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ES2260199T3 - Derivatives of purina. - Google Patents
Derivatives of purina.
ES2260199T3
ES2260199T3 ES01902583T ES01902583T ES2260199T3 ES 2260199 T3 ES2260199 T3 ES 2260199T3 ES 01902583 T ES01902583 T ES 01902583T ES 01902583 T ES01902583 T ES 01902583T ES 2260199 T3 ES2260199 T3 ES 2260199T3
ES01902583T
Simon John Pfizer Global Res. and Dev. MANTELL
Sandra M. Pfizer Global Res. and Dev. MONAGHAN
Peter T. Pfizer Global Res. and Dev. STEPHENSON
Pfizer Ltd
2000-02-18 Priority to GBGB0003960.2A priority Critical patent/GB0003960D0/en
2000-02-18 Priority to GB0003960 priority
2001-02-09 Application filed by Pfizer Ltd filed Critical Pfizer Ltd
2006-11-01 Publication of ES2260199T3 publication Critical patent/ES2260199T3/en
C07—ORGANIC CHEMISTRY
C07D—HETEROCYCLIC COMPOUNDS
C07D473/00—Heterocyclic compounds containing purine ring systems
C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
C07H15/02—Acyclic radicals, not substituted by cyclic structures
C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
C07H19/16—Purine radicals
A compound with the formula: (See formula) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, each optionally substituted with 1 or 2 substituents selected each one independently of hydroxyl, fluorenyl, phenyl and naphthyl, said phenyl and naphthyl being optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halo or cyano; A is a C1-C6 alkylene or bond; R2 is (i) hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or naphthyl, said C3-C7 cycloalkyl, phenyl and naphthyl being optionally substituted with C1-C6 alkyl, phenyl, C1-C6 alkoxy-C1 alkyl -C6, amino-C1-C6 alkyl, fluoro-C1-C6 alkyl, C1-C6 fluoro-alkoxy, C2-C5 alkanoyl, halo, -OR3, cyano, -COOR3, C3-C7 cycloalkyl, -S (O) mR4 , -NR3R3, -SO2NR3R3, -CONR3R3, -NR3COR4 or -NR3SO2R4, provided that R2 is not hydrogen when A is a bond, or (ii) when A is C2-C6 alkylene, -NR3R3, -OR3, -COOR3 , -OCOR4, -SO2R4, -CN, -SO2NR3R3, -NR3SO2R4, -NR3COR4 or -CONR3R3, or (iii) a heterocycle linked by a C, between 4 and 11 members, mono or bicyclic that has in the ring or between 1 and 4 nitrogen atom (s), or 1 or 2 nitrogen atoms and 1 oxygen atom or a sulfur atom, with a C optionally substituted by oxo, (C1-C6) alkoxy-C1-C6 alkyl, amino- C1-C6 alkyl, fluoro-C1-C6 alkyl, fluoro-C1-C6 alkoxy, C2-C5 fluoro-alkanoyl, halo, cyano, -OR5, R6, -COR 5, -NR5R5, -COOR5, -S (O) mR6, -SO2NR5R5, -CONR5R5, -NR5SO2R6 or -NR5COR6 and with an N optionally substituted by (C1-C6) alkoxy-C1-C6 alkyl, C2-C6 aminoalkyl, fluoro-C1-C6 alkyl, fluoro-C2-C5 alkanoyl, R6, -COR5, -COOR6, -S (O) 2R6, -SO2NR5R5 or -CONR5R5, or (iv) when A is C2-C6 alkylene, azetidinyl linked by an N, pyrrolidinyl, morpholinyl, tetrahydroisoquinolinyl, piperidinyl or piperazinyl, each having a C atom optionally substituted with C1-C6 alkyl, phenyl, (C1-C6) alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, fluoro -C1-C6 alkyl, C1-C6 fluoroalkoxy, C2-C5 alkanoyl, halo, -OR3, cyano, -COOR3, C3-C7 cycloalkyl, -S (O) mR4, -NR3R3, -SO2NR3R3, -CONR3R3, -NR3COR4 or -NR3SO2R4 and said piperazinyl having an N atom substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-C1-C6 alkyl, amino C2-C6 alkyl, fluoro-C1-C6 alkyl, C2-C5 alkanoyl , -COOR4, C3-C7 cycloalkyl, -SO2R4, -SO2NR3R3 or -CONR3R3; each R3 is independently selected from H, C1-C6 alkyl, phenyl or pyridinyl; R4 is C1-C6 alkyl or phenyl; R5 is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het; R6 is C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het; m is 0, 1 or 2; R7 is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl, azetidin-3-yl, pyrrolidin-3-yl, piperidin-3yl, piperidin-4-yl or het, said azetidin-3-yl being said, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl optionally substituted with C1-C6 alkyl; R8 is H or C1-C6 alkyl and ¿het¿, used in the definitions of R 5, R 6 and R 7, means pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, linked by a C, each optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, cyano or halo.
Purine derivatives.
The present invention relates to certain purine derivatives. More particularly, the present invention relates to purin-2-ylcarboxamide derivatives, their preparation and the compositions, uses and intermediates used in the preparation thereof. These derivatives are selective and functional agonists of the human adenosine A2a receptor and can be used as anti-inflammatory agents in the treatment of, inter alia , respiratory tract diseases.
Adenosine is a ubiquitous molecule that has a major role in the intermediate metabolism of mammals. Independently, adenosine acts on several surface receptors to produce a variety of responses. The classification of the receptors has revealed the presence of at least four subtypes: A1, A2a, A2b and A3. It has been reported that stimulation of adenosine A2 receptors on the surface of human neutrophils potently inhibits a range of neutrophil functions. Activated neutrophils can damage lung tissue by releasing oxygen reactive species, such as superoxide anion radicals (O2 -) and granular products, such as human neutrophil elastase (ENH), among other intermediates. inflammatory In addition, activated neutrophils de novo carry out both the synthesis and release of arachidonate products such as leukotriene B 4 (LTB 4). LTB 4 is a potent chemo attractant that attracts additional neutrophils to the inflammatory center, while O 2 - and ENH adversely affect the pulmonary extracellular matrix. It is admitted that the A2 receptor subtype that mediates many of these responses (release of O 2 - and LTB 3 / ENH and cell adhesion) is A2a. The A2 receptor subtype (A2a or A2b) that mediates the other effects remains undefined.
The selective agonist activity is considered of the A2a receptor offers a greater therapeutic benefit than that of the non-selective adenosine receptor agonists because the interaction with other receptor subtypes is associated with effects harmful in the lung in animal models and in studies with human tissues For example asthma sufferers, although this does not occurs in the case of those who are not sick with asthma, suffer bronchoconstriction when tested for adenosine inhaled This response is due, at least in part, to activation of subtype A1 receptor. Activation of A1 receptors It also promotes neutrophil chemotaxis and adherence to endothelial cells, thus promoting lung lesions. In addition, many patients with a respiratory illness are β2 agonists will have co-prescribed and in animal studies has shown a negative interaction between isoprenaline and adenosine receptors negatively coupled to adenylate cyclase Mast cell degranulation is promoted by the activation of adenosine A2b receptors, so the Selectivity on this receptor is also advantageous.
Now, surprisingly we have discovered that the purine derivatives of the present invention inhibit the neutrophil function and are selective agonists of the receptor of adenosine A2a.
The compounds of the present invention can be used to treat any disease for which the A2a adenosine receptor agonist is indicated. They can be used to treat a disease in which tissue damage induced by leukocytes is involved (eg, neutrophils, eosinophils, basophils, lymphocytes, macrophages). They are useful as anti-inflammatory agents in the treatment of respiratory tract diseases, such as adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis . The compounds of the present invention can also be used in the treatment of septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischemic reperfusion injuries, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis , allergic dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, gastritis with Heliobacter pylori , gastritis without Heliobacter pylori , damage induced by non-steroidal anti-inflammatory drugs in the gastrointestinal tract or can be used in a psychotic disorder, or for wound healing
Therefore, in one aspect the present Invention provides a compound with the formula:
or a salt or solvate pharmaceutically acceptable from same,
wherein R 1 is hydrogen, alkyl C 1 -C 6, cycloalkyl C_ {3} -C_ {7}, each substituted so optional with 1 or 2 substituents each selected independent between hydroxyl, fluorenyl, phenyl and naphthyl, being said phenyl and naphthyl optionally substituted with alkyl C 1 -C 6, alkoxy C 1 -C 6, halo or cyano;
A is a bond or alkylene C 1 -C 6;
R2 is (i) hydrogen, alkyl C 1 -C 6, cycloalkyl C 3 -C 7, phenyl or naphthyl, said being C 3 -C 7 cycloalkyl, phenyl and naphthyl optionally substituted with alkyl C 1 -C 6, phenyl, alkoxy (C 1 -C 6) - alkyl C 1 -C 6, amino-alkyl C 1 -C 6, fluoro-alkyl C 1 -C 6, fluoroalkoxy C 1 -C 6, alkanoyl C 2 -C 5, halo, -OR 3, cyano, -COOR 3, C 3 -C 7 cycloalkyl, -S (O) m R 4, -NR 3 R 3, -SO 2 NR 3 R 3, -CONR 3 R 3, -NR 3 COR 4 or -NR 3 SO 2 R 4, provided that R 2 does not be hydrogen when A is a bond, or
(ii) when A is C 2 -C 6 alkylene, -NR 3 R 3, -OR 3, -COOR 3, -OCOR 4, -SO 2 R 4, -CN, -SO 2 NR 3 R 3, -NR 3 SO 2 R 4,
-NR 3 COR 4 or -CONR 3 R 3, or
(iii) a heterocycle linked by a C, of between 4 and 11 members, mono or bicyclic that you have in the ring or between 1 and 4 nitrogen atom (s), or 1 or 2 atoms of nitrogen and 1 oxygen atom or a sulfur atom, with a C optionally substituted by oxo, alkoxy (C 1 -C 6) - alkyl C 1 -C 6, amino-alkyl C 1 -C 6, fluoro-alkyl C 1 -C 6, fluoroalkoxy C 1 -C 6, fluoro-alkanoyl C 2 -C 5, halo, cyano, -OR 5, R 6, -COR 5, -NR 5 R 5, -COOR 5, -S (O) m R 6, -SO 2 NR 5 R 5, -CONR 5 R 5, -NR 5 SO 2 R 6 or -NR 5 COR 6 and with an optionally substituted N by (C 1 -C 6) alkoxy-alkyl C 1 -C 6, amino-alkyl C 2 -C 6, fluoro-alkyl C 1 -C 6, fluoro-alkanoyl C 2 -C 5, R 6, -COR 5, -COOR 6, -S (O) 2 R 6, -SO 2 NR 5 R 5 or -CONR 5 R 5, or
(iv) when A is alkylene C 2 -C 6, azetidinyl linked by an N, pyrrolidinyl, morpholinyl, tetrahydroisoquinolinyl, piperidinyl or piperazinyl, each having an optionally C atom substituted with C 1 -C 6 alkyl, phenyl, (C 1 -C 6) alkoxy-alkyl C 1 -C 6, amino-alkyl C 1 -C 6, fluoro-alkyl C 1 -C 6, fluoroalkoxy C 1 -C 6, alkanoyl C 2 -C 5, halo, -OR 3, cyano, -COOR 3, C 3 -C 7 cycloalkyl, -S (O) m R 4, -NR 3 R 3, -SO 2 NR 3 R 3, -CONR 3 R 3, -NR 3 COR 4 or
-NR 3 SO 2 R 4 and having said piperazinyl an N atom substituted by alkyl C 1 -C 6, phenyl, alkoxy (C 1 -C 6) - alkyl C 1 -C 6, amino-alkyl C 2 -C 6, fluoro-alkyl C 1 -C 6, alkanoyl C 2 -C 5, -COOR 4, cycloalkyl C 3 -C 7, -SO 2 R 4, -SO 2 NR 3 R 3 or -CONR 3 R 3;
each R3 is selected so independent between H, C 1 -C 6 alkyl, phenyl or pyridinyl;
R 4 is alkyl C 1 -C 6 or phenyl;
R 5 is H, alkyl C 1 -C 6, cycloalkyl C 3 -C 7, phenyl, naphthyl or het;
R 6 is alkyl C 1 -C 6, cycloalkyl C 3 -C 7, phenyl, naphthyl or het;
m is 0, 1 or 2;
R 7 is hydrogen, alkyl C 1 -C 6, cycloalkyl C 3 -C 7, phenyl, naphthyl, azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl or het, being said azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl and piperidin-4-yl optionally substituted with C 1 -C 6 alkyl;
R 8 is H or alkyl C_ {1} -C_ {6} and
"het", used in the definitions of R 5, R 6 and R 7, means pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, linked by a C, each of them being optionally substituted by alkyl C 1 -C 6, alkoxy C 1 -C 6, cyano or halo.
Preferably, R1 is cyclohexyl or optionally substituted C 1 -C 6 alkyl. More preferably, R1 is alkyl Optionally substituted C_ {C} {C5} and most preferably R 1 is C 1 -C 2 alkyl optionally substituted.
Preferably, the alkyl substituents C 1 -C 6, C 1 -C 5 or C 1 -C 2 are selected from benzyl, fluorenyl, phenyl and hydroxyl.
Preferably, when R1 is substituted With phenyl, there are 1 or 2 phenyl group (s).
Preferably, R1 is selected from 2,2-diphenylethyl, cyclohexyl, 1-ethylpropyl, 1-benzyl-2-hydroxyethyl, 9H-fluoren-9-ylmethyl, Y 1-benzyl-2-phenylethyl.
Preferably, R1 is 2,2-diphenylethyl.
Preferably, A is alkylene C_ {1} -C_ {6}.
Preferably, A is selected from methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene.
Preferably, A is 1,2-ethylene.
Preferably, R2 is selected from phenyl, pyrrolidinyl, pyridinyl, piperidinyl optionally substituted, optionally substituted piperazinyl, imidazolyl optionally substituted, morpholinyl, tetrahydroisoquinoline, (C 1 -C 6) alkyl amino, di (C 1 -C 6) alkyl amino, pyridinylamino and -NR 3 SO 2 R 4.
Preferably, R2 is selected from phenyl, 2-pyridinyl, 1-piperazinyl, 4-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, 3,4-tetrahydro-2 (1H) -isoquinolinyl, dialkyl (C 1 -C 3) amino, and 1H-imidazol-4-yl replaced.
Preferably, R2 is selected from isopropylamino, methylamino, dimethylamino, diethylamino, 1-methyl-1H-imidazol-4-yl, 5-methyl-1H-imidazol-4-yl, methylpiperazin-1-yl, 1- (2-propyl) piperidin-4-yl and 2-pyridylamino.
