents in a mammal. These agents may include, but are not limited to, cyclosporin A (e.g., Sandimmune * or Neoral *), rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolates (e.g., Cellcept *), azathioprine (e.g., Imuran *), daclizumab (e.g., Zenapax *), OKT3 (e.g., Orthoclone *), AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (e.g., prednisolone or dexamethasone). These agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, according to the same or different dosing regimens, in accordance with standard pharmaceutical practice.
FK-506 (tacrolimus) was administered orally at 0.10-0.15mg/kg body weight every 12 hours during the first 48 hours after surgery. The dose was monitored by serum tacrolimus trough levels.
Cyclosporin a (an oral or intravenous preparation of Sandimmune, or an oral solution or capsule of Neoral *) was administered orally at 5mg/kg body weight every 12 hours within 48 hours after surgery. The dose was monitored by blood cyclosporin a pool levels.
The active agent may be formulated in sustained release dosage forms according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in U.S. patents 3,538,214, 4,060,598, 4,173,626, 3,119,742 and 3,492,397.
The following in vitro assay tests show that compounds of formula I or pharmaceutically acceptable salts thereof inhibit Janus kinase 3 and thus demonstrate their ability to treat disorders or diseases characterized by Janus kinase 3.
Biological assay
JAN3(JH 1: GST) enzyme assay
JAK3 kinase assay employs proteins (fusion proteins of GST and catalytic domain of human JAK3) purified by glutathione-agarose affinity chromatography and expressed in baculovirus-infected SF9 cells. The reaction substrate was poly-glutamic acid-tyrosine (PGT (4: 1), Sigma catalog # P0275) applied at 100. mu.g/ml to Nunc Maxi Sorp dishes overnight at 37 ℃. The next morning after coating, plates were washed three times and JAK3 was added to wells containing 100. mu.l of kinase buffer (50mM HEPES, pH7.3, 125mM NaCl, 24mM MgCl2, 0.2. mu.M ATP, 1mM sodium orthovanadate). The reaction was carried out at room temperature for 30 minutes and the plates were washed three more times. The level of phosphorylated tyrosine in a given well was quantified by a standard ELISA assay using an anti-phosphotyrosine antibody (ICN PY20, Cat # 69-151-1).
Inhibition of human IL-2 dependent T-blast proliferation
This screening method measures the inhibition of IL-2 dependent T-blast proliferation in vitro by compounds. Since signaling through the IL-2 receptor requires JAK-3, inhibitors of cellular activity of JAK-3 should inhibit IL-2 dependent T-blast proliferation.
The cells used in this assay were isolated from fresh human blood. After isolation of monocytes using System-Histopaque-1077(Sigma # A7054), primary human T-cells were isolated by negative selection using Lympho-Kwik T (One Lambda, Inc., Cat # LK-50T). 1-2X 10% in culture medium (RPMI + 10% heat-inactivated fetal bovine serum (Hyclone Cat # A-1111-L) + 1% penicillin/streptomycin (Gibco))6T-cells were cultured per ml and proliferation was induced by addition of 10. mu.g/ml PHA (Murex Diagnostics, Cat # HA 16). At 37 ℃ and 5% CO2After the next 3 days, the cells were washed 3 times in the medium and resuspended in medium plus 100 units/ml human recombinant IL-2 (R)&D Systems, Cat #202-IL), density was 1-2X 106Cells/ml. After 1 week, cells were IL-2 dependent and were able to survive for 3 weeks by supplying equal volumes of medium +100 units/ml IL-2 twice a week.
To determine the ability of test compounds to inhibit IL-2 dependent T-cell proliferation, IL-2 dependent cells were washed 3 times, resuspended in culture medium, and then plated (50,000 cells/well/0.1 ml) in flat-bottomed 96-well microtiter dishes (Falcon # 353075). From a 10mM DMSO stock solution of test compound, serial 2-fold dilutions of compound were added in triplicate, starting at 10 μ M. After one hour, 10 units/ml IL-2 were added to each test well. The plates were then incubated at 37 ℃ and 5% CO2And culturing for 72 hours. Then adding the mixture into the plate in a pulse mode3H-thymidine (0.5. mu. Ci/well) (NEN Cat # NET-027A) was cultured for another 18 hours. The plates were then harvested using a 96-well plate harvester and binding in proliferating cells was determined by counting on a Packard Top Count scintillation counter3Amount of H-thymidine. Data were analyzed by plotting% inhibition of proliferation versus the concentration of test compound. Determination of IC from the graph50Value (. mu.M).
