Derivative 6-cycloalkanes 1.5 dyhidropirazol [3,4-d] pyrimidine-4-one and their use as inhibitors pde9a
8 claims: 1 independent, 7 dependent
- 1Claims Revendications 1, Compose de formule (I) 1, Compound of formula (I) R) :est un groupe hétéroaryle à 5 ou 6 chaînons, 1,2, 3 ou 4, de préférence 1,2 ou 3 atomes du cycle étant des hétéroatomes qui sont choisis indépendamment les uns des autres parmi N, 0 ou s, ledit groupe hétéroarvle aromatique à 5 ou 6 chaînons pouvant être 10 facultativement substitué par 1,2, 3 ou 4, de préférence par 1 ou 2 substituants, lesdits substituants pouvant être choisis indépendamment les uns des autres dans le groupe constitué du fluor, du chlore, du brome, HO-, NC-, F3C-, HF2C-, FHC-, d'un groupe méthyle, HN- et (CH)2N- ;R): is a 5- or 6-membered heteroaryl group, 1,2, 3 or 4, preferably 1,2 or 3 ring atoms being heteroatoms which are independently selected from one another from N, 0 or s, said aromatic heteroaryl group 5 or 6 membered which may be optionally substituted by 1, 2, 3 or 4, preferably by 1 or 2 substituents, said substituents being independently selectable from one another from the group consisting of fluorine, chlorine, bromine, HO-, NC-, F3C-, HF2C-, FHC-, a methyl group, HN- and (CH) 2N-;R2 : est choisi dans le groupe constitué du fluor, NC-, F3C-, HF2C-, FHC- et d’un 15 groupe méthyle, de préférence du fluor, NC-, F3C- et d’un groupe méthyle ;R2 : is selected from the group consisting of fluorine, NC-, F3C-, HF2C-, FHC- and a methyl group, preferably fluorine, NC-, F3C- and a methyl group;D : est choisi dans le groupe constitué des groupes cyclopentyle, cyclohexyle, tétrahydrofuranyle, tétrahydropyranyle, 2-, 3- et 4-pyridyle, les groupes cyclopentyle et cyclohexyle pouvant être facultativement substitués par 1 ou 2 substituants, lesdits substituants pouvant être sélectionnés 20 indépendamment l’un de l’autre dans le groupe constitué du fluor, NC-, F3C-, HF2Cet FHC-;D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl, where cyclopentyl and cyclohexyl may be optionally substituted with 1 or 2 substituents, said substituents being independently selectable. each other from the group consisting of fluorine, NC-, F3C-, HF2C and FHC-;les groupes tétrahydrofuranyle et tétrahydropyranyle pouvant être facultativement substitués par 1 ou 2 substituants, lesdits substituants pouvant être choisis indépendamment l’un de l’autre dans le groupe constitué du fluor, NC-, F3C-, 25 HF2C- et FHC-;the tetrahydrofuranyl and tetrahydropyranyl groups being optionally substituted with 1 or 2 substituents, said substituents being independently of one another selected from the group consisting of fluorine, NC-, F3C-, HF2C- and FHC-;le groupe pyridyle pouvant être facultativement substitue par 1, 2, 3 ou 4 substituants, lesdits substituants pouvant être choisis indépendamment les uns des the pyridyl group possibly being optionally substituted by 1, 2, 3 or 4 substituents, said substituents being able to be chosen independently of one of the -108Mk -108Mk 35575Β1 35575Β1 Boehringer Ingelheim International GmbH P01-2655 / PCT Boehringer Ingelheim International GmbH P01-2655/PCT PCT / EP2611 / 063705 other in the group consisting of fluorine, chlorine, bromine, NC-, FC, HC-, FHC-, F CCH-, C | -C6 alkyl and C3-C7 cycloalkyl ;PCT/EP2611/063705 autres dans le groupe constitue du fluor, du chlore, du brome, NC-, FC, HC-, FHC-, F CCH-, d’un groupe alkyle en C|-Cô et cycloalkyle en C3-C7 ;m : est choisi parmi 1 ou 2, m valant de préférence 1 ;m: is chosen from 1 or 2, m preferably being 1;n : est choisi parmi 0, 1 ou 2, n valant de préférence 0 ou 1, de manière davantage préférée n valant 0, sin = 2. ces deux groupes R2 étant choisis indépendamment l’un de l’autre ;n: is chosen from 0, 1 or 2, n preferably equaling 0 or 1, more preferably n being equal to 0, sin = 2. these two groups R2 being chosen independently of one another;and salts, preferably their pharmaceutically acceptable salts;et des sels, de préférence, ses sels pharmaceutiquement acceptables ;provided that the compound is not either in the form of any possible stereoisomer or of a mixture of all or part thereof. à condition que le composé ne soit pas que ce soit sous la forme de n’importe quel stéreoisomere possible ou bien de mélange de tout ou partie de ceux-ci.