Preferably, R2 is piperidinyl optionally substituted with C 1 -C 6 alkyl or with methoxy.
Preferably, R2 is piperidinyl optionally substituted in position 1- or in the position 4- with C 1 -C 6 alkyl or with methoxy.
Preferably, R2 is piperidinyl attached by an N with a C atom optionally substituted by alkyl C 1 -C 6 or with methoxy.
Preferably, R2 is piperidinyl attached by an N with a C atom optionally substituted by methyl, methoxy or propyl.
Preferably, R2 is piperidinyl attached by an optionally substituted N in position 4- by methyl, methoxy or propyl.
Preferably, R2 is piperidin-1-yl, 4- (methyl) piperidin-1-yl, 4- (methoxy) piperidin-1-yl or 4- (prop-2-yl) piperidin-1-yl.
Preferably, R 3 is methyl.
Preferably, R 4 is methyl or phenyl.
Preferably, R 7 is alkyl C_ {1} -C_ {6}.
Preferably, R 7 is ethyl or n-propyl.
Preferably, R 8 is H.
In another aspect of the present invention, provides a compound with the formula (II), (III), (XI), (XIII), (XIV), (XV), (XVI), (XIX), (XIXb), (XIXc) or (XIXd):
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in which R 1 to R 8, A, "het" and m, when present, are as defined previously; P 1, P 2 and P 3 are protecting groups and Z is a group outgoing.
In another aspect of the present invention, provides a method for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, method that It comprises the reaction step of an ester of formula (II):
with an amine with the formula R 2 -A-NHR 8 (X), in which R 1 to R 8, A, "het" and m, when present, are as defined previously.
In another aspect of the present invention, provides a method for the preparation of a compound with the formula (II):
method comprising the stage of deprotection of a compound of formula (III):
in which P1 and P2 are protective groups that may be the same or different, or may be part of the same protecting group and in which R 1 to R 8, A, "het" and m, when present, are as defined previously.
In another aspect of the present invention, provides a method for the preparation of a compound with the formula (III):
method comprising the stage of the reaction of a compound of formula (XI):
where P 1 and P 2 are protecting groups, with trimethylsilyltrifluoromethanesulfonate and with a compound with the formula (IV):
in which the compound of formula (IV) is derivatized with N, O-bis (trimethylsilyl) acetamide and a It is then reacted with the compound of formula (XI) and where R 1 to R 8, A, "het" and m, when they are present, they are as defined previously.
In another aspect of the present invention, provides a method for the preparation of a compound of formula (IV):
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through alcohololysis and subsequent hydrolysis of a nitrile of formula (V):
where R 1 is R 8, A, "het" and m, when present, are as defined previously.
In another aspect of the present invention, provides a method for the preparation of a compound with the formula (V):
by checking out a compound of formula (SAW):
in which P3 is a group protector and R 1 to R 8, A, "het" and m, when they are present, they are as defined previously.
In another aspect of the present invention, provides a method for the preparation of a compound with the formula (VI):
by replacing the group chlorine in a compound with the formula (VII):
with a cyano group, in which R 1 is R 8, A, "het" and m, when present, are as defined previously.
In another aspect of the present invention, provides a method for the preparation of a compound with the formula (VII):
by reacting a compound of formula (VIII):
with an amino compound of formula R 1 NH 2 (XII), wherein R 1 to R 8, A, "het" and m, when present, are as defined previously.
In another aspect of the present invention, provides a method for the preparation of a compound with the formula (VIII):
by protecting 2,6-dichloro-9H-purine (IX):
In the previous definitions, halo means fluorine, chlorine, bromine or iodine and alkyl, alkylene, alkanol groups and alkoxy containing the number of carbon atoms required they can be unbranched or branched chains. The heterocycle, such as defined above in R2, part (iii), can be aromatic or may be totally or partially saturated. The expression "linked by a C" used in the definitions of R2 and of het means that the group is attached to the adjacent atom by a carbon atom of the ring. The expression "joined by an N" used in the definitions of R2 means that the group is attached to the adjacent atom by a ring nitrogen atom. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. The examples Alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene and 1,2-propylene. The Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The pharmaceutically acceptable salts of Compounds with the formula (I) include acid addition salts and base of them. Suitable acid addition salts are formed from acids that form non-toxic salts and examples of they are the salts of hydrochloride, hydrobromide, iodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, sucrate, benzoate, methanesulfonate, ethanesulfonate, becenosulfonate, p-toluenesulfonate and palmoate.
Suitable base salts are formed from of bases that form non-toxic salts and examples thereof are the salts of sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine
For a review of suitable salts, see Berge et al. J. Pharm. Sci ., 1977, 66 , 1-19.
The pharmaceutically acceptable solvates of compounds with the formula (I) include the hydrates of the same.
Within the scope of the compounds with the formula (I) of the present invention are also the compounds polymorphs thereof.
A compound with the formula (I) may contain one or more additional asymmetric carbon atoms and therefore It can exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds with the formula (I) together with the mixtures thereof together with, if appropriate, the individual tautomers of the compounds with the formula (I) and includes mixtures thereof.
The separation of diastereoisomers can be achieved by conventional techniques, for example by fractional crystallization, purification by chromatography or by HPLC, of a stereoisomeric mixture of a compound with the formula (I) or of a salt or a suitable derivative thereof. An individual enantiomer of a compound with the formula (I) can also be prepared from a corresponding optically active intermediate compound or by resolution, such as by HPLC purification of the corresponding racemate using a suitable chiral support, or by fractional crystallization. of the diastereoisomeric salts formed by the reaction of the corresponding racemate with a suitable optically active acid or base, according to
All compounds with the formula (I) are they can prepare by conventional routes such as by the methods described in the general methods presented below, or by the specific methods described in the section dedicated to the examples or by methods similar to those same. The present invention also encompasses any one or more of these methods for the preparation of the compounds of formula (I), in addition to any of the new intermediate compounds used in they. In the general methods described, R1, R2, R 7, R 8 and A are as defined above for a compound with the formula (I) unless indicated contrary.
All compounds with the formula (I) are they can prepare according to the route shown in scheme 1, in which R 9 is C 1 -C 4 alkyl, preferably methyl or ethyl and P 1, P 2 and P 3 They represent protective groups.
(Scheme turns to page next)
Scheme one
In scheme 1, the compounds with the formula (I) can be prepared by reacting an ester with the formula (II) with an amine with the formula
(X) .R2 -A-NHR8
The reaction can be carried out at a high temperature, preferably between 100 and 150 ° C and so optional in the presence of a suitable solvent, such as ethanol. In a typical method, the compound with the formula (II) and the amine with the formula (X) are heated together at about 120 ° C.
The compounds of formula (II) can be prepare by deprotecting a compound with the formula (III) in which the protective groups P 1 and P 2 can be same or different and can optionally be part of Same protective group. Examples of suitable protecting groups they will be obvious to experts in the field [see, for example, "Protecting Groups in Organic Synthesis (Second Edition)", Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. Preferred individual protecting groups are alkanol and aroyl. Preferred protecting groups in which P1 and P2 they are part of the same protective group are those in which P1 and P2 taken together are alkylene C_ {1} -C_ {6}. The individual protecting groups Especially preferred are acetyl and benzoyl. A protective group especially preferred when P1 and P2 are part of the same protecting group is when P1 and P2 taken together they are dimethylmethylene. The right conditions for deprotection are well known in the art [see, for example, "Protecting Groups in Organic Synthesis (Second Edition)", Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical method, in which P1 and P2 are each benzoyl, the protective groups can be removed by treating a solution of the compound with the formula (III) in a solvent suitable, such as methanol, with a base such as carbonate of potassium, typically at room temperature. The compounds with the formula (III) can be prepared by reacting a compound with the formula (XI):
(in which P1 and P2 are as defined above) with trimethylsilyltrifluoromethanesulfonate and with a compound with the formula (IV) that has been derivatized with N, O-bis (trimethylsilyl) acetamide. In a typical method, the compound with the formula (IV) is heated in presence of a suitable solvent, such as 1,1,1-trichloroethane and in the presence of N-O-bis (trimethylsilyl) acetamide at an elevated temperature, preferably at reflux. Then the mixture is allowed to cool to room temperature and removed the solvent The residue is treated with a solution of the compound with the formula (XI) in a suitable solvent such as toluene, followed by trimethylsilyltrifluoromethanesulfonate and the mixture is heats under a nitrogen atmosphere at a temperature included between room temperature and the reflux temperature of chosen solvent, to provide the compound with the formula (III). In the case of using toluene, for example, the temperature preferred is 110 ° C. The compounds with the formula (IV) can be prepare by an alcoholysis and hydrolysis sequence applied to a nitrile with the formula (V). In a typical method, it treat a solution of nitrile with the formula (V) in a solvent alcoholic R 9 OH with a sodium alkoxide with the formula R 9 ONa and heated to reflux (R 9 is as defined previously). The resulting mixture is cooled, evaporated, evaporated. dissolved in a suitable solvent such as tetrahydrofuran and treat with an acid such as hydrochloric acid, preferably with 2 N hydrochloric acid, to provide a compound with the formula (IV). Compounds with the formula (V) can be prepared by deprotection of a compound with the formula (VI) in which P3 is a suitable protecting group. The examples of groups Appropriate protectors will be obvious to those skilled in the art [see, for example, "Protecting Groups in Organic Synthesis (Second Edition) ", Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. A preferred protecting group is one in the that P3 represents tetrahydropyran-2-yl. The suitable conditions for deprotection are well known in the technique [see, for example, "Protecting Groups in Organic Synthesis (Second Edition) ", Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical method, in which P3 is tetrahydropyranyl, the protecting group can be removed by treating a solution of the compound with the formula (VI) in a suitable solvent, such as ethanol, with a acid such as hydrochloric acid. Compounds with the formula (VI) they can be prepared by replacing the chlorine group in a composed with the formula (VII) by a cyano group. In a method typical, a solution of the compound is treated with the formula (VII) in a suitable solvent, such as N, N-dimethylformamide, with zinc cyanide, tetrakis (triphenylphosphine) palladium (0) and with an acceptor acid such as triethylamine and is heated under an atmosphere of nitrogen at between 80 and 120 ° C, preferably at 100 ° C. The product of the reaction is normally contaminated with an amount of corresponding compound with the formula (V), which can be separated by purification by chromatography routine
The compounds with the formula (VII) can be prepare by reacting a compound with the formula (VIII) with an amine with the formula
(XII) .R1 NH2
In a typical method, a solution of the compound with the formula (VIII) in a suitable solvent such as Isopropyl alcohol with the compound with the formula (XII) and heats to reflux, optionally in the presence of an acid acceptor such as N-ethyl-N-isopropyl-2-propylamine. Compounds with the formula (VIII) can be prepared by protection of 2,6-dichloro-9H-purine (IX). Examples of suitable P3 protecting groups will be obvious to experts in the field [see, for example, "Protecting Groups in Organic Synthesis (Second Edition)", Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. A Preferred protecting group is one in which P3 represents tetrahydropyran-2-yl. The suitable conditions for protection are well known in the technique [see, for example, "Protecting Groups in Organic Synthesis (Second Edition) ", Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical method, in which P3 is tetrahydropyran-2-yl, it heats a solution of 2,6-dichloro-9H-purine (IX) and an acid catalyst, such as acid 4-toluenesulfonic monohydrate, in a solvent suitable, such as ethyl acetate, at between 30 and 70 ° C, preferably at 50 ° C and treated with a solution of 2,3-dihydropyran in a suitable solvent, such as ethyl acetate.
All compounds with the formula (I) also can be prepared according to the route shown in scheme 2, wherein R 9, P 1, P 2 and P 3 are as is defined above.
Scheme 2
In scheme 2, the compounds of formula (I) they can be prepared by deprotecting a compound with the formula (XIII). Suitable conditions for deprotection are well known in the art [see, for example, "Protecting Groups in Organic Synthesis (Second Edition) ", Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical method, in which P1 and P2 are each benzoyl, the groups protectors can be removed by treating a dissolution of the compound with the formula (XIII) in a solvent suitable, such as methanol, with a base such as carbonate of potassium, typically at room temperature. The compounds with the formula (XIII) can be prepared by reacting a compound with the formula (XI):
(in which P1 and P2 are as defined above) with trimethylsilyltrifluoromethanesulfonate and with a compound with the formula (XIV) that has been derivatized with N, O-bis (trimethylsilyl) acetamide. In a typical method, the compound with the formula (XIV) is heated in presence of a suitable solvent, such as 1,1,1-trichloroethane and in the presence of N-O-bis (trimethylsilyl) acetamide at an elevated temperature, preferably at reflux. Then the mixture is allowed to cool to room temperature and removed the solvent The residue is treated with a solution of the compound with the formula (XI) in a suitable solvent such as toluene, followed by trimethylsilyl trifluoromethanesulfonate and the mixture is heats under a nitrogen atmosphere at a temperature included between room temperature and the reflux temperature of chosen solvent, to provide the compound with the formula (XIII). In the case of using toluene, for example, the temperature preferred is 90 ° C. Compounds with the formula (XIV) can be prepare by deprotecting a compound with the formula (XV). The right conditions for deprotection are fine known in the art [see, for example, "Protecting Groups in Organic Synthesis (Second Edition) ", Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical method, wherein P3 is tetrahydropyranyl, the protecting group can be remove by treating a solution of the compound with formula (XV) in a suitable solvent, such as ethanol, with a acid such as hydrochloric acid. Compounds with the formula (XV) they can be prepared by reacting an ester with the formula (XVI) with an amine with the formula (X):
(X) R 2 -A-NHR 8
at an elevated temperature, preferably at 100 to 150 ° C. In a typical method, the compound with the formula (XVI) and the amine with the formula (X) is heat together at 130 ° C. Compounds with the formula (XVI) are they can prepare by means of an alcoholysis and hydrolysis sequence carried out on a nitrile with the formula (VI). In a method typical, a solution of the nitrile is treated with the formula (VI) in an alcohol solvent R 9 OH with sodium alkoxide with the formula R9 ONa and heated to reflux. The resulting mixture is cools, evaporates, dissolves in a suitable solvent, such as in a mixture of tetrahydrofuran and water (preferably 3: 1 in volume) and is treated with an acid such as acetic acid. Mix resulting is heated to an elevated temperature, preferably at reflux, to provide the compound with the formula (XVI).
Compounds with the formula (XI), as used in schemes 1 and 2, can be prepared as shown in scheme 3, in which P1 and P2 are as defined above.