The following examples illustrate the preparation of the compounds of the present invention but are not limited to these details. The melting point is uncorrected. NMR data are reported in parts per million (δ), quoted as the deuterium lock signal from the sample solvent (deuterated chloroform unless otherwise specified). Commercial reagents were used without further purification. THF means tetrahydrofuran. DMF refers to N, N-dimethylformamide. Low Resolution Mass Spectra (LRMS) were recorded using chemical ionization (ammonium) on a Hewlett Packard 5989 *, or using a 50/50 mixture of acetonitrile/water on a Fisons (or Micro Mass) Atmospheric Pressure Chemical Ionization (APCI) platform with 0.1% formic acid as the ionizing agent. The room temperature or ambient temperature means 20-25 ℃.
Example 1
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -ethanone
Method A
(1-benzyl-4-methyl-piperidin-3-yl) -methyl-amine
1-benzyl-4-methyl-piperidin-3-one was prepared by the method of Iorio, M.A. and Damia, G., Tetrahedron, 26, 5519(1970) and Grieco et al, Journal of the American Chemical Society, 107, 1768(1985) (both of which are incorporated herein by reference in their entirety), using 5% methanol as a co-solvent, and was dissolved in 23ml of a 2M solution of methylamine in tetrahydrofuran, to which was added 1.4ml (23mmol) of acetic acid, and the resulting mixture was stirred in a sealed tube at room temperature for 16 hours. Sodium triacetoxyborohydride (4.9 g, 23mmol) was added and the new mixture was stirred in a sealed tube at room temperature for 24 h, at which time 1N sodium hydroxide (50ml) was added to quench the reaction. The reaction mixture is then extracted with 3X 80ml of diethyl ether, the diethyl ether layers are combined and washed with sodium sulfate (Na)2SO4) Dry and concentrate to dryness in vacuo to give 1.7 g (69%) of the title compound as a white solid. LRMS: 219.1(M +1)
Method B
(1-benzyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
4-Chloropyrrolo [2, 3-d ] pyrimidine was prepared by the method of Davoll, J.Am.chem.Soc. (Proc. USA chemical society), 82, 131(1960) (incorporated herein by reference in its entirety), which (2.4 g, 15.9mmol) and the product of method A (1.7 g, 7.95mmol) were dissolved in 2 equivalents of triethylamine and the solution was heated in a sealed tube at 100 ℃ for 3 days. After cooling to room temperature and concentration under reduced pressure, the residue was purified by flash chromatography (silica; dichloromethane with 3% methanol) to yield 1.3 g (50%) of the title compound as a colorless oil. LRMS: 336.1(M +1)
Method C
Methyl- (4-methyl-piperidin-3-yl) - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
To a solution of the product of method B (0.7 g, 2.19mmol) in 15ml of ethanol was added 1.5ml of 2N hydrochloric acid and the reaction mixture was degassed by purging with nitrogen. 0.5 grams of 20% palladium on carbon hydroxide (50% water) (Aldrich) was then added to the reaction mixture, and the resulting mixture was shaken (Parr-Shaker) under a 50psi hydrogen atmosphere at room temperature for 2 days. The reaction mixture filtered through celite was concentrated to dryness in vacuo and the residue was purified by flash chromatography (silica; 5% methanol in dichloromethane) to give 0.48 g (90%) of the title compound. LRMS: 246.1(M +1)
Method D
1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl ] -ethanone
To a stirred solution of product of method C (0.03 g, 0.114mmol) in 5ml of 10: 1 dichloromethane/pyridine was added acetyl chloride (0.018 g, 0.228mmol) and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was then stirred in dichloromethane with saturated sodium bicarbonate (NaHCO)3) Are distributed among the devices. The organic layer was again washed with saturated NaHCO3Washed, dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by Preparative Thin Layer Chromatography (PTLC) (silica; containing4% methanol in dichloromethane) to yield 0.005mg (15%) of the title compound as a colorless oil. LRMS: 288.1(M +1)
The title compounds of examples 2-26 were prepared by a method analogous to that described for example 1.