1,189 paragraphs in 161 sections, as filed
The invention relates to
Abstract news 6-cycloalkyl-pyrazolopyrimidinones of formula (I).
<img file="MA35575B1_D0001.tif" />
wherein r 'is a 5- or 6-membered aromatic heteroaryl group, R<sup>2</sup> is an optional substituent, D is cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or 2-, 3- or 4-pyridyl optionally substituted, m = 1 or 2 and n is 0, 1 or 2.
The new compounds are intended to be used respectively as active ingredients of medicaments or for the manufacture of medicaments, in particular of particular medicaments for treating diseases related to a deficit in perception, concentration, learning or memory. . These disorders can, for example, be associated with Alzheimer's disease, schizophrenia and other diseases. The new compounds are, for example, also intended for the manufacture of medicaments and / or for use in treating these diseases, in particular the cognitive disorders associated with these diseases. The compounds of the invention exhibit properties which inhibit PDE9.
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<td>Boehringer Ingelheim International GmbH</td><td>P01-2655 / PCT PCEP2011 / 063705</td>
Derivatives of 6-cvcloalkvl-DvrazoloDvrimidinones and their use as PDE9A inhibitors
The present invention relates to novel pyrazolopyrimidinones of formula (I):
<img file="MA35575B1_D0002.tif" />
wherein R 'is a 5- or 6-membered aromatic heteroaryl group, R<sup>2</sup> is an optional substituent, D is a cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl orr 2-, 3- or 4-pyridyl group optionally substituted, m 1 or 2 and n is 0, 1 or 2.
The new compounds are intended to be used respectively as an active principle in medicaments or for the manufacture of medicaments, in particular medicaments for treating pathologies linked to disorders of perception, concentration, learning or memory. . These pathologies can be associated, for example, with Alzheimer's disease, schizophrenia and other diseases. The new compounds are also intended, for example, for the manufacture of medicaments and / or for being used to treat these pathologies, in particular as regards the cognitive disorders associated with this type of pathology. The compounds of the invention exhibit properties which inhibit PDE9.
BACKGROUND OF THE INVENTION
Inhibition of phosphodiesterase 9Α (PDE9A) is one of the current concepts to find other new ways to treat cognitive disorders due to CNS disorders such as Alzheimer's disease, schizophrenia and other conditions or due to any other
MY
35575Β1
Boehringer Ingelheim International GmbH P01-2655 / PCT
PCTEP2011 / 063705 Neurodegenerative process of the brain. With the present invention, new compounds according to this concept are presented.