Compounds with the formula (XI) can be prepare by treating a compound with the formula (XVII) with a mixture of acetic acid, acetic anhydride and an acid strong such as hydrochloric or sulfuric acid with cooling (typically at -10 ° C). A compound of formula (XVII) is it can be prepared from an acid with the formula (XVIII) by acid activation, such as, for example, hydrochloric acid and by treating this activated intermediate with an amine with the formula (XIXa):
(XIXa) R 7 NH 2
In a typical method, a compound of formula (XVIII) is dissolved in a suitable inert solvent (for example, in dichloromethane) and treated with oxalyl chloride and with a catalytic amount of N, N-dimethylformamide. After removal of excess solvent and reagent by evaporation under reduced pressure, the residue is dissolved in anhydrous dichloromethane and treated with an amine with the formula (XIXa). In relation to the conditions employed in the subsequent steps, it may be appropriate to change the protective groups P 1 and P 2 in the compounds of formula (XVII). Alternatively, suitable protecting groups are well known to those skilled in the art [see, for example, "Protecting Groups in Organic Synthesis (Second Edition)", Theodora W. Green and Peter GM Wuts, John Wiley and Sons, 1991 ]. In a typical case, a solution of the compound of formula (XVII) in which P 1 and P 2 taken together are dimethylmethylene in a suitable solvent, such as methanol, can be treated with an acid such as - pyridinium toluenesulfonate, to provide a compound of formula (XVII) in which P 1 and P 2 are both substituted by H atoms, positions that can be subsequently protected again with other functionality. For example, the compound of formula (XVII) in which P1 and P2 are both replaced by H, can be dissolved in a suitable solvent such as dichloromethane and the resulting solution can be treated with an acceptor acid such as pyridine and with benzoyl chloride, to provide a compound of formula (XVII) in which P1 and P2 are each benzoyl. The compounds of formula (XVIII) are known in the art, for example in J. Amer. Chem. Soc ., 1958, 80 , 5168, wherein P 1 and P 2 taken together are dimethylmethylene.
The amines with the formulas R 7 NH 2 (XIXa), R1 NH2 (XII) and R 2 -A-NHR 8 (X) or se are commercially available, or can be prepared by standard techniques well known to experts in the technique.
All compounds with the formula (I) are they can prepare alternatively by condensing a acid with the formula (XIX) with an amine with the formula (X), such as shown in scheme 4.
Condensation is typically carried out under conventional peptide coupling conditions. For example, a solution of the acid (XIX) in a solvent can be treated suitable such as dichloromethane, with a coupling agent suitable such as carbonyl diimidazole and subsequently with a compound with the formula (X). An acid with the formula (XIX) can be prepare by hydrolysis of a compound with the formula (II). In order to carry out the hydrolysis, typically a compound with the formula (II) in a suitable solvent such as ethanol and treated with a suitable base, such as a solution aqueous sodium hydroxide.
The compounds with the formula (I) can be alternatively prepare by a reaction of aminocarbonylation of a compound with the formula (XIXb):
in which Z is a leaving group suitable such as bromine, iodine, Sn (alkyl C 1 -C 12) 3 or CF 3 SO 2 O-, preferably iodine, with a compound of formula R 2 -A-NHR 8 (X) in the presence of carbon monoxide and a coupling catalyst. Preferably, the catalyst is a palladium (II) catalyst, more preferably 1,1'-bis (diphenylphosphino) ferrocenodichloropaladium (II) (optionally as a 1: 1 complex with dichloromethane). Alternatively, acetate can be used. palladium (II) in the presence of a suitable ligand, such as 1,1'-bis (diphenylphosphino) ferrocene, triphenylphosphine, tri (o-tolyl) phosphine or (R) -, (S) - or 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl racemic
In a typical method, the reaction is carried out. in an airtight container in the presence of carbon monoxide at a high pressure, for example at approximately 345 kPa (50 psi), at an elevated temperature, for example at about 60 ° C and in a suitable solvent, for example tetrahydrofuran, methanol or ethanol. Optionally, a suitable organic base may be present, such as a tertiary amine, for example triethylamine, ethyldiisopropylamine or 4-methylmorpholine.
Intermediates with the formula (XIXc) they can be prepared as shown in example 5.
in which Z is as defined above for the compound with the formula (XIXb) and Ac is acetyl.
In a typical method, a compound with the formula (XIXd) is reacted with an amide with the formula R 1 NH 2 (XII) in the presence of a suitable acid acceptor, for example triethylamine and in a suitable solvent, for example acetonitrile, at an elevated temperature, if necessary. He product with the formula (XIXc) obtained can be checked out by hydrolysis to provide a compound with the formula (XIXb) by a conventional method, such as through the use of a suitable inorganic base, for example sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate and in a suitable solvent, for example methanol, ethanol, isopropanol, 1,2-dimethoxyethane, tetrahydrofuran, dimethylformamide, acetone, 2-butanone or 4-methyl-2-pentanone, optionally under aqueous conditions, between 0ºC and the temperature of reflux of the solvent, for example at room temperature. From alternatively, deprotection can be carried out using an appropriate amine base, such as triethylamine, diisopropylethylamine, 4-methylmorpholine, ammonia, methylamine, ethylamine or dimethylamine in a suitable solvent such like methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or dichloromethane at between 0 ° C and the temperature of solvent reflux. Compounds with the formula (XIXd) are they can prepare by a conventional method.
You can easily prepare a salt pharmaceutically acceptable of a compound with the formula (I) by jointly mixing solutions of a compound with the formula (I) and the desired acid or base, as appropriate. The salt it can precipitate in a solution and can be collected by filtration or can be recovered by evaporation of solvent
The anti-inflammatory properties of the compounds with the formula (I) are demonstrated by their ability to inhibit neutrophil function, indicating agonist activity of the A2a receptor. This is evaluated by determining the profile of the compound in an assay in which the production of superoxide was measured from neutrophils activated by fMLP. Neutrophils were isolated from human peripheral blood using sedimentation in dextran followed by centrifugation through a Ficoll-Hypaque solution. Any contaminating erythrocyte in the granulocyte sediment was removed by lysis with ice distilled water. The production of superoxide from neutrophils was induced by fMLP in the presence of a priming concentration of cytochalasin B. Adenosine deaminase was included in the assay to eliminate any endogenously produced adenosine that could suppress superoxide production. The effect of the compound on the response induced by fMLP was controlled colorimetrically from the reduction of cytochrome C within the assay buffer. The potency of the compounds was evaluated by the concentration that provided 50% inhibition (IC 50) compared to the response of the control versus
to the fMLP.
In this test, the compounds of the present The invention has IC50 values of less than 200 nM. The Compounds of examples 7, 10, 12, 16, 20, 21, 27 and 31 are the more effective and have IC 50 values less than 40 nM.
Thus, the present invention provides a Pharmaceutical composition that includes a compound with the formula (I) as defined above, or a salt or a solvate pharmaceutically acceptable thereof, together with an excipient, pharmaceutically acceptable diluent or carrier.
The present invention also provides a compound with the formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or composition of the same, for use as a medicine.
The present invention also provides a compound with the formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or composition of the same, for use as a medicine to treat a disease for which is indicated by an A2a receptor agonist.
The present invention also provides the use of a compound with the formula (I) as defined above, or of a salt, solvate or pharmaceutical composition acceptable for the manufacture of a medicine for treat a disease for which an agonist of the A2a receptor.
The present invention also provides a compound with the formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or composition of the same, for use as an anti-inflammatory agent.
The present invention also provides the use of a compound with the formula (I) as defined above, or of a salt, solvate or pharmaceutical composition acceptable thereof, for the manufacture of an agent anti-inflammatory
The present invention also provides the use of a compound with the formula (I) as defined above, or of a salt, solvate or pharmaceutical composition acceptable for the manufacture of a medicine for Treatment of a respiratory illness. The present invention also provides the aforementioned use in which the disease is selected from the group consisting of the syndrome of adult respiratory distress (ARDS), bronchitis, bronchitis chronic, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis.
The present invention also provides the use of a compound with the formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of septic shock, erectile dysfunction. in the male, hypertension, stroke, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischemic reperfusion injuries, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, gastritis with Heliobacter pylori , gastritis without Heliobacter pylori , damage induced by non-steroidal anti-inflammatory drugs in the gastrointestinal tract or for the treatment of a psychotic disorder, or for wound healing.
The present invention also provides a method for treating a mammal, including a being human, to treat a disease for which a A2a receptor agonist that includes the treatment of said mammal with an effective amount of a compound with the formula (I) as defined above, or with a salt, solvate or pharmaceutically acceptable composition thereof.
The present invention also provides a method for treating a mammal, including a being human, to treat an inflammatory disease that includes the treatment of said mammal with an effective amount of a compound with the formula (I) as defined above, or with a pharmaceutically acceptable salt, solvate or composition of the same.
The present invention also provides a method for treating a mammal, including a being human, to treat a respiratory disease that includes the treatment of said mammal with an effective amount of a compound with the formula (I) as defined above, or with a pharmaceutically acceptable salt, solvate or composition of the same. The present invention also provides the cited method. previously, in which the disease is selected from the group constituted by adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, lung disease chronic obstructive, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis.
The present invention also provides a method for treating a mammal, including a human being, to treat septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischemia, peripheral vascular disease, postischemic reperfusion injuries, diabetes. , rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, gastritis with Heliobacter pylori , gastritis without Heliobacter pylori , damage induced by non-steroidal anti-inflammatory drugs in the gastrointestinal tract or to treat a psychotic disorder, or for wound healing, including treating said mammal with an effective amount of a compound with the formula (I) as defined above, or with a pharmaceutically acceptable salt, solvate or composition thereof.
The compounds with the formula (I) can be administered alone, although they will usually be administered in a mixture with a suitable excipient, diluent or carrier pharmaceutically acceptable selected in relation to the route of desired administration and with standard pharmaceutical practice.
For example, the compounds with the formula (I) they can be administered orally, orally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavor enhancers or agents dyes, for immediate release, delayed applications, held, pressed or controlled.
Such tablets may contain excipients. such as microcrystalline cellulose, cellulose, lactose, citrate sodium, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn starch, potato or tapioca), sodium starch glycolate, croscarmellose sodium, certain complex silicates and granulation binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. So Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talcum powder.
In gelatin capsules you can also use solid compositions of similar type as fillers. In this sense, preferred excipients include lactose, starch, cellulose, lactose or a high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, compounds with the formula (I) can be combined with various sweeteners or enhancers of flavor, coloring substances or dyes, with emulsifying agents and / or of suspension and with diluents such as water, ethanol, propylene glycol or glycerin and with combinations thereof.
Compounds with the formula (I) are also can be administered parenterally, for example, by route intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, intramuscular or subcutaneously, or they can be administered by infusion techniques. The best way to use the compounds with the formula (I) is in the form of a sterile aqueous solution that may contain other substances, for example, salts or glucose in sufficient quantity such as to make the solution isotonic with blood. Preferably, the aqueous solutions should be buffered from suitable form (preferably at a pH between 3 and 9), if it is necessary. The preparation of formulations suitable for parenteral administration under sterile conditions easily performed by standard pharmaceutical techniques well known to those skilled in the art. For administration by oral or parenteral route to human patients, the daily dose level of the compounds with the formula (I) will normally be between 0.01 and 100 mg / kg body weight of the individual to be treated, preferably between 0.1 and 100 mg / kg (in individual doses or in doses divided).
Thus, the tablets or capsules of the compound with the formula (I) may contain between 5 and 500 mg of a active compound for individual administration or for administration of two or more tablets or capsules each time, according to agree. In any case, the doctor will determine the actual dose, which will be the most appropriate dose for any particular patient and that will vary with age, with weight and with the response of particular patient. The above doses are given by way of example of the average dose. Of course, there may be cases. individuals who deserve higher dose intervals or lower and such cases are within the scope of the present invention.
The compounds of formula (I) can also be administered intranasally or by inhalation and conveniently supplied in the form of an inhaler of dry powder or in a spray spray presentation from a container pressurized, pump, spray, atomizer or nebulizer with the use of a suitable propellant, for example, dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [brand commercial]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trademark]), carbon dioxide or other appropriate gas. In the case of a pressurized spray, the dosing unit can be determined by supplying a valve for Deliver a measured quantity. The pressurized container, pump, spray, atomizer or nebulizer may contain a solution or a suspension of the active compound, for example using a mixture of ethanol and the propellant as solvent, which may contain additionally a lubricant, for example, sorbitol trioleate. The capsules and cartridges (made, for example, of gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mixture of a compound with the formula (I) and a base in suitable powder such as lactose or starch.
Preferably, formulations in the form of spray or dry powder are prepared so that each measured dose or each "puff" (each "vaharada") contains between 20 and 4000 mug of a compound with the formula (I) for administration to patient. The total daily dose with a spray will be in the range between 20 µg and 20 mg, which can be administered in a single dose or, more commonly, in divided doses to throughout the day
Alternatively, compounds with the formula (I) can be administered in the form of a suppository or a pessary, or they can be applied topically in the form of a lotion, solution, cream, ointment, gel, suspension, fine powder, spray or form of drug incorporated into a bandage (for example, a bandage of tulle, a gauze bandage impregnated with white soft paraffin or with polyethylene glycol, or a bandage with hydrogel, hydrocolloid, alginate or a bandage with film). The compounds with the formula (I) can also be administered transdermally, for example, by using an epidermal patch.
For topical application to the skin, the compounds with the formula (I) can be formulated in the form of a suitable ointment containing the active compound in suspension or dissolved in, for example, a mixture with one or more of the following Compounds: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, wax emulsifier and water. Alternatively, compounds with the formula (I) can be formulated in the form of a lotion or cream suitable, suspended or dissolved in, for example, a mixture of one or more of the following compounds: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Too they can be formulated in the form of hydrogel with cellulose derivatives or of polyacrylate or with other viscosity modifiers.
It should be noted that all references to This invention to a treatment includes a curative treatment, palliative and prophylactic.
The following examples illustrate the preparation of the compounds with the formula (I). Resonance spectra 1 H nuclear magnetic (NMR) were consistent in all cases With the proposed structures. Chemical shifts (δ) are provided in parts per million taking as reference tetramethylsilane and using the abbreviations Conventional for the designation of the main peaks: example, s, singlet; d, double up; t, triplet; q, quadruplet; m multiplet; br, width. Mass spectra (m / z) were recorded. in the thermospray ionization mode. For solvents Common the following abbreviations have been used: CDCl_ {3}, deuterochloroform; DMSO, dimethylsulfoxide; THF, tetrahydrofuran. In the cases in which thin layer chromatography has been used (CCF), these cases refer to CCF on silica gel using 60 F 254 silica gel plates, R f is the distance traveled by a compound divided by the distance traveled by the solvent against a CCF plate.