Example 2
[1- (2-amino-ethanesulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
[1- (2-amino-ethanesulfonyl) -4-methyl-piperidin-3-yl ] -methyl-amine. LRMS: 353
Example 3
(1-ethanesulfonyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
(1-ethanesulfonyl-4-methyl-piperidin-3-yl) -methyl-amine. LRMS: 338
Example 4
[1- (butane-1-sulfonyl) -4-methyl-piperidin-3-yl ] -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
[1- (but-1-sulfonyl) -4-methyl-piperidin-3-yl ] -methyl-amine. LRMS: 366
Example 5
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid isobutyl ester
4-methyl-3-methylamino-piperidine-1-carboxylic acid isobutyl ester. LRMS: 346
Example 6
N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -ethyl) -propionamide
N- [2- (4-methyl-3-methylamino-piperidine-1-sulfonyl) -ethyl ] -propionamide. LRMS: 409
Example 7
(2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } ethyl) -carbamic acid methyl ester
[2- (4-methyl-3-methylamino-piperidine-1-sulfonyl) -ethyl ] -carbamic acid methyl ester. LRMS: 411
Example 8
N- (2- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-sulfonyl } -ethyl) -isobutyramide
N- [2- (4-methyl-3-methylamino-piperidine-1-sulfonyl) -ethyl ] -isobutyramide. LRMS: 423
Example 9
(1-methanesulfonyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
(1-methanesulfonyl-piperidin-3-yl) -methyl-amine. LRMS: 310
Example 10
(1-Ethanesulfonyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
(1-ethanesulfonyl-piperidin-3-yl) -methyl-amine. LRMS: 324
Example 11
Methyl- [1- (propane-1-sulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
(1-propanesulfonyl-piperidin-3-yl) -methyl-amine. LRMS: 338
Example 12
[1- (buta-1-sulfonyl) -piperidin-3-yl 1-methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
(1-butanesulfonyl-piperidin-3-yl) -methyl-amine. LRMS: 352
Example 13
2, 2-dimethyl-N- (2- [ 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino 1-piperidine-1-sulfonyl } -ethyl) -propionamide
2, 2-dimethyl-N- [2- (4-methyl-3-methylamino-piperidine-1-sulfonyl) -ethyl ] -propionamide. LRMS: 437
Example 14
3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) amino ] -piperidin-1-yl } -3-oxo-propionitrile
3- (4-methyl-3-methylamino-piperidin-1-yl) -3-oxo-propionitrile. LRMS: 313
Example 15
(3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxopropyl) -carbamic acid tert-butyl ester
[3- (4-methyl-3-methylamino-piperidin-1-yl) -3-oxo-propyl ] -carbamic acid tert-butyl ester. LRMS: 417
Example 16
Methyl- [ 4-methyl-1- (propane-1-sulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
Methyl- [ 4-methyl-1- (propane-1-sulfonyl) -piperidin-3-yl ] -amine. LRMS: 352
Example 17
3-amino-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl ] -propan-1-one
3-amino-4- (4-methyl-3-methylamino-piperidin-1-yl) -propan-1-one. LRMS: 317
Example 18
2-methoxy-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl ] -ethanone
2-methoxy-1- (4-methyl-3-methylamino-piperidin-1-yl) -ethanone. LRMS: 318
Example 19
2-dimethylamino-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino } -piperidin-1-yl ] -ethanone
2-dimethylamino-1- (4-methyl-3-methylamino-piperidin-1-yl) -ethanone. LRMS: 331
Example 20
(3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propyl) -carbamic acid tert-butyl ester
[3- (4-methyl-3-methylamino-piperidin-1-yl) -3-oxo-propyl ] -carbamic acid tert-butyl ester. LRMS: 417
Example 21
3, 3, 3-trifluoro-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] piperidin-1-yl } -propan-1-one
3, 3, 3-trifluoro-1- (4-methyl-3-methylamino-piperidin-1-yl) -propan-1-one
Example 22
N- (2- (4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } 2-oxo-ethyl) -acetamide
N- [2- (4-methyl-3-methylamino-piperidin-1-yl) -2-oxo-ethyl ] -acetamide. LRMS: 345
Example 23
3-ethoxy-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -propan-1-one
3-ethoxy-1- (4-methyl-3-methylamino-piperidin-1-yl) -propan-1-one. LRMS: 346
Example 24
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid carboxamide
4-methyl-3-methylamino-piperidine-1-carboxylic acid formamide. LRMS: 303
Example 25
4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidine-1-carboxylic acid diethylamide
4-methyl-3-methylamino-piperidine-1-carboxylic acid diethylamide. LRMS: 345
Example 26
Methyl- [ 4-methyl-1- (2-methylamino-ethanesulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine
Methyl- [ 4-methyl-1- (2-methylamino-ethanesulfonyl) -piperidin-3-yl ] -amine. LRMS: 367
Claims (10)
1. A compound of the formula or a pharmaceutically acceptable salt thereof,
wherein
R1Is a radical of the formula
Wherein y is 0, 1 or 2;
R4selected from hydrogen and (C)1-C6) An alkyl group;
R5is piperidinyl substituted with one to five of the following groups: (C)1-C6) Alkyl, (C)1-C6) Acyl, amino (C)1-C6) Acyl group, ((C)1-C6) Alkyl radical)2Amino (C)1-C6) Acyl, (C)1-C6) alkyl-S (O)mOr a group of the formula:
wherein
m is 0, 1 or 2;
a is 0, 1, 2,3 or 4;
b. c, e, f and g are each independently 0 or 1;
d is 0, 1, 2 or 3;
x is S (O)nWherein n is 0, 1 or 2; oxygen, carbonyl or-C (═ N-cyano) -;
y is S (O)nWherein n is 0, 1 or 2; or a carbonyl group;
z is carbonyl, C (O) O-or S (O)nWherein n is 0, 1 or 2;
R6、R7、R8、R9、R10and R11Each is hydrogen;
R12is cyano, amino, trifluoromethyl, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylamino or (C)1-C6) An acylamino group; while
R2And R3Each is hydrogen.