Phosphodiesterase 9Α belongs to the large family of phosphodiesterases. These enzymes modulate the levels of cyclic 5'-3 'adenosine monophosphate (cAMP) and 5'-3' cyclic guanosine monophosphate (cGMP) nucleotides. These cyclic nucleotides (cAMP and cGMP) are important second messengers and therefore play a central role in cellular signal transmission cascades. Each of them reactivates, among others but not exclusively, protein kinases. The protein kinase activated by cAMP is called protein kinase A (PKA) and the protein kinase activated by cGMP is called protein kinase G (PKG). Activated PKA and PKG are in turn capable of phosphorylating a number of cellular effector proteins (eg, ion channels, G protein coupled receptors, structural proteins, and transcription factors). In this way, it is possible for the second messengers cAMP and cGMP to control a wide range of physiological processes in a wide range of organs. However, cyclic nucleotides are also able to act directly on effector molecules. We therefore know, for example, that cGMP is capable of acting directly on ion channels and that it is therefore capable of influencing the cellular ionic concentration (study in: Wei et al., Prog. Neurobiol., 1998, 56, 37-64). Phosphodiesterases (PDE) are a mechanism for controlling the activity of cAMP and cGMP, which in turn are controlled for the corresponding physiological processes. PDEs hydrolyze cyclic monophosphates to obtain the inactive AMP and GMP monophosphates. 11 families of PDE are currently defined on the basis of the sequence homology of the corresponding genes. Individual PDE genes of the same family are differentiated by letters (eg, PDEIA and PDEIB). In the event that different splice variants are also present within a gene, then this is indicated by an additional number following the letters (eg, PDEIAI).
Human PDE9A was cloned and sequenced in 1998. The amino acid identity with other PDEs does not exceed 34٥ / ο (PDE8A) and is never less than 28٥ / ο (PDE5A). With the Michaelis-Menten constant (Km) of 170 nanomolar (nM), PDE9A exhibits a high affinity for cGMP. In addition, PDE9A is selective with respect to cGMP (Km for cAMP = 230 micromolar (μΜ)). PDE9A lacks a cGMP binding domain, suggesting that the enzymatic activity is not regulated by cGMP. Analysis
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PCEP2011 / 063705 by Western blot indicated that PDE9A is expressed in humans, inter alia, in the testes, brain, small intestine, skeletal muscles, heart, lungs, thymus and spleen. The strongest expression was found in the brain, small intestine, kidneys, prostate, colon and spleen (Fisher et al., J. Biol. Chem., 1998, 273 (25), 1555915564; Wang et al., Gene, 2003, 314, 15-27). The human PDE9A gene is located on chromosome 21q22.3 and consists of 21 exons. 4 other splice variants of PDE9A have been identified (Guipponi et al., Hum. Genet., 1998, 103, 386-392). Conventional PDE inhibitors do not inhibit human PDE9A. IBMX, dipyridamole, SKF94120, rolipram and vinpocetine therefore do not exhibit inhibition on the enzyme isolated at concentrations up to 100 micromolar (μΜ). An IC50 of 35 micromolar (μΜ) has been demonstrated for zaprinast (Fisher et al., J. Biol. Chem., 1998, 273 (25), 15559-15564).
Murine PDE9A was cloned and sequenced in 1998 by Soderling et al. (ر Biol. Chem., 1998, 273 (19), 15553-15558). This has, like the human form, a great affinity for cGMP with a Km value of 70 nanomolar (nM). Particularly prominent expression has been found in the kidneys, brain, lungs and liver of mice. Murine PDE9A is not inhibited by 1ΊΒΜΧ at concentrations below 200 micromolar either; the IC50 of zaprinast is 29 micromolar (Soderling et al., J. Biol. Chem., 1998, 273 (19), 15553-15558). It has been found that PDE9A is highly expressed in certain regions of the rat brain. These regions include the olfactory bulb, hippocanrp, cortex, basal ganglia, and basal forebrain (Andreeva et al., 3. Neurosci., 2001, 21 (22), 9068-9076). The hippocampus, the cortex and the basal forebrain in particular play an important role in the learning and memory processes. As already mentioned above, PDE9A is distinguished by having a particularly high affinity for cGMP. PDE9A is therefore active, even at low physiological concentrations, unlike PDE2A (Km = 10 micromolar (μΜ); Martins et al., J. Biol. Chem., 1982, 257, 1973-1979), to PDE5A (Km = 4 micromolar (μΜ); Francis et al., 1 Biol. Chem., 1980, 255, 620-626), to PDE6A (Km = 17 micromolar (μΜ); Gillespie and Beavo, J. Biol. Chem., 1988, 263 (17). 8133-8141) and to PDEl IA (Km = o, 52 micromolar (μΜ); Fawcett el al., Proc Nat Acad Sci. 2000, 97 (7), 3702-3707). Unlike PDE2A (Murashima et al., Biochemistry, 1990, 29, 5285-5292), the catalytic activity of PDE9A is not increased by cGMP because it lacks a GAF domain (which results in the binding of cGMP via where PDE activity is allosterically enhanced) (Beavo et al., Current Opinion in Cell Biology.