Example 1 6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide
A solution of benzoate of (2 R , 3 R , 4 R , 5 S ) -4- (benzoyloxy) -2- [6 - [(2,2-diphenylethyl) amino] -2 - ({[2- (1-piperidinyl) -ethyl] amino} carbonyl) -9 H -purin-9-yl] -5 - [(ethylamino) carbonyl] tetrahydro-3-furanyl (prepared 7) (104 mg, 0.12 mmol) in methanol (3 ml) with potassium carbonate (100 mg, 0.72 mmol). The mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane: methanol (90: 10 by volume) to give the title compound as a white solid (44 mg).
1 H NMR (400 MHz, CDCl 3) δ: 8.76 (1H, s), 8.67 (1H, br m), 7.63 (1H, br m), 7.38-7.19 (10H, m), 6.92 (1H, m), 6.07 (1H, br m), 5.10 (2H, m), 4.55 (1H, m), 4.36 (4H, m), 3.52 (2H, m), 3.40 (2H, m), 2.60 (2H, br m), 2.40 (4H, br m), 1.37 (6H, m), 1.23 (3H, t).
LRMS (thermospray): m / z [MH +] 643, [MNa +] 665.
Example 2 6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (4-Isopropyl-1-piperidinyl) ethyl] -9 H -purine-2-carboxamide
They were heated at 120 ° C for three hours under nitrogen atmosphere 6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] - Methyl 3,4-dihydroxytetra-hydro-2-furanyl} -9 H -purine-2-carboxylate (prepared 11) (100 mg, 0.18 mmol) and 2- (4-isopropyl-1-piperidinyl) ethylamine ( prepared 17) (300 mg, 1.76 mmol). The reaction mixture was allowed to cool to room temperature and was purified by silica gel column chromatography eluting with dichloromethane: methanol: concentrated aqueous ammonia solution (90: 10: 10 by volume) to provide the title compound as of a white solid (76 mg, 62%).
1 H NMR (400 MHz, CDCl 3) δ: 8.80 (1H, br s), 8.60 (1H, br s), 7.55 (2H, br m), 7.35-7.20 (10H, m), 6.95 (1H, br m), 5.95 (1H, br m), 5.10 (2H, m), 4.50 (1H, br m), 4.40-4.20 (5H, m), 3.60-3.30 (5H, m), 2.85 (1H, br m), 2.60 (2H, br m), 1.95 (1H, br m), 1.60-1.50 (3H, br m), 1.30-0.90 (6H, m), 0.80 (6H, d).
LRMS (thermospray): m / z [MH +] 686.
Examples 3-34
Examples 3 to 33 were prepared by a similar method to that used for example 2 or for example 34 (for examples 10, 11, 20 and 28). Mass spectroscopy data were obtained by the electrospray method.
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - (2-pyridinylmethyl) -9 H -purine-2-carboxamide
1 H NMR (400 MHz, CDCl 3) δ:
9.35 (1H, br s), 8.75 (1H, s), 8.30 (1H, br s), 7.70 (1H, t), 7.40 (1H, br s), 7.35-7.15 (10H, m), 6.85 (1H, m), 6.60 (1H, m), 5.00 (1H, s), 4.75 (2H, m), 4.55-4.30 (5H, m), 3.40 (2H, m), 1.20 (3H, t).
[MH +] 623, [MNa +] 645.
N -benzyl-6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2 -furanyl} -9 H -purine-2-carboxamide
8.85 (1H, s), 8.50 (1H, br s), 7.40-7.10 (15H, m), 6.95 (1H, d), 6.80 (1H, br s), 5.10 (1H, s), 4.65 (2H, m), 4.50 (1H, m), 4.35 (2H, m), 4.25 (2H, m), 3.25 (2H, m), 1.05 (3H, t).
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - (2-phenylethyl) -9 H -purine-2-carboxamide
δ: 8.80 (1H, s), 8.20 (1H, m), 7.45 (1H, m), 7.40-7.10 (15H, m), 6.95 (1H, d), 6.30 (1H, br s), 5.10 (1H, s), 4.50 (1H, m), 4.35 (2H, m), 4.20 (1H, br s), 3.70 (2H, m), 3.40 (2H, m), 2.90 (2H, t), 1.20 (3H, t).
N - [2- (dimethylamino) ethyl] -6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] - 3,4-dihydroxytetrahydro-2-furanyl} -9 H -purine-2-carboxamide
δ: 8.80 (2H, s), 7.70-7.45 (2H, m), 7.35-7.20 (10H, m), 6.95 (1H, d), 6.00 (1H, br s), 5.20 (1H, m), 5.10 (1H, m), 4.50 (1H, s), 4.40-4.20 (4H, m), 3.55-3.35 (4H, m), 2.55 (2H, m), 2.10 (6H, s), 1.20 (3H, t).
[MH +] 604.
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (1-pyrrolidinyl) propyl] -9 H -purine-2-carboxamide
δ: 8.75 (1H, br s), 8.40 (1H, br s), 7.35-7.20 (10H, m), 6.90 (1H, br s), 6.00 (1H, br s), 5.10 (2H, m), 4.60 (1H, br s), 4.40-4.20 (4H, m), 3.55 (2H, m), 3.40 (2H, m), 2.60-2.40 (6H, m), 1.85 (2H, m), 1.70 (4H, br s), 1.20 (3H, t).
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (2-pyridinyl) ethyl] -9 H -purine-2-carboxamide
δ: 9.02 (1H, m), 8.80 (1H, s), 8.06 (1H, br s), 7.77 (1H, s), 7.61 (1H, m), 7.50 (1H, t), 7.23-7.39 (10H, m), 7.12 (1H, d), 7.00 (1H, d), 6.92 (1H, m), 5.95 (1H, br s), 5.18 (1H, d), 5.11 (1H, s), 4.55 (1H, d), 4.18-4.42 (4H, m), 3.88 (2H, m), 3.43 (2H, m), 3.11 (2H, t), 1.22 (3H, t).
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (4-morpholinyl) ethyl] -9 H -purine-2-carboxamide
δ: 8.80 (1H, s), 8.65 (1H, br s), 7.60 (1H, br s), 7.50 (1H, br s), 7.20-7.40 (10H, m), 6.95 (1H, d), 6.00 (1H, br d), 5.10 (2H, m), 4.55 (1H, d), 4.20-4.40 (4H, m), 3.30-3.60 (8H, m), 2.60 (2H, t), 2.40 (4H, m), 1.25 (3H, t).
9 {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -6 - [(1-ethylpropyl) amino] - N - [ 2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide
Four. Five
1 H NMR (400 MHz, CD 3 OD) δ:
δ: 8.45 (1H, s), 6.10 (1H, d), 4.85 (1H, t), 4.35-4.50 (3H, m), 3.60 (2H, t), 3.25-3.45 (3H, m), 2.40-2.70 (6H, m), 1.40-1.80 (10H, m), 1.05 (3H, t), 0.95 (6H, m).
Example eleven
6 - {[(1 S ) -1-benzyl-2-hydroxyethyl] amino} -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3.4- dihydroxytetrahydro-2-furanyl} - N - [2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide
δ: 8.45 (1H, s), 7.30 (2H, m), 7.15 (2H, m), 7.05 (1H, m), 6.10 (1H, d), 4.80 (1H, t), 4.45 (1H, s), 4.40 (1H, d), 3.70 (2H, m), 3.55 (2H, m), 3.20-3.45 (2H, m), 3.10 (1H, m), 2.95 (1H, m), 2.40-2.70 (7H, m), 1.65 (4H, m), 1.50 (2H, m), 1.05 (3H, t).
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (4-Isopropyl-1-piperidinyl) ethyl] -9 H -purine-2-carboxamide
δ: 8.80 (1H, br s), 8.55 (1H, br s), 7.65 (2H, br m), 7.55 (1H, br s), 7.20-7.35 (10H, m), 6.95 (1H, br d), 5.95 (1H, br s), 5.05-5.15 (2H, m), 4.55 (1H, br s), 4.20-4.45 (4H, m), 3.30-3.60 (4H, m), 2.85 (2H, br s), 2.55 (2H, br s), 1.95 (2H, br t), 0.90-1.55 (9H, m), 0.80 (6H, d).
N - [2- (3,4-dihydro-2 (1 H ) -isoquinolinyl) ethyl] -6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -9 H -purine-2-carboxamide
δ: 8.75 (1H, br s), 8.60 (1H, br s), 7.50 (2H, br m), 6.85-7.30 (15H, m), 5.85 (1H, br s), 5.05 (2H, br m), 4.50 (1H, br s), 4.05-4.40 (4H, m), 3.50-3.75 (4H, m), 3.40 (2H, m), 2.60-2.90 (6H, m), 1.20 (3H, t).
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [4-piperidinylmethyl] -9 H -purine-2-carboxamide
1 H NMR (400 MHz, CDCl 3 + DMSO-d6) δ:
δ: 8.45 (1H, s), 8.10 (1H, br s), 7.00-7.40 (11H, m), 6.55 (1H, br s), 6.25 (1H, br s), 4.15-4.90 (6H, m), 3.15-3.50 (4H, m), 3.00-3.15 (2H, m), 1.55-1.75 (3H, m), 0.90-1.40 (5H, m).
Example fifteen
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [4- (1-piperidinyl) butyl] -9 H -purine-2-carboxamide
δ: 8.73 (1H, m), 8.56-8.42 (1H, m), 7.52-7.40 (1H, m), 7.40-7.26 (10H, m), 6.90 (1H, m), 6.06-5.94 (1H, m), 5.05 (1H, m), 4.69-4.53 (1H, m), 4.45-4.16 (4H, m), 3.61-3.29 (4H, m), 2.77-2.60 (3H, m), 1.85-1.73 (2H, m), 1.24-1.14 (3H, m), 1.00-0.93 (6H, m).
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (isopropylamino) propyl] -9 H -purine-2-carboxamide
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (2-piperidinylamino) propyl] -9 H -purine-2-carboxamide
δ: 8.45 (2H, m), 7.80-7.60 (1H, m), 7.40 (1H, m), 7.30-7.00 (10H, m), 6.80-6.64 (1H, m), 6.48 (1H, m), 6.35 (1H, m), 5.03-4.90 (1H, m), 4.77-4.60 (1H, m), 4.52-4.13 (4H, m), 3.68-3.20 (8H, m), 1.97-1.85 (2H, m), 1.20-1.05 (3H, m).
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - {3- [methyl (phenylsulfonyl) amino] propyl} -9 H -purine-2-carboxamide
δ: 8.95 (1H, m), 8.76 (1H, m), 7.75 (2H, m), 7.63-7.40 (5H, m), 7.40-7.06 (10H, m), 6.97 (1H, m), 6.00-5.87 (1H, m), 5.16 (1H, m), 5.10 (1H, m), 4.60-4.24 (5H, m), 3.70-3.55 (2H, m), 3.48-3.34 (2H, m), 3.22-3.00 (2H, m), 2.82-2.60 (3H, m), 1.93-1.73 (2H, m), 1.23 (3H, t).
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - {3- [methyl (methylsulfonyl) amino] propyl} -9 H -purine-2-carboxamide
δ: 8.93-8.80 (1H, m), 8.77-8.68 (1H, m), 7.53-7.45 (1H, m), 7.30-7.20 (10H, m), 6.90 (1H, m), 5.97-5.87 (1H, m), 5.19-5.10 (1H, m), 5.06 (1H, m), 4.56-4.27 (5H, m), 3.64-3.48 (2H, m), 3.47-3.30 (2H, m), 3.30-3.16 (2H, m), 2.90-2.77 (3H, m), 2.60-2.43 (3H, m), 1.90-1.74 (2H, m), 1.22 (3H, t).
Example twenty
9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -6 - [(9 H -fluoren-9-ylmethyl) amino] - N - [2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide
1 H NMR (400 MHz, CD 3 OD)
δ: 8.45 (1H, s), 7.80 (2H, m), 7.68 (2H, m), 7.34 (2H, m), 7.24 (2H, m), 6.13 (1H, m), 4.84 (1H, m), 4.43 (1H, m), 4.40 (2H, m), 4.27-4.18 (2H, m), 3.53 (2H, m), 3.40-3.23 (2H, m), 2.55 (2H, m), 2.50-2.35 (4H, m), 1.55-1.42 (4H, m), 1.42-1.32 (2H, m), 1.06 (3H, t).
Example twenty-one
N - [3- (diethylamino) propyl] -6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] - 3,4-dihydroxytetrahydro-2-furanyl} -9 H -purine-2-carboxamide
δ: 8.95-8.60 (2H, m), 7.90-7.65 (1H, m), 7.65-7.50 (1H, m), 7.45-7.30 (10H, m), 7.05-6.90 (1H, m), 6.10-5.85 (1H, m), 5.25-5.05 (2H, m), 4.60-4.50 (1H, m), 4.50-4.20 (4H, m), 3.65-3.30 (4H, m), 2.60-2.50 (2H, m), 2.50-2.30 (4H, m), 1.80-1.70 (2H, m), 1.30-1.15 (3H, m), 1.00-0.85 (1H, m).
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (4-morpholinyl) propyl] -9 H -purine-2-carboxamide
1 H NMR (400 MHz, CDCl 3 + DMSO-d6)
δ: 8.65-8.50 (1H, m), 8.30-8.10 (1H, m), 7.60-7.45 (1H, m), 7.35-7.15 (10H, m), 7.15-7.00 (1H, m), 6.75-6.65 (1H, m), 6.30-6.15 (1H, m), 5.00-4.85 (2H, m), 4.50-4.45 (1H, m), 4.45-4.35 (2H, m), 4.35-4.15 (2H, m), 3.65-3.55 (4H, m), 3.55-3.30 (4H, m), 2.45-2.25 (6H, m), 1.85-1.70 (2H, m), 1.15 (3H, t).
Example 2. 3
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (methylamino) propyl] -9 H -purine-2-carboxamide
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (5-methyl-1 H -imidazol-4-yl) ethyl] -9 H -purine-2-carboxamide
δ: 8.20 (1H, s), 7.40-7.10 (11H, m), 6.10 (1H, d), 4.90-4.70 (1H, m), 4.55-4.25 (5H, m), 3.70-3.55 (2H, m), 3.45-3.20 (2H, m), 2.90-2.80 (2H, m), 2.25-2.05 (3H, m), 1.10 (1H, t).