2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein
R1Is a radical of the formula
Wherein y is 0;
R4is (C)1-C6) An alkyl group;
R5is piperidinyl substituted with one to five of the following groups: (C)1-C6) Alkyl, (C)1-C6) Acyl, amino (C)1-C6) Acyl group, ((C)1-C6) Alkyl radical)2Amino (C)1-C6) Acyl, (C)1-C6) alkyl-S (O)mOr a group of the formula:
wherein m is 0, 1 or 2;
d is 1;
R9and R10Each is hydrogen;
R12is cyano, amino, trifluoromethyl, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylamino or (C)1-C6) An acylamino group; while
R2And R3Are all hydrogen.
3. The compound according to claim 1, wherein the compound is selected from the group consisting of:
methyl- [ 4-methyl-1- (propane-1-sulfonyl) -piperidin-3-yl ] - (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amine;
3, 3, 3-trifluoro-1- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -propan-1-one;
3- { 4-methyl-3- [ methyl- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -amino ] -piperidin-1-yl } -3-oxo-propionitrile.
4. A compound according to claim 1 which 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.
5. A pharmaceutical composition comprising a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition according to claim 5, further comprising one or more additional agents that modulate the immune system or anti-inflammatory agents in a mammal.
7. Use of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting a mammalian protein kinase or Janus kinase 3.
8. The use according to claim 7, wherein said compound or pharmaceutically acceptable salt thereof is further combined with one or more additional agents that modulate the immune system or anti-inflammatory agents of a mammal.
9. Use according to claim 7 or 8, wherein the medicament is for the treatment or prevention of the following disorders or diseases: organ transplant rejection, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia.
10. Use according to claim 7 or 8, wherein the mammal is a human.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US17017999P | 1999-12-10 | 1999-12-10 | |
| US60/170,179 | 1999-12-10 | ||
| PCT/IB2000/001742 WO2001042246A2 (en) | 1999-12-10 | 2000-11-23 | PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1051195A1 HK1051195A1 (en) | 2003-07-25 |
| HK1051195B true HK1051195B (en) | 2005-07-29 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1195755C (en) | Pyrrolo [2,3-d] pyrimidine compounds | |
| CN1717236A (en) | Methods of treating transplant rejection | |
| CN1729192A (en) | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors | |
| US20050113395A1 (en) | Method of treatment of atherosclerosis | |
| CN1893952A (en) | Pyrrolo[2,3-D]pyrimidine compounds for treating transplant rejection | |
| CN1726192A (en) | 3-Amino-piperidine derivative and its preparation method | |
| CN1668592A (en) | Piperidine derivatives and their use as selective inhibitors of MIP-1alpha binding to its receptor CCR1 | |
| HK1051195B (en) | Pyrrolo(2,3-d)pyrimidine compounds | |
| HK1081440A (en) | Method of treatment of transplant rejection | |
| HK1082501A (en) | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl)-methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors | |
| HK1097740A (en) | Pyrrolo (2,3-d) pyrimidine compounds for treating transplant rejection | |
| HK1084107A (en) | 3-amino-piperidine derivatives and processes for their preparation |