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PCT / EP2O11 / O637O5 2000, 12, 174-179). PDE9A inhibitors may therefore lead to an increase in the reference concentration of cGMP.
This overview will demonstrate that PDE9A participates in specific physiological processes in a way that is both characteristic and unique: this is what distinguishes the role of PDE9A characteristically from any other member of the family of PDE.
wo 2004/099210 discloses 6-arylmethyl substituted pyrazolopyrimidinones which are inhibitors of PDE9.
WO 2004/099211 discloses pyrazolopyrimidines substituted with 6-cyclylmethyl and substituted with 6-alkylmethyl and their use for the purpose of improving cognition, concentration, etc.,
DE 102 38 722 discloses the use of inlribitors of PDE9A for the purpose of improving cognition and concentration.
WO 2004/018474 discloses pyrazolopyrimidines substituted with a phenyl group and their use for the purpose of improving perception, concentration, learning and / or memory.
WO 2004/026876 discloses pyrazolopyrimidines srrbstitués by an alkyl group and their use with the aim of improving the capacities of perception, concentration, learning and / or the mnesic performances.
WO 2004/096811 discloses heterocyclic bicycles as PDE9 inhibitors for treating diabetes, including type 1 and type 2 diabetes, hyperglycemia, dyslipidemia, glucose intolerance, metabolic syndrome and / or cardiovascular disease.
WO 2009068617 discloses PDE9 inhibitor compounds derived from pyrazolopyrimidinones with a phenylmethyl or pyridylmethyl group substituted in the 6 position.
WO 2010112437 discloses PDE9 inhibitor compounds derived from pyrazolopyrimidinones with an arylmethyl or heteroarylmethyl group substituted with a phenyl or heteroaryl group in the 6 position.
WO 2009/121919 discloses inhibitors of PDE9 derived from pyrazolopyrimidinones with a non-aromatic heterocyclic group in position 1, among which is the tetrahydropyranyl group.
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PCT / EP2011 / 063705
WO 2010/026214 discloses inhibitors of PDE9 derived from pyrazolopyrimidinones with a cycloalkyl group or a cycloalkenyl group in position 1, among which there is the 4,4-difluorocyclohexyl group.
Some prior art relates to chemical derivatives of nucleosides. As an example, reference is made to wo 2002/057425 which discloses nucleoside derivatives which are inhibitors of viral RNA-dependent RNA polymerase, or to wo 2001/060315 which discloses nucleoside derivatives intended to be treated. infections by the hepatitis c virus or else EP 679657 which discloses compounds serving as analogues of ribonucleosides or us 2002058635 which discloses compounds of purine L-nucleosides, wherein the purine rings and the carbohydrate cycle (pentose ring) are both either modified, or functionalized, or both. The carbohydrate ring, for example, should at least show one esterified hydroxy group.
WO 2005/051944 discloses oxetane-containing nucleosides for treating disorders related to nucleoside analogues such as disorders involving cell proliferation and infection.