N - [4- (dimethylamino) butyl] -6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] - 3,4-dihydroxytetrahydro-2-furanyl} -9 H -purine-2-carboxamide
δ: 8.60-4.50 (1H, m), 8.20-8.10 (1H, m), 7.35-7.25 (10H, m), 6.80-6.60 (1H, m), 6.10-5.90 (1H, m), 4.45-4.20 (4H, m), 3.70-3.50 (1H, m), 3.45-3.20 (3H, m), 2.60-2.35 (1H, m), 2.30-2.10 (9H, m), 1.80-1.50 (6H, m), 1.15-1.00 (3H, m).
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (4-methyl-1-piperazinyl) propyl] -9 H -purine-2-carboxamide
δ: 8.90-8.70 (1H, m), 8.35-8.20 (1H, m), 7.70-7.40 (2H, m), 7.40-7.25 (10H, m), 7.00-6.85 (1H, m), 6.10-5.90 (1H, m), 5.20-5.00 (2H, m), 4.65-4.50 (1H, m), 4.45-4.20 (4H, m), 3.60-3.30 (4H, m), 2.55-2.30 (8H, m), 2.30-2.15 (3H, m), 1.90-1.85 (2H, m), 1.30-1.10 (3H, m).
N - [3- (dimethylamino) propyl] -6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] - 3,4-dihydroxytetrahydro-2-furanyl} -9 H -purine-2-carboxamide
δ: 8.90-8.70 (1H, m), 7.60-7.45 (1H, m), 7.45-7.25 (10H, m), 7.00-6.90 (1H, m), 6.00-5.90 (1H, m), 5.20-5.00 (2H, m), 4.65-4.50 (1H, m), 4.45-4.20 (4H, m), 3.60-3.45 (2H, m), 3.45-3.30 (2H, m), 2.45-2.30 (2H, m), 2.15-2.00 (6H, m), 1.85-1.70 (2H, m), 1.25-1.10 (3H, m).
6 - [(1-Benzyl-2-phenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl } - N - [2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide
δ: 8.40 (1H, s), 7.30-7.25 (4H, m), 7.20-7.10 (4H, m), 7.10-7.05 (2H, m), 6.05-6.00 (1H, m), 5.10-5.00 (1H, m), 4.40 (1H, s), 4.40-4.30 (1H, m), 3.60-3.50 (2H, m), 3.40-3.20 (2H, m), 3.10-3.00 (2H, m), 3.00-2.90 (2H, m), 2.65-2.60 (2H, m), 2.60-2.50 (4H, m), 1.70-1.60 (4H, m), 1.55-1.45 (2H, m), 1.05 (3H, t).
9 - {(2 R , 3 R , 4 S , 5 S ) -3,4-dihydroxy-5 - [(propylamino) carbonyl] tetrahydro-2-furanyl} -6 - [(2,2-diphenylethyl) amino] - N - [2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide
δ: 8.75 (1H, s), 8.65 (1H, s), 7.50 (1H, s), 7.35-7.15 (10H, m), 6.90 (1H, m), 6.10 (1H, m), 5.05 (1H, s), 4.55 (1H, s), 4.45-4.20 (4H, m), 3.60-3.40 (2H, m), 3.40-3.20 (2H, m), 2.70-2.50 (2H, m), 2.50-2.30 (4H, m), 1.65-1.50 (2H, m), 1.50-1.20 (6H, m), 0.95 (3H, m).
6 - [(- 2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (1-Isopropyl-4-piperidinyl) ethyl] -9 H -purine-2-carboxamide
δ: 8.80-8.70 (1H, m), 8.15-8.05 (1H, m), 7.75-7.55 (1H, m), 7.50-7.40 (1H, m), 7.40-7.20 (10H, m), 7.00-6.90 (1H, m), 5.15-5.00 (2H, m), 4.60-4.50 (1H, m), 4.45-4.15 (4H, m), 3.55-3.30 (4H, m), 2.90-2.80 (2H, m), 2.80-2.60 (1H, m), 2.10-1.95 (2H, m), 1.75-1.50 (4H, m), 1.40-1.15 (6H, m), 1.05-0.95 (6H, m).
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (4-methyl-1-piperidinyl) ethyl] -9 H -purine-2-carboxamide
δ: 8.75 (1H, s), 8.60-8.50 (1H, m), 7.60-7.50 (1H, m), 7.40-7.20 (10H, m), 7.00-6.90 (1H, m), 6.00-5.90 (1H, m), 5.20-5.00 (2H, m), 4.50-4.45 (1H, m), 4.45-4.20 (4H, m), 3.60-3.35 (4H, m), 2.80-2.70 (2H, m), 2.60-2.50 (2H, m), 2.00-1.90 (2H, m), 1.55-1.40 (2H, m), 1.40-1.10 (5H, m), 1.10-0.95 (2H, m), 0.95-0.80 (3H, m).
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (4-methoxy-1-piperidinyl) ethyl] -9 H -purine-2-carboxamide
δ: 8.80 (1H, s), 8.65-8.55 (1H, m), 7.70-7.50 (2H, m), 7.40-7.20 (10H, m), 7.00-6.95 (1H, m), 6.00-5.90 (1H, m), 5.10 (2H, s), 4.55-4.50 (1H, m), 4.40-4.20 (4H, m), 3.55-3.35 (4H, m), 3.20-3.10 (1H, m), 2.70-2.50 (4H, m), 2.25-2.15 (2H, m), 1.75-1.40 (5H, m), 1.25-1.20 (3H, t).
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [(1-methyl-1 H -imidazol-4-yl) methyl] -9 H -purine-2-carboxamide
δ: 8.75 (1H, s), 8.65-8.55 (1H, s), 7.55 (1H, s), 7.35-7.20 (10H, m), 6.95-6.90 (1H, m), 6.80 (1H, s), 5.05 (1H, s), 4.60-4.20 (6H, m), 3.60 (3H, s), 3.40-3.25 (2H, m), 1.20-1.10 (3H, t).
6- (Cyclohexylamino) -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (1 -piperidinyl) ethyl] -9 H -purine-2-carboxamide
A solution of (2 S , 3 S , 4 R , 5 R ) -5- [6- (cyclohexylamino) -2-iodo-9 H -purin-9-yl] - N -ethyl-3,4-dihydroxytetrahydro- 2-furancarboxamide (prepared 31) (125 mg, 0.24 mmol), 2- (1-piperidinyl) ethylamine (0.14 ml, 0.96 mmol) and tetrakis (triphenylphosphino) palladium (0) (20 mg, 0.024 mmol) in THF (5 ml) was carbonized at 60 ° C and under a pressure of 345 kPa of carbon monoxide for 18 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with dichloromethane: methanol: concentrated aqueous ammonia solution (95: 5: 1 by volume). After evaporation of the appropriate fractions, the residue was triturated with diethyl ether, filtered and dried to give the objective compound as a beige powder, (77 mg, 58%).
1 H NMR (400 MHz, CDCl 3) δ: 8.45 (1H, s), 6.15-6.10 (1H, m), 4.90-4.85 (1H, m), 4.50-4.30 (3H, m), 3.65-3.50 (2H, m), 3.45-3.25 (2H, m), 2.65-2.45 (6H, m), 2.10-2.00 (2H, m), 1.90-1.80 (2H, m), 1.75-1.30 (13H, m), 1.10-1.05 (3H, m).
The following preparations describe the preparation of certain intermediates used in the examples previous.
Prepared one
2,6-Dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine
2,6-Dichloro-9 H -purine (20 g, 0.11 mol) and 4-toluenesulfonic acid monohydrate (0.2 g) were dissolved in ethyl acetate (300 ml), the mixture was heated to 50 ° C and slowly added for 30 minutes a solution of 2,3-dihydropyran (12.6 ml, 0.14 mol) in ethyl acetate (50 ml). Then, the reaction mixture was cooled to room temperature, water (100 ml) was added and the pH of the solution was adjusted to 7 by the addition of a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was made to form an azeotrope with pentane (x 2) to provide the title compound as a slightly impure white solid (30.9 g).
1 H NMR (400 MHz, CDCl 3) δ: 8.30 (1H, s), 5.75 (1H, dd), 4.25-4.15 (1H, m), 3.85-3.70 (1H, m), 2.20-1.60 (6H, m).
Prepared 2
2-Chloro- N - (2,2-diphenylethyl) -9-tetrahydro-2 H -pyran-2-yl-9 H -purine-6-amine
A solution of 2,6-dichloro-9-tetrahydro-2 H -pyran-2-yl-9 H -purine (prepared 1) (30.9 g, 0.11 mol) in isopropanol (600 ml) was treated with N -ethyl- N -isopropyl-2-propanoamine (47.5 ml, 0.27 mol) and with 2,2-diphenylethylamine (24.8 g, 0.13 mol) and the resulting mixture was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was made to form an azeotrope with ethyl acetate. The residue was then purified by silica gel column chromatography eluting with a gradient system of ethyl acetate: hexane (60: 40 by volume) to provide the title compound as a foam (49.7 g) .
1 H NMR (400 MHz, CDCl 3) δ: 7.95-7.75 (1H, br s), 7.35-7.15 (10H, m), 5.80-5.70 (1H, br s), 5.65 (1H, d), 4.35 (1H, m), 4.30-4.18 (1H, br s), 4.10 (1H, d), 3.70 (1H, t), 2.05-1.95 (2H, m), 1.95-1.80 (1H, m), 1.80-1.55 (3H, m).
6 - [(2,2-Diphenylethyl) amino] -9-tetrahydro-2 H -pyran-2-yl-9 H -purine-2-carbonitrile
A solution of 2-chloro- N - (2,2-diphenylethyl) -9-tetrahydro-2 H -pyran-2-yl-9 H -purin-6-amine (prepared 2) (1.0 g, 2, 31 mmol), zinc cyanide (0.162 g, 1.38 mmol), triethylamine (0.28 g, 2.77 mmol) and tetrakis (triphenylphosphino) palladium (0) (0.133 g, 0.12 mmol) in N, N- dimethylformamide (3 ml) was heated at 100 ° C under a nitrogen atmosphere for 6 hours. The reaction mixture was allowed to cool and was partitioned between ethyl acetate (100 ml) and a 2M sodium hydroxide solution (100 ml). The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting 1: 1 mixture of 6 - [(2,2-diphenylethyl) amino] -9-tetrahydro-2 H -pyran-2-yl-9 H -purine-2-carbonitrile and 6 - [(2,2- diphenylethyl) amino] -9 H -purine-2-carbonitrile (prepared 8) was separated by silica gel column chromatography eluting with a gradient system of ethyl acetate: hexane (40: 60 by volume) that gradually changed to ethyl acetate: hexane (60: 40 by volume) to provide the title compound as a white solid (0.4 g).
1 H NMR (400 MHz, CDCl 3) δ: 8.00 (1H, s), 7.40-7.20 (10H, m), 6.00-5.75 (1H, br s), 5.70 (1H, d), 4.40-4.20 (3H, m), 4.20-4.10 (1H, m), 3.80-3.70 (1H, m), 2.20-1.90 (3H, m), 1.90-1.60 (3H, m).
6 - [(2,2-Diphenylethyl) amino] -9-tetrahydro-2 H -pyran-2-yl-9 H -purine-2-carboxylate methyl
A suspension of 6 - [(2,2-diphenylethyl) amino] -9-tetrahydro-2 H -pyran-2-yl-9 H -purine-2-carbonitrile (prepared 3) (1.00 g, 2) was treated , 36 mmol) in methanol (20 ml) with sodium methoxide (0.14 g, 2.59 mmol) and the resulting mixture was refluxed under a nitrogen atmosphere for 20 hours. Analysis by TLC showed that some of the starting material remained, consequently additional sodium methoxide (64 mg, 1.18 mmol) was added and the mixture was heated under reflux under a nitrogen atmosphere for an additional hour. The mixture was then cooled to room temperature and the solvent was removed under reduced pressure. Tetrahydrofuran (30 ml) and water (10 ml) were added to the residue and the pH was adjusted to 4 by the addition of acetic acid (1 ml). This mixture was heated at reflux for 1 hour. Analysis by TLC showed that some of the starting material remained and consequently additional acetic acid (0.5 ml) was added and the heating was refluxed for 18 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane: methanol (98.5: 1.5 by volume) to provide the title compound (521 mg).
1 H NMR (400 MHz, CDCl 3) δ: 8.05 (1H, br s), 7.37-7.18 (10H, m), 5.84 (2H, m), 4.40 (3H, m), 4.14 (1H, d), 4.00 (3H, s), 3.78 (1H, t), 2.17-1.60 (6H, m).
6 - [(2,2-Diphenylethyl) amino] - N - [2- (1-piperidinyl) ethyl] -9-tetrahydro-2 H -pyran-2-yl-9 H -purine-2-carboxamide
They were heated together at 130 ° C for 2 hours 6 - [(2,2-diphenylethyl) amino] -9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carboxylate methyl (prepared 4) (100 mg, 0.22 mmol) and 1- (2-aminoethyl) piperidine (0.31 ml, 2.19 mmol). The excess amine was removed under reduced pressure and the residue It was purified by silica gel column chromatography eluting with dichloromethane: methanol (95: 5 by volume) to provide the title compound in the form of a colored foam yellow (104 mg).
1 H NMR (400 MHz, CDCl 3) δ: 8.43 (1H, br m), 8.00 (1H, br s), 7.17-7.36 (10H, m), 5.94 (1H, d), 5.80 (1H, br m), 4.37 (3H, m), 4.33 (1H, d), 3.78 (1H, t), 3.57 (2H, m), 2.55 (2H, m), 2.40 (4H, br m), 1.65-2.17 (6H, m), 1.26-1.33 (6H, br m).
6 - [(2,2-Diphenylethyl) amino] - N - [2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide
A solution of 6 - [(2,2-diphenylethyl) amino] - N - [2- (l-piperidinyl) ethyl] -9-tetrahydro-2 H -pyran-2-yl-9 H -purine-2-carboxamide (prepared 5) (420 mg, 0.76 mmol) in ethanol (20 ml) was treated with hydrochloric acid (2 M, 0.9 ml). The mixture was heated at reflux for 30 minutes after which time a white precipitate had formed. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and an aqueous solution of 10% by weight ammonia. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the title compound as a white solid (319 mg).
1 H NMR (400 MHz, CDCl 3) δ: 8.57 (1H, br m), 8.30 (1H, s), 7.40-7.20 (10H, m), 5.93 (1H, br s), 4.39 (3H, m), 3.62 (2H, m), 2.56 (2H, t), 2.40 (4H, br m), 1.47-1.24 (6H, br m).