WO 2006/084281 discloses inhibitors of the E1 activating enzyme which have a sulfonamide moiety.
WO 1998/40384 discloses pyrazolopyrimidinones which are inhibitors of PDE1, 2 and 5 and which can be used to treat cardiovascular and cerebrovascular disorders as well as troribles of the urogenital system.
CH 396 924, CH 396 925, CH 396 926, CH 396 927, DE 1147234 and DE 1149013 describe pyrazolopyrimidines which have a coronarodilator effect and which can be used to treat blood flow disturbances in the myocardium.
US 3732225 describes pyrazolopyrimidines which have an anti-inflammatory effect and a hypoglycemic effect.
DE 2408906 describes styrylpyrazolopyrimidinones which can be used as antimicrobial and anti-inflammatory agents to treat edemas for example.
OBJECTIVE OF THE INVENTION
The changes occurring in the substitution configuration of pyrazolopyrimidinones lead to interesting modifications in terms of biological activity, respectively in terms of changes in affinity towards different target enzymes.
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PCÏ / EP2011 / 063705
Therefore, an objective of the present invention is to provide compounds as described herein, especially in the claims, which effectively modulate PDE9A for the purpose of developing a medicament, in particular for treating diseases or disorders, treatment which is accessible via a modulation of the PDE9A.
Another object of the present invention is to provide compounds which are useful for making a medicament for treating CNS disorders.
Yet another object of the present invention is to provide compounds which exhibit a favorable safety profile.
Another object of the present invention is to provide compounds which have a profile selectively favorable to the inhibition of PDE9A relative to other members of the PDE family and other pharmacological targets and which can thus provide an advantage. .
Yet another object is to provide a medicament which not only can be therapeutic, but which could also be used to prevent or modify the corresponding disease or disorder.
The present invention further provides a pharmaceutical composition comprising a compound as described herein, especially in the claims, and a pharmaceutically acceptable carrier.
The present invention further provides a method for treating any disorder described herein in a mammal in need of such treatment, preferably a human, and which comprises administering to that mammal a therapeutically effective amount of composed as described herein, in particular in the claims.
The present invention further provides a compound as described herein, especially in the claims, for use in a therapeutic method for a human or an animal.
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Boehringer Ingelheim International GmbH PO1-2655 / PC1
PC٢ ΕΡ2011 / 063705
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The compounds of the present invention are characterized by the general formula (I):
<img file="MA35575B1_D0003.tif" />
Ri: is a 5 or 6 membered heteroaryl group, 1, 2, 3 or 4, preferably 1, 2 or 3 ring atoms being heteroatoms which are independently selected from N, O or s, said aromatic heteroaryl group 5 or 6-membered which may be optionally substituted by 1, 2, 3 or 4, preferably by 1 or 2 substituents, said stibstituents being able to be chosen independently of one another from the group consisting of fluorine, chlorine, bromine, HO -, NC-, FC-, HC-, FHC-, a methyl group, HN- and (CH) N;
R<sup>2</sup> : is selected from the group consisting of fluorine, NC-, FC-, HFC, FHC- and a methyl group, preferably fluorine, NC-, FC- and a methyl group;
D: is selected from the group consisting of cyclopentyl, cyclohexyl.
tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl.