Benzoate (2 R , 3 R , 4 R , 5 S ) -4- (benzoyloxy) -2- [6 - [(2,2-diphenylethyl] amino] -2 - ({[2- (1-piperidinyl) -ethyl] amino} carbonyl) -9 H -purin-9-yl] -5 - [(ethylamino) carbonyl] tetrahydro-3-furanyl
A suspension of 6 - [(2,2-diphenylethyl) amino] -N- [2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide (prepared 6) (100 mg, 0.21 mmol) in 1,1,1-trichloroethane (2 ml) it was treated with N, O-bis (trimethylsilyl) acetamide (0.21 ml, 0.85 mmol). The mixture was heated at reflux for 90 minutes. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was treated with a benzoate solution of (2 S , 3 R , 4 R , 5 R ) - and (2 S , 3 R , 4 R , 5 S ) -5- (acetyloxy) -4- (benzoyloxy) -2 - [(ethylamino) carbonyl] tetrahydro-3-furanyl (prepared 15) (111 mg, 0.25 mmol) in anhydrous toluene (2 ml) and with trimethylsilyl trifluoromethanesulfonate (0.05 ml, 0.30 mmol). Then, the resulting solution was heated at 90 ° C under a nitrogen atmosphere for 1 hour. Analysis by TLC showed that some of the starting material remained and consequently additional trimethylsilyl trifluoromethanesulfonate (0.05 ml, 0.30 mmol) was added and heating was maintained for 2 hours. Again, analysis by TLC showed that some of the starting material remained and consequently additional trimethylsilyl trifluoromethanesulfonate (0.025 ml, 0.15 mmol) was added and heating was maintained for an additional hour. The mixture was cooled to room temperature, diluted with ethyl acetate (20 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloro-
methane: methanol (90: 10 by volume) to provide the title compound as a foam (109 mg).
1 H NMR (400 MHz, CDCl 3) δ: 8.35 (1H, br m), 8.06 (3H, d), 7.93 (2H, d), 7.69-7.18 (15H, m), 6.44 (1H, d), 6.23 (2H, br m), 5.91 (1H, br m), 4.92 (1H, d), 4.37 (3H, m), 3.53 (4H, m), 2.60 (2H, br m), 2.44 (4H, br m), 1.40 (6H, m), 1.13 (3H, t).
6 - [(2,2-Diphenylethyl) amino] -9 H -purine-2-carbonitrile
A solution of 6 - [(2,2-diphenylethyl) amino] -9-tetrahydro-2 H -pyran-2-yl-9 H -purine-2-carbonitrile (prepared 3) (17 g, 40.1 mmol) in ethanol (850 ml), it was treated with a 2M aqueous hydrochloric acid solution (50 ml) and the mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethanol and the solvent was removed again under reduced pressure. The residue was triturated with diethyl ether, filtered,
washed with diethyl ether and pentane and dried to give the title compound as a solid (13.6 g).
1 H NMR (400 MHz, DMSO- d 6) δ: 8.30 (1H, s), 8.20-8.05 (1H, br s), 7.40-7, 10 (10H, m), 4.60-4.40 (1.4H, m), 4.20-4.00 (1.6H, m).
Methyl 6 - [(2,2-Diphenylethyl) amino] -9 H -purine-2-carboxylate
A solution of 6 - [(2,2-diphenylethyl) amino] -9 H -purine-2-carbonitrile (prepared 8) (5.0 g, 14.7 mmol) and sodium methoxide (4.0 g, 74 , 1 mmol) in methanol (300 ml) was heated at reflux for 24 hours. Sodium methoxide (2.0 g, 37 mmol) and additional methanol (100 ml) were then added and heating was maintained for an additional 24 hours. The mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in THF (375 ml), 2M hydrochloric acid (125 ml) was added and the mixture was stirred at room temperature for 24 hours. THF was removed under reduced pressure and the pH of the suspension was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution. Ethyl acetate (100 ml) was then added and the white solid consisting mainly of the desired product was filtered, washed with a little water and ethyl acetate and dried. Purification by silica gel column chromatography with a gradient system of dichloromethane: methanol (90: 10 by volume) that gradually changed to dichloromethane: methanol (75: 25 by volume) provided the title compound as a white solid (1.25 g). Evaporation of the ethyl acetate filtrate returned 2.6 g of the starting material.
1 H NMR (400 MHz, CDCl 3) δ: 12.40 (1H, br s), 8.05 (1H, s), 7.55 (1H, s), 7.30-7.20 (10H, m), 4.80 (2H, m), 4.75 (1H, m), 3.80 (3H, s).
Prepared 10
9 - {(2 R , 3 R , 4 R , 5 S ) -3,4-bis (benzoyloxy) -5 - [(ethylamino) carbonyl] tetrahydro-2-furanyl} -6 - [(2,2-diphenylethyl ) amino] -9 H -purine-2-methyl carboxylate
A suspension of methyl 6 - [(2,2-diphenylethyl) amino] -9 H -purine-2-carboxylate (prepared 9) (440 mg, 1.18 mmol) in 1,1,1-trichloroethane (25 ml ) was treated with N, O-bis (trimethylsilyl) acetamide (1.7 ml, 6.95 mmol). The mixture was heated at reflux for one hour. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was treated with a benzoate solution of (2 S , 3 R , 4 R , 5 R ) - and (2 S , 3 R , 4 R , 5 S ) -5- (acetyloxy) -4- (benzoyloxy) -2 - [(ethylamino) carbonyl] tetrahydro-3-furanyl (prepared 15) (620 mg, 1.4 mmol) in anhydrous toluene (25 ml) and with trimethylsilyl trifluoromethanesulfonate (0.26 ml, 1.42 mmol). Then, the resulting solution was heated at 110 ° C under a nitrogen atmosphere for 2.5 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (200 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane: ethyl acetate (5: 1 by volume) and then with dichloromethane: ethyl acetate (1: 1 by volume) to provide the title compound as a foam (540 mg).
1 H NMR (400 MHz, CDCl 3) δ: 8.10 (3H, m), 7.80 (2H, d), 7.60 (1H, m), 7.50-7.40 (4H, m), 7.35-7.20 (16H, m), 6.40 (1H, m), 6.20 (2H, m), 5.90 (1H, m), 4.90 (1H, d), 4.40 (3H, m), 4.00 (3H, s), 3.55 (1H, m), 3.35 (1H, m), 1.15 (3H, t).
LRMS (thermospray): m / z [MNa +] 777.
Prepared eleven
6 - [(2,2-Diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - 9 H -purine-2-methyl carboxylate
A solution of 9 - {(2 R , 3 R , 4 R , 5 S ) -3,4-bis (benzoyloxy) -5 - [(ethylamino) carbonyl] -tetrahydro-2-furanyl} -6 - [(2 , Methyl 2-diphenylethyl) -9 H -purine-2-carboxylate (prepared 10) (3.4 g, 4.5 mmol) and sodium carbonate (50 mg) in dry methanol (60 ml) was stirred at room temperature for four hours. The solvent was removed under reduced pressure and the residue was taken up in a mixture of dichloromethane: methanol (95: 5 by volume, 60 ml). The inorganic salts were filtered and the filtrate was evaporated under reduced pressure. The residue was triturated with ether, filtered and dried to give the objective compound as a white solid (2.4 g).
1 H NMR (400 MHz, d_ {6} -DMSO) δ: 8.60 (1H, m), 8.15 (2H, br s), 7.40-7.15 (10H, m), 6.00 (1H, br m), 5.60 (1H, br s), 5.50 (1H, br s), 4.60-4.40 (3H, m), 4.30 (1H, s), 4.10-4.05 (2H, m), 4.00-3.80 (3H, m), 3.20 (2H, m), 1.00 (3H, t).
(3a S , 4 S , 6 R , 6a R ) - N -Ethyl-6-methoxy-2,2-dimethyltetrahydrofuro [3,4- d ] [1,3] dioxol-4-carboxamide
Oxalyl chloride (14.0 ml, 160 mmol) was added dropwise to a stirred solution of acid (3 R , 4 S , 6 R , 6 R ) -6-methoxy-2,2-dimethyltetrahydrofide [3,4 - d ] [1,3] dioxol-4-carboxylic acid ( J. Am. Chem. Soc ., 1958, 80 , 5168) (23.30 g, 107 mmol) in anhydrous dichloromethane (120 ml) and N, N- dimethylformamide (2 drops) and the mixture was stirred at room temperature for 3 hours until gas evolution ceased. Analysis by TLC showed that some of the starting material remained and in this way additional N, N-dimethylformamide (2 drops) was added and stirring was maintained for 1 hour. The solvent was removed under reduced pressure and the residue was made to form an azeotrope with anhydrous dichloromethane (x 2). The residue was then dissolved in anhydrous dichloromethane (200 ml) and the solution was treated dropwise with ethylamine (2 M in tetrahydrofuran, 140 ml, 280 mmol). This solution was maintained at room temperature for 48 hours. Diethyl ether (250 ml) was added and the mixture was stirred for 15 minutes. The mixture was filtered and the solvent was removed from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient system of dichloromethane: ethyl acetate (100: 0 by volume) that gradually changed to dichloromethane: ethyl acetate (44: 66 by volume) to provide the title compound as a yellow solid (24.70 g).
1 H NMR (400 MHz, CDCl 3) δ: 6.53 (1H, br m), 5.12 (1H, dd), 5.07 (1H, d), 4.60 (1H, d), 4.54 (1H, dd), 3.46 (3H, s), 3.32 (2H, m), 1.51 (3H, s), 1.34 (3H, s), 1.15 (3H, t).
(2 S , 3 S , 4 R , 5 R ) - and (2 S , 3 S , 4 R , 5 S ) - N -Ethyl-3,4-dihydroxy-5-methoxytetrahydro-2-furancarboxamide
A solution of (3a S , 4 S , 6 R , 6a R ) - N -ethyl-6-methoxy-2,2-dimethyltetrahydrofuro [3,4- d ] [1,3] dioxol-4-carboxamide (prepared 12 ) (24.60 g, 100 mmol) and pyridinium p-toluenesulfonate (2.50 g, 10 mmol) in methanol (500 ml) was heated at reflux for 18 hours. NMR analysis showed that some of the starting material remained. The solvent was removed under reduced pressure. The residue was dissolved in methanol (500 ml) and heated at reflux for 8 hours. NMR analysis showed that some of the starting material remained and therefore the solvent was removed under reduced pressure once more. The residue was dissolved in methanol (500 ml) and the resulting solution was heated at reflux for 24 hours. Then, the solvent was removed under reduced pressure and the residue was made to form an azeotrope with dichloromethane (x 3) to provide the title compound as an oil (20.50 g).
1 H NMR (400 MHz, CDCl 3) δ: 6.58 (1H, br m), 4.99 (0.25H, d), 4.94 (0.75H, d), 4.46 (0.25H, d), 4.37 (1.5H, m), 4.24 (0.25H, dd), 4.05 (1H, m), 3.52 (0.75H, s), 3.47 (2.25H, s), 3.30 (2H, m), 1.16 (3H, m).
Benzoate (2 S , 3 R , 4 R , 5 S ) - and (2 R , 3 R , 4 R , 5 S ) -4- (benzoyloxy) -5 - [(ethylamino) carbonyl] -2-methoxytetrahydro- 3-furanyl
A solution of benzoyl chloride (30.0 ml, 259 mmol) in dichloromethane (100 ml) was slowly added to a solution of (2 S , 3 S , 4 R , 5 R ) - and (2 S , 3 S , 4 R , 5 S ) - N -ethyl-3,4-dihydroxy-5-methoxytetrahydro-2-furancarboxamide (prepared 13) (20.50 g, 100 mmol) and pyridine (33.0 ml, 409 mmol) in dichloromethane (400 ml) and the resulting mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between diethyl ether and hydrochloric acid (1 M, 300 ml). The layers were separated and the aqueous layer was extracted again with diethyl ether. The organic layers were combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient system of dichloromethane: diethyl ether (95: 5 by volume) that gradually changed to dichloromethane: diethyl ether (80: 20 by volume) to provide the title compound in the form of an oil and as a mixture of the α and β anomers (37.0 g).
1 H NMR (400 MHz, CDCl 3) δ: 8.16 (0.5H, d), 7.95 (1.5H, d), 7.88 (1.5H, d), 7.81 (0.5H, d), 7.66-7.25 (6H, m), 6.65 (1H, br m), 5.88 (1H, m), 5.60 (0.75H, dd), 5.46 (0.25H, d), 5.23 (0.75H, d), 5.17 (0.25H, t), 4.80 (1H, m), 3.59 (2.25H, s), 3.49 (0.75H, s), 3.39 (2H, m), 1.23 (3H, t).
Prepared fifteen
Benzoate (2 S , 3 R , 4 R , 5 R ) - and (2 S , 3 R , 4 R , 5 S ) -5- (acetyloxy) -4- (benzoyloxy) -2 - [(ethylamino) carbonyl ] tetrahydro-3-furanyl
A benzoate solution of (2 S , 3 R , 4 R , 5 S ) - and (2 R , 3 R , 4 R , 5 S ) -4- (benzoyloxy) -5 - [(ethylamino) carbonyl] - 2-Methoxytetrahydro-3-furanyl (prepared 14) (37.0 g, 89.6 mmol) in a mixture of acetic acid (330 ml, 5.77 moles) and acetic anhydride (67 ml, 709 mmol) cooled to -10 ° C and treated dropwise with hydrochloric acid (12 N, 7.0 ml, 132 mmol). The mixture was stirred for 18 hours, during which time it was allowed to warm to room temperature. After cooling the mixture to 0 ° C, it was diluted with water (1,000 ml) and then extracted with ethyl acetate (3 x 500 ml). The organic layers were combined, washed sequentially with water, with a saturated aqueous solution of sodium hydrogen carbonate and with brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient system of diethyl ether: pentane (66: 44 by volume) that gradually changed to diethyl ether: pentane (100: 0 by volume). The residue was further purified by silica gel column chromatography eluting with a gradient system of dichloromethane: diethyl ether (95: 5 by volume) that gradually changed to dichloromethane: diethyl ether (90: 10 by volume) to provide the title compound as a mixture of the α- and β- anomers (15.40 g).
1 H NMR (400 MHz, CDCl 3) δ: 8.12 (0.8H, d), 7.97 (1.2H, d), 7.92 (1.2H, d), 7.79 (0.8H, d), 7.65-7.24 (6H, m), 6.73 (0.4H, d), 6.62 (0.4H, br m), 6.46 (0.6H, br m), 6.42 (0.6H, d), 6.07 (0.4H, dd), 5.95 (0.6H, t), 5.72 (0.6H, d), 5.44 (0.4H, t), 4.94 (0.4H, d), 4.86 (0.6H, d), 3.36 (2H, m), 2.17 (1.8H, s), 2.10 (1.2H, s), 1.20 (3H, m).