wherein cyclopentyl and cyclohexyl may be optionally substituted with 1 or 2 substituents, said substituents being independently selectable from the group consisting of fluorine, NC-, F٠٦C-, HF2C andFHC-;
the tetrahydrofuranyl and tetrahvdropyranyl groups being optionally substituted with 1 or 2 substituents, said substitutes being independently selectable from the group consisting of fluorine, NC-, FC-, HC- and FHC-;
the pyridyl group being optionally substituted with 1, 2, 3 or 4 substituents, said substituents being independently selectable from one of
-٦i
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PCT ΕΡ2011063705 others in the group constitutes ؛ fluorine, chlorine, bromine. NC-. FC-. HF٦C-. FHC-, F CCH-, C 1 -C alkyl and C3-C7 cycloalkyl;
m: is chosen from 1 or 2, preferably 1;
n: is chosen from 0, 1 or 2, preferably 0 yes, more preferably 0, sin = 2. these two groups R<sup>2</sup> being chosen independently of one another;
and salts, preferably their pharmaceutically acceptable salts, their solvates and the solvates of their salts mentioned above;
provided that the compound is not the following oxadiazolyl derivative
<img file="MA35575B1_D0004.tif" />
whether in the form of any possible steeoisomer or of a mixture of all or part of these, or of one of their salts or else of one of their solvates or else of a solvate of one of their salts.
This embodiment is Embodiment 1 of the present invention.
Regarding the above condition, it should be understood that throughout this description, this definition of the compound, and in particular "the oxadiazolyl derivative hereinafter
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PO1-2655 C
PC / EP2O11 / O637O5
<img file="MA35575B1_D0005.tif" />
whether in the form of any possible steeoisomer or of a mixture of all or part of these ”encompasses the following stereoisomers, in addition to mixtures of these compounds:
<img file="MA35575B1_D0006.tif" />
Embodiment 2 of the present invention: Another embodiment of the invention relates to a compound of general formula (I), in which
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Boehringer Ingelheim International GmbH P01-2655 / PCT
PCT / EP2011 / 063705 r ': is a heteroaryl group with 5 or 6 members, 1, 2, 3 or 4, preferably 1,2 or 3 atoms of the ring being heteroatoms chosen independently of one another from N, O or S, 'possibly being optionally substituted by 1, 2, 3 or 4, preferably by 1 or 2 substituents, said substituents being able to be chosen independently of each other from the group consisting of fluorine, chlorine, bromine, NC-, F3C-, HFC- FHC-. a methyl group, HN- and (CH) 2N-;
R<sup>2</sup> : is selected from the group consisting of fluorine, NC-, FC-, HF2C-. FHC- and a methyl group, preferably fluorine, NC-, F3C- and a methyl group;
D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrouranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl groups, the cyclopentyl and cyclohexyl groups possibly being optionally substituted with 1 or 2 substituents, said substituents being independently selectable from each other from the group consisting of fluorine, FC-, HF2C- and FHC-;
the tetrahydropyranyl and tetrahydropyranyl groups possibly being optionally substituted by 1 or 2 substituents, said substituents possibly being selected independently of one another from the group consisting of fluorine, FC-, HF2CetFHC-;
where the pyridyl group may be optionally substituted with 1, 2, 3 or 4, preferably with 1, 2 or 3, more preferably with 1 or 2 substituents, said substituents being independently selectable from the group consisting of fluorine, chlorine, bromine, NC-, F3C-, HF2C-, FHC-, F3C-CH2-, C1-C6 alkyl and C3-C7 cycloalkyl;
m: is chosen from 1 or 2, m preferably being 1;
n: is chosen from 0, 1 or 2, n preferably being 0ol, n being equal to 0; if n = 2.these two groups R<sup>2</sup> being chosen independently of one another;
and salts, preferably, its pharmaceutically acceptable salts, its solvates and the solvates of its salts mentioned above;
provided that the compound is not the following oxadiazolyl derivative
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Boehringer Ingelheim International GmbH
PO1-2655 / PC
PCTEP2011 / 063705
<img file="MA35575B1_D0007.tif" />
whether in the form of any possible steroisomer or of a mixture of all or part of these, or of one of their salts or of one of their solvates or else of a solvate of one of their salts.