Benzoates of (2 S , 3 R , 4 R , 5 R ) - and (2 S , 3 R , 4 R , 5 S ) -5- (acetyloxy) -4- (benzoyloxy) -2 - [(propylamino ) carbonyl] tetrahydro-3-furanyl were prepared similarly.
2- [2- (4-Isopropyl-1-piperidinyl) ethyl] -1 H -isoindol-1,3 (2 H ) -dione
A solution of 4-isopropylpiperidine (3.3 g, 20.2 mmol) and 2-Bromoethylphthalimide (5.4 g, 21.3 mmol) in acetonitrile (100 ml) with potassium carbonate (5.9 g, 45.4 mmol), it was heated at reflux for 2.5 hours and then stirred at room temperature overnight. The solvent was removed at reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and the aqueous layer was separated. extracted with additional ethyl acetate (100 ml). Extracts combined organics were dried over sodium sulfate and the Solvent was removed under reduced pressure. The resulting oil is purified by silica gel column chromatography eluting with a dichloromethane gradient system: diethyl ether (50: 50 by volume) which changed to pure diethyl ether to provide the title compound (3.3 g).
1 H NMR (400 MHz, CDCl 3) δ: 7.80 (2H, m), 7.70 (2H, m), 3.80 (2H, t), 3.00 (2H, m), 2.60 (2H, t), 1.95 (2H, m), 1.60 (2H, m), 1.40 (1H, m), 1.20 (2H, dq), 0.95 (1H, m), 0.80 (6H, d).
2- (4-Isopropyl-1-piperidinyl) ethylamine
A solution of (2- [2- (4-isopropyl-1-piperidinyl) ethyl] -1 H -isoindol-1,3 (2 H ) -dione (prepared 16) (3.2 g, 10.6 mmol) in a solution of 33% methylamine in ethanol (60 ml) it was heated under reflux for three hours.The solvent was removed under reduced pressure, additional ethanol (60 ml) was added and the solvent was removed again under reduced pressure. The residue was suspended in dichloromethane (100 ml) and the solid was filtered and washed with additional dichloromethane (100 ml) The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography, eluting with dichloromethane: methanol: concentrated aqueous solution of ammonia (90: 10: 1 by volume) to provide a colorless oil Bulb to bulb distillation (150-160 ° C, 4.0 kPa (30 mm Hg)) provided the title compound (1, 0 g)
1 H NMR (400 MHz, CDCl 3) δ: 2.90 (2H, m), 2.80 (2H, t), 2.40 (2H, t), 1.95 (2H, m), 1.65 (2H, m), 1.40 (1H, m), 1.30-1.20 (4H, m), 1.00 (1H, m), 0.85 (6H, d).
(2 R , 3 R , 4 S , 5 S ) -2- (2-amino-6-chloro-9 H -purin-9-yl) -4- (benzoyloxy) -5 - [(ethylamino) carbonyl benzoate ] -tetrahydro-3-furanyl
A suspension of 2-amino-6-chloropurine (4.60 g, 27.13 mmol) in 1,1,1-trichloroethane (230 ml) was treated with N, O-bis (trimethylsilyl) acetamide (20 ml, 81 , 4 mmol). The mixture was heated at reflux for 6 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was treated with a benzoate solution of (2 S , 3 R , 4 R , 5 R ) - and (2 S , 3 R , 4 R , 5 S ) -5- (acetyloxy) -4- (benzoyloxy) ) -2- (ethylamino) carbonyl] tetrahydro-3-furanyl (prepared 15) (14.39 g, 32.6 mmol) in anhydrous toluene (230 ml) and trimethylsilyl trifluoromethanesulfonate (20 ml, 108.5 mmol). Then, the resulting solution was heated at 90 ° C under a nitrogen atmosphere for 90 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate (250 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate (350 ml) and then with brine (350 ml). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane: methanol (98: 2 by volume) to give the title compound as a white foam (8.1 g).
1 H NMR (400 MHz, CDCl 3) δ: 8.10-7.95 (3H, m), 7.80 (2H, m), 7.50-7.30 (6H, m), 6.90 (1H, m), 6.40-6.20 (3H, m), 5.20 (2H, br s), 4.90 (1H, m), 3.45 (1H, m), 3.30 (1H, m), 1.15 (3H, t).
LRMS: m / z [MH +] 552.
(2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9 H -purin-9-yl) -5 - [(ethylamino) carbonyl benzoate ] -tetrahydro-3-furanyl
N-Butyl nitrite (4.65 ml, 39.7 mmol) was added to a benzoate suspension of (2 R , 3 R , 4 S , 5 S ) -2- (2-amino-6-chloro-9 H -purin-9-yl) -4- (benzoyloxy) -5 - [(ethylamino) carbonyl] -tetrahydro-3-furanyl (prepared 18) (8.10 g, 14.7 mmol), iodine (3.73 g, 14.7 mmol), copper (I) iodide (6.16 g, 32.3 mmol) and diiodomethane (12.55 ml, 155.8 mmol) in THF (100 ml) and the mixture was heated to reflux for 2.5 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was divided between an aqueous solution of sodium metabisulfite (5%, 100 ml) and dichloromethane (100 ml). The organic layer was separated, filtered through arbacel, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with dichloromethane: methanol (99: 1 by volume) to give the title compound as a yellow foam (7.55 g, 78%).
1 H NMR (400 MHz, CDCl 3) δ: 8.55 (1H, s), 8.05 (2H, m), 7.80 (2H, m), 7.65-7.30 (6H, m), 6.75 (1H, m), 6.50 (1H, m), 6.10-6.00 (2H, m), 4.90 (1H, m), 3.60-3.40 (2H, m), 1.25 (3H, t).
LRMS: m / z [MNa +] 684.
Prepared twenty
(2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- {6 - [(2-benzyl-3-phenylpropyl) amino] -2-iodo-9 H -purin-9 benzoate -il} -5 - [(ethylamino) carbonyl] -tetrahydro-3-furanyl
A benzoate solution of (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9 H -purin-9-yl) 5 - [(ethylamino ) carbonyl] -tetrahydro-3-furanyl (prepared 19) (0.25 g, 0.38 mmol) and 2-benzyl-3-phenylpropylamine (0.16 g, 0.76 mmol) in isopropanol (10 ml) is stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol (99: 1 by volume) to provide the title compound as a yellow foam (0.26 g,
83%)
1 H NMR (400 MHz, CDCl 3) δ: 8.00 (2H, m), 7.80 (3H, m), 7.60-7.40 (5H, m), 7 , 35-7.15 (9H, m), 6.25 (1H, m), 6.15-6.05 (2H, m), 5.75 (1H, br s), 4.90-4, 80 (2H, m), 3.65 (1H, m), 3.50 (1H, m), 3.00-2.85 (4H, m), 1.20 (3H,
t).
Prepared twenty-one
(2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- (6 - {[2,2-bis (3-phenyl) ethyl] amino} -2-iodo-9 H benzoate -purin-9-yl) -5 - [(ethylamino) carbonyl] -tetrahydro-3-furanyl
It was prepared from (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9 H -purin-9-yl) -5- benzoate [(ethylamino) carbonyl] -tetrahydro-3-furanyl (prepared 19) and 2,2-bis (phenyl) ethylamine by the same method as prepared 20. The title compound was obtained as a yellow foam .
1 H NMR (400 MHz, CDCl 3) δ: 8.05 (2H, m), 7.80 (3H, m), 7.60-7.40 (5H, m), 7.35-7.15 (9H, m), 6.25 (1H, m), 6.15-6.05 (2H, m), 5.75 (1H, br s), 4.90 (1H, m), 4.40 (1H, m), 4.25 (1H, br s), 3.65 (1H, m), 3.50 (1H, m), 1.25 (3H, t).
(2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -5 - [(ethylamino) carbonyl] -2- {6 [(1-ethylpropyl) amino] -2-iodine-9 H benzoate -purin-9-yl} tetrahydro-3-furanyl
It was prepared from (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9 H -purin-9-yl) -5- benzoate [(ethylamino) carbonyl] -tetrahydro-3-furanyl (preparation 19) and 1-ethylpropylamine by the same method as that of preparation 20. The title compound was obtained as a yellow foam.
1 H NMR (400 MHz, CDCl 3) δ: 8.10-8.00 (3H, m), 7.80 (2H, m), 7.60 (1H, m), 7.50-7.40 (3H, m), 7.30 (2H, m), 6.40 (1H, m), 6.15-6.05 (2H, m), 5.75 (1H, br s), 4.90 (1H, m), 4.40 (1H, m), 4.00 (1H, m), 3.55 (1H, m), 3.35 (1H, m), 1.75 (2H, m), 1.10 (2H, m), 1.25 (6H, t).
Prepared 2. 3
Benzoate (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- (6 - {[(1 S ) -1-benzyl-2-hydroxyethyl] amino} -2-iodine-9 H -purin-9-yl) -5 - [(ethyl-amino) carbonyl] -tetrahydro-3-furanyl
It was prepared from (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9 H -purin-9-yl) -5- benzoate [(ethylamino) carbonyl] -tetrahydro-3-furanyl (prepared 19) and (2 S ) -2-amino-3-phenyl-1-propanol by the same method as in preparation 20. The title compound was obtained in Shape of a yellow foam.
1 H NMR (400 MHz, CDCl 3) δ: 8.20 (1H, s), 8.05 (2H, d), 7.80 (2H, d), 7.60 (1H, m), 7.50-7.35 (4H, m), 7.30-7.20 (6H, m), 6.40 (1H, m), 6.30-6.10 (3H, m), 4.90 (1H, m), 3.90 (1H, m), 3.80 (1H, m), 4.25 (1H, br s), 3.55 (1H, m), 3.40 (1H, m), 3.10 (2H, m), 1.15 (3H, t).
Benzoate (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -5 - [(ethylamino) carbonyl] -2- {6 - [(9 H- fluoren-9-ylmethyl) amino] - 2-iodo-9 H -purin-9-yl} tetrahydro-3-furanyl
It was prepared from (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9 H -purin-9-yl) -5- benzoate [(ethylamino) carbonyl] -tetrahydro-3-furanyl (preparation 19) and 9 H- fluoren-9-ylmethylamine by the same method as that of preparation 20. The title compound was obtained as a yellow foam.
1 H NMR (400 MHz, CDCl 3) δ: 8.05 (2H, m), 7.80 (4H, m), 7.70-7.25 (13H, m), 6.25 (1H, m), 6.15-6.05 (2H, m), 5.85 (1H, br s), 4.90 (1H, m), 4.40 (1H, m), 4.15 (1H, br s), 3.65 (1H, m), 3.50 (1H, m), 1.25 (3H, t).
Benzoate (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- [6- (cyclohexylamino) -2-iodo-9 H -purin-9-yl] -5 - [(ethylamino ) carbonyl] -tetrahydro-3-furanyl
It was prepared from (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- (6-chloro-2-iodo-9 H -purin-9-yl) -5- benzoate [(ethylamino) carbonyl] -tetrahydro-3-furanyl (preparation 19) and cyclohexylamine by the same method as that of preparation 20. The title compound was obtained as a yellow foam.
1 H NMR (400 MHz, CDCl 3) δ: 8.05 (2H, m), 7.80 (3H, m), 7.60 (1H, m), 7.50-7.40 (4H, m), 7.30-7.25 (2H, m), 6.25 (1H, m), 6.15-6.05 (2H, m), 5.70 (1H, br s), 4.90 (1H, m), 4.15 (1H, br s), 3.65 (1H, m), 3.50 (1H, m), 2.10 (2H, m), 1.80 (2H, m), 1.65 (1H, m), 1.50-1.40 (2H, m), 1.30-1.20 (6H, m).
(2 S , 3 S , 4 R , 5 R ) -5- {6 - [(2-Benzyl-3-phenylpropyl) amino] -2-iodo-9 H -purin-9-yl} - N -ethyl- 3,4-dihydroxytetrahydro-2-furancarboxamide
A benzoate solution of (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- {6 [(2-benzyl-3-phenylpropyl) amino] -2-iodine-9 H -purin -9-yl} -5 - [(ethylamino) carbonyl] -tetrahydro-3-furanyl (prepared 20) (0.26 g, 0.31 mmol) and sodium carbonate (33 mg, 0.3 mmol) in methanol (5 ml) was stirred at room temperature for 14 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane: methanol (99: 1 by volume; 5 ml) and filtered. The solvent was evaporated again under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a beige powder (0.17 g, 86%).
1 H NMR (400 MHz, CD 3 OD) δ: 8.10 (1H, m), 7.30-7.10 (10H, m), 5.90 (1H, d), 4.70 (1H, m), 4.55-4.30 (2H, m), 3.55-3.40 (2H, m), 3.30 (1H, m), 3.00-2.90 (4H, m), 1.20 (3H, t).
(2 S , 3 S , 4 R , 5 R ) -5- {6 - [(2,2-Diphenylethyl) amino] -2-iodo-9 H -purin-9-yl} - N -ethyl-3, 4-dihydroxytetrahydro-2-furancarboxamide
It was prepared from (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- (6 - {[2,2-bis (3-phenyl) ethyl] amino} -2 benzoate -iodo-9 H -purin-9-yl) -5 - [(ethylamino) carbonyl] -tetrahydro-3-furanyl (preparation 21) by the same method as that of preparation 26. The title compound was obtained as A yellow powder.
1 H NMR (400 MHz, CD 3 OD) δ: 8.10 (1H, m), 7.35-7.15 (10H, m), 5.90 (1H, m), 4.75 (1H, m), 4.45 (1H, m), 4.40 (1H, m), 4.35 (1H, m), 4.20 (2H, m), 3.55-3.40 (2H, m), 1.20 (3H, t).
(2 S , 3 S , 4 R , 5 R ) - N -Ethyl-5- {6 - [(1-ethylpropyl) amino] -2-iodo-9 H -purin-9-yl} -3.4- dihydroxytetrahydro-2-furancarboxamide
It was prepared from (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -5 - [(ethylamino) carbonyl] -2- {6 [(1-ethylpropyl) amino] -2 benzoate -iodo-9 H -purin-9-yl} tetrahydro-3-furanyl (preparation 22) by the same method as that of preparation 26. The title compound was obtained as a yellow powder.
1 H NMR (400 MHz, CDCl 3) δ: 8.10 (1H, m), 7.75 (1H, br s), 5.95 (1H, d), 5.70 (1H, m), 5.15 (1H, br s), 4.80 (1H, m), 4.60-4.45 (3H, m), 3.50 (1H, m), 3.25 (1H, m), 1.70 (2H, m), 1.50 (2H, m), 1.10 (3H, m), 0.90 (6H, t).
(2 S , 3 S , 4 R , 5 R ) -5- (6 - {[(1 S ) -1-Benzyl-2-hydroxyethyl] amino} -2-iodo-9 H -purin-9-yl) - N -ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide
It was prepared from (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- (6 - {[(1 S ) -1-benzyl-2-hydroxyethyl] amino} - benzoate 2-iodo-9 H -purin-yl) -5 - [(ethylamino) carbonyl] tetrahydro-3-furanyl (preparation 23) by the same method as that of preparation 26.
The title compound was obtained in the form of a yellow powder
1 H NMR (400 MHz, CDCl 3) δ: 8.10 (1H, br s), 7.50-7.10 (5H, m), 6.65 (1H, br s), 5.95 (1H, m), 4.80 (1H, m), 4.60-4.40 (2H, m), 3.70 (1H, m), 3.50 (1H, m), 3.35 (1H, m), 3.10 (2H, m), 1.15 (3H, t).
(2 S , 3 S , 4 R , 5 R ) - N -Ethyl-5- {6 - [(9 H- fluoren-9-ylmethyl) amino] -2-iodo-9 H -purin-9-yl} -3,4-dihydroxytetrahydro-2-furancarboxamide
It was prepared from (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -5 - [(ethylamino) carbonyl] -2- {6 - [(9 H -fluoren-9-) benzoate ilmethyl) amino] -2-iodo-9 H -purin-9-yl} tetrahydro-3-furanyl (prepared 24) by the same method as that of prepared 26. The title compound was obtained as a colored powder yellow.
1 H NMR (400 MHz, CD 3 OD) δ: 8.10 (1H, s), 7.80 (2H, d), 7.65 (2H, m), 7.40-7.20 (4H, m), 5.90 (1H, d), 4.75 (1H, m), 4.40 (1H, s), 4.35 (2H, br s), 4.10 (2H, m), 3.45 (2H, m), 1.20 (3H, t).
(2 S , 3 S , 4 R , 5 R ) -5- [6- (Cyclohexylamino) -2-iodo-9 H -purin-9-yl] - N -ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide
It was prepared from (2 R , 3 R , 4 S , 5 S ) -4- (benzoyloxy) -2- [6- (cyclohexylamino) -2-iodo-9 H -purin-9-yl] - benzoate - 5 - [(ethylamino) carbonyl] tetrahydro-3-furanyl (prepared 25) by the same method as that of prepared 26. The title compound was obtained as a yellow powder.
1 H NMR (400 MHz, CD 3 OD) δ: 8.15 (1H, s), 5.90 (1H, d), 4.70 (1H, m), 4.40 (1H, s), 4.30 (1H, d), 4.05 (1H, br s), 3.50-3.40 (2H, m), 2.00 (2H, m), 1.80 (2H, m), 1.60 (1H, m), 1.50-1.20 (6H, m), 1.15 (3H, t).
1. A compound with the formula:
2. A compound according to claim 1, in the that R 1 is cyclohexyl or C 1 -C 6 alkyl optionally substituted.
3. A compound according to claim 2, in the that R 1 is C 1 -C 5 alkyl optionally replaced.
5. A compound according to any of the claims 2, 3 or 4, wherein the alkyl substituents C 1 -C 6, C 1 -C 5 or C 1 -C 2 are selected from benzyl, fluorenyl, phenyl and hydroxyl.
6. A compound according to claim 5, in the that there is 1 or 2 phenyl group (s) when R1 is substituted with phenyl.
7. A compound according to any of the claims 2 to 5, wherein R 1 is selected from 2,2-diphenylethyl, cyclohexyl, 1-ethylpropyl, 1-benzyl-2-hydroxyethyl, 9H-fluoren-9-ylmethyl Y 1-benzyl-2-phenylethyl.
8. A compound according to claim 7, in the that R1 is diphenylethyl.
9. A compound according to claim 8, in the that R1 is 2,2-diphenylethyl.
10. A compound according to any of the preceding claims, wherein A is alkylene C_ {1} -C_ {6}.
11. A compound according to claim 10, in which A is C 1 -C 4 alkylene.
12. A compound according to claim 11, in which A is selected from methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene.
13. A compound according to claim 12, in which A is 1,2-ethylene.
14. A compound according to any of the preceding claims, wherein R2 is selected from phenyl, pyrrolidinyl, pyridinyl, piperidinyl optionally substituted, optionally substituted piperazinyl, imidazolyl optionally substituted, morpholinyl, tetrahydroisoquinoline, (C 1 -C 6) alkyl amino, di (C 1 -C 6) alkyl amino, pyridinylamino and -NR 3 SO 2 R 4.
15. A compound according to claim 14, in which R2 is selected from phenyl, 2-pyridinyl, 1-piperidinyl, 4-piperazinyl, 1-pyrrolidinyl, 4-morpholinyl, 3,4-tetrahydro-2 (1H) -isoquinolinyl, (C 1 -C 3) alkyl amino, dialkyl (C 1 -C 3) amino and 1H-imidazol-4-yl replaced.
16. A compound according to claim 15, in which R2 is selected from 3-isopropylamino, methylamino, dimethylamino, diethylamino, 1-methyl-1H-imidazol-4-yl, 5-methyl-1H-imidazol-4-yl, 4-methylpiperazin-1-yl, 1- (2-propyl) piperidin-4-yl and 2-pyridylamino.
17. A compound according to claim 15, in which R 2 is piperidinyl optionally substituted with alkyl C 1 -C 6 or methoxy.
18. A compound according to claim 17, in which R2 is piperidinyl optionally substituted in the position 1- or position 4- with alkyl C 1 -C 6 or methoxy.
19. A compound according to claim 18, in which R2 is piperidinyl linked by an N with a C atom optionally substituted with C 1 -C 6 alkyl or methoxy.
21. A compound according to claim 20, in which R2 is piperidinyl linked by an N with a C atom optionally substituted by methyl, methoxy or propyl.
22. A compound according to claim 21, in which R2 is piperidinyl linked by an N optionally substituted in the 4- position by methyl, methoxy or propyl
23. A compound according to claim 22, in which R2 is piperidin-1-yl, 4- (methyl) piperidin-1-yl, 4- (methoxy) piperidin-1-yl, or 4- (prop-2-yl) piperidin-1-yl.
24. A compound according to any of the preceding claims, wherein R 3 is methyl.
25. A compound according to any of the preceding claims, wherein R 4 is methyl or phenyl.
26. A compound according to any of the preceding claims, wherein R 7 is alkyl C_ {1} -C_ {6}.
27. A compound according to claim 26, in which R 7 is C 1 -C 4 alkyl.
28. A compound according to claim 27, in which R 7 is ethyl or n-propyl.
29. A compound according to any of the preceding claims, wherein R 8 is H.
30. A compound according to claim 1 selected from the group consisting of:
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - (2-pyridinylmethyl) -9 H -purine-2-carboxamide;
N -benzyl-6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5- (ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2- furanyl} -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - (2-phenylethyl) -9 H -purine-2-carboxamide;
N - [2- (dimethylamino) ethyl] -6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] - 3,4-dihydroxytetrahydro-2-furanyl} -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (1-pyrrolidinyl) propyl] -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (2-pyridinyl) ethyl] -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (4-morpholinyl) ethyl] -9 H -purine-2-carboxamide;
9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -6 - [(1-ethylpropyl) amino] - N - [2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide;
6 - {[(1 S ) -1-benzyl-2-hydroxyethyl] amino} -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3.4- dihydroxytetrahydro-2-furanyl} - N - [2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (4-Isopropyl-1-piperidinyl) ethyl] -9 H -purine-2-carboxamide;
N - [2- (3,4-dihydro-2 (1 H ) -isoquinolinyl) ethyl] -6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - (4-piperidinylmethyl) -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [4- (l-piperidinyl) butyl] -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (isopropylamino) propyl] -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (2-pyridinylamino) propyl] -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - {3- [methyl (phenylsulfonyl) amino] propyl} -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - {3- [methyl (methylsulfonyl) amino] propyl} -9 H -purine-2-carboxamide;
9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} -6 - [(9 H -fluoren-9-ylmethyl) amino] - N - [2- (1-piperidinyl) ethyl] -9 H- purine-2-carboxamide;
N - [3- (diethylamino) propyl] -6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] - 3,4-dihydroxytetrahydro-2-furanyl} -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (4-morpholinyl) propyl] -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (methylamino) propyl] -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (5-methyl-1 H -imidazol-4-yl) ethyl] -9 H -purine-2-carboxamide;
N - [4- (dimethylamino) butyl] -6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] - 3,4-dihydroxytetrahydro-2-furanyl} -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [3- (4-methyl-1-piperazinyl) propyl] -9 H -purine-2-carboxamide;
N - [3- (dimethylamino) propyl] -6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] - 3,4-dihydroxytetrahydro-2-furanyl} -9 H -purine-2-carboxamide;
6 - [(1-benzyl-2-phenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl } - N - [2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide;
9 - {(2 R , 3 R , 4 S , 5 S ) -3,4-dihydroxy-5 - [(propylamino) carbonyl] tetrahydro-2-furanyl} -6 - [(2,2-diphenylethyl) amino] - N - [2- (1-piperidinyl) ethyl] -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (4-methyl-1-piperidinyl) ethyl] -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (4-methoxy-1-piperidinyl) ethyl] -9 H -purine-2-carboxamide;
6 - [(2,2-diphenylethyl) amino] -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [(1-methyl-1 H -imidazol-4-yl) methyl] -9 H -purine-2-carboxamide and
6- (cyclohexylamino) -9 - {(2 R , 3 R , 4 S , 5 S ) -5 - [(ethylamino) carbonyl] -3,4-dihydroxytetrahydro-2-furanyl} - N - [2- (1 -piperidinyl) ethyl] -9 H -purine-2-carboxamide,
or a pharmaceutically acceptable salt or solvate thereof.
31. A pharmaceutical composition that includes a compound with the formula (I) according to any of the preceding claims, or a pharmaceutically salt or solvate acceptable thereof, together with an excipient, diluent or vehicle pharmaceutically acceptable.
32. A compound with the formula (I) according to any one of claims 1 to 30, or a salt, solvate or pharmaceutically acceptable composition thereof, for use as medicine.
33. The use of a compound with the formula (I) according to any one of claims 1 to 30, or of a salt, solvate or pharmaceutically acceptable composition thereof, for manufacture of an anti-inflammatory agent.
34. The use of a compound with the formula (I) according to any one of claims 1 to 30, or of a salt, solvate or pharmaceutically acceptable composition thereof, for manufacture of a medicine for the treatment of a disease respiratory
35. Use according to claim 34, wherein the disease is selected from the group consisting of the syndrome of adult respiratory distress (ARDS), bronchitis, bronchitis chronic, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis.
36. The use of a compound with the formula (I) according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of septic shock, erectile dysfunction in the male, hypertension, stroke, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischemic reperfusion injuries, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, gastritis with Heliobacter pylori , gastritis without Heliobacter pylori , damage induced by non-steroidal anti-inflammatory drugs in the gastrointestinal tract or for the treatment of a psychotic disorder, or for the healing of
37. A compound with the formula: (II), (III), (XI), (XIII), (XIV), (XV), (XVI), (XIX), (XIXb), (XIXc) or (XIXd):
in which R 1 to R 8, A, "het" and m, when present, are as defined in claim 1; in which P1 and P2 are groups protectors selected from alkanoyl and aroyl and when taken together they are C 1 -C 6 alkylene and in the that P3 is a protecting group that is tetrahydropyran-2-yl and in which Z is a leaving group selected from bromine, iodine, Sn (C 1 -C 12 alkyl) 3 or CF 3 SO 2 O-.
38. A method for the preparation of a compound of formula (I), or of a pharmaceutically acceptable salt thereof, according to claim 1, method comprising the step of the reaction of an ester of formula (II).
with an amine with the formula R 2 -A-NHR 8 (X), in which R 1 to R 8, A, "het" and m, when present, are as defined in the claim one.
39. A method for the preparation of a compound with the formula (III):
where P 1 and P 2 are protecting groups, as defined in claim 37, with trimethylsilyltrifluoromethanesulfonate and with a compound with the formula (IV):
in which the compound of formula (IV) is derivatized with N, O-bis (trimethylsilyl) acetamide and a It is then reacted with the compound of formula (XI) and where R 1 to R 8, A, "het" and m, when they are present, are as defined in the claim one.
40. A method for the preparation of a compound of formula (IV):
in which R 1 is R 8, A, "het" and m, when present, are as defined in the reinvidication one.
41. A method for the preparation of a compound with the formula (VI):
with a cyano group, in which R 1 is R 8, A, "het" and m, when present, are as defined in the claim one.
42. A method for the preparation of a compound with the formula (VII)
with an amino compound of formula R 1 NH 2 (XII), wherein R 1 to R 8, A, "het" and m, when present, are as defined in the claim one.
43. A method for the preparation of a compound of formula (I), or of a pharmaceutically acceptable salt thereof, according to claim 1, method comprising the step of the deprotection of a compound with the formula (XIII):
in which P1 and P2 are protecting groups as defined in claim 37 and in the that R 1 to R 8, A, "het" and m, when present, are as defined in the claim one.
44. A method for the preparation of a compound of formula (XIII), or of a pharmaceutically salt acceptable thereof, method comprising the reaction stage of a compound of formula (XI)
with trimethylsilyltrifluoromethanesulfonate and with a compound with the formula (XIV) as defined in claim 42, which has been derivatized with N, O-bis (trimethylsilyl) acetamide, in the that R 1 to R 8, A, "het" and m, when present, are as defined in the claim one.
45. A method for the preparation of a compound of formula (I), or of a pharmaceutically acceptable salt thereof, according to claim 1, a method comprising the condensation of an acid with the formula (XIX) with an amine with the formula R 2 -A-NHR 8 (X):
46. A method for the preparation of a compound of formula (I), or of a pharmaceutically acceptable salt thereof, according to claim 1, a method comprising a aminocarbonylation reaction of a compound with the formula (XIXb):
in which Z is a leaving group suitable as defined in claim 37, with a compound of formula R 2 -A-NHR 8 (X) in the presence of monoxide carbon.
ES01902583T 2000-02-18 2001-02-09 Derivatives of purina. Active ES2260199T3 (en)
GBGB0003960.2A GB0003960D0 (en) 2000-02-18 2000-02-18 Purine derivatives
GB0003960 2000-02-18
ES2260199T3 true ES2260199T3 (en) 2006-11-01
ES01902583T Active ES2260199T3 (en) 2000-02-18 2001-02-09 Derivatives of purina.
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TN (1) TNSN01028A1 (en)
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