Embodiment 3 of the present invention: another embodiment of the invention relates to a compound of general formula (I), in which r! : is a 5 membered heteroaryl group, 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 2 or 3 of the ring atoms being heteroatoms which are independently selected from N, o or s, said 5-membered aromatic heteroaryl group being optionally substituted by 1, 2, 3 or 4, preferably by 1 or 2 substituents, said substituents being independently selectable from one another from the group consisting of fluorine, chlorine , bromine, NC-. F3C-, HC-, FHC-. a methyl group, HN- and (CH) N;
R<sup>2</sup> : is selected from the group consisting of fluorine, NC-, FC-, HFC, FHC- and a methyl group, preferably fluorine, NC-, FC- and a methyl group;
D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3-and 4-pyridyl, where cyclopentyl and cyclohexyl may be optionally substituted with 1 or 2 substituents, said substituents may be selected independently of each other from the group consisting of fluorine, FC-, HC- and FHC-;
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35575Β1
Boehringer Ingelheim International GmbH P01-2655 / PCT
PCEP2011 / 063705 wherein the tetrahydrofuranyl and tetrahydropyranyl groups may be optionally substituted with 1 or 2 substituents, said substituents may be independently selected from one another from the group consisting of fluorine, FC-, HCetFHC-;
the pyridyl group being optionally substituted by 1, 2, 3 or 4, preferably by 1, 2 or 3, more preferably 1 or 2 substituents, said substituents being independently of one another selected from the group consisting of fluorine , chlorine, bromine, NC-, FC-, HC-, FHC-F3C-CH2-, C1-C٠6 alkyl and C3-C7 cycloalkyl;
m: is chosen from 1 or 2, m preferably being 1;
n: is chosen from 0, 1 or 2, n preferably being 0 or 1, n being more preferably 0, if n: 2, these two groups R<sup>2</sup> being chosen independently of one another;
and salts, preferably, its pharmaceutically acceptable salts, its solvates and the solvates of its salts mentioned above;
provided that the compound is not the following oxadiazolyl derivative
<img file="MA35575B1_D0008.tif" />
whether it is in the form of any possible stereoisomer or else of a mixture of all or part of these or of one of their salts or of their solvates or of a solvate of one of their salts.
Embodiment 4 of the present invention: Another embodiment of the invention relates to a compound of general formula (I), wherein
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PCÎ / EP2011 / 063705 r! : is a 6-membered heteroaryl group, 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 2 or 3 of the ring atoms being heteroatoms which are independently selected from N, 0 or s, said 6-membered aromatic heteroaryl group being optionally substituted by 1, 2, 3 or 4, preferably by 1 or 2 substituents, said substituents being independently of one another selected from the group consisting of fluorine, chlorine , bromine, NC-, F<sub>3</sub>C-, HFC-, HC-, a methyl group, HN- and (CH<sub>3</sub>)<sub>2</sub>N٠;
r2: is selected from the group consisting of fluorine, NC-, FC-, HC-, FHC- and a methyl group, preferably fluorine, NC-, F<sub>3</sub>C- and a methyl group;
D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl, where cyclopentyl and cyclohexyl may be optionally substituted with 1 or 2 substituents, said substituents may be independently selected from 'one from the other in the group constitutes fluorine, F<sub>3</sub>C-, HC- and FHC-;
the tetrahydrofuranyl and tetrahydropyranyl groups possibly being optionally substituted with 1 or 2 substituents, said substituents possibly being selected independently of one another from the group consisting of fluorine, F<sub>3</sub>C-, HC andFHC-;
wherein the pyridyl group may be optionally substituted with 1, 2, 3 or 4, preferably by 1, 2 or 3, more preferably by 1 or 2 substituents, said substituents being independently selectable from the group consisting of fluorine, chlorine, bromine, NC-, F<sub>3</sub>C-, HC-, FHC-, FC-CH-, a C | C alkyl group and a C cycloalkyl group<sub>3</sub>-VS<sub>7</sub> ;
m: is chosen from 1 or 2, m preferably being 1;
n: is chosen from 0, 1 or 2, n preferably equal to 0 or 1, more preferably, n equal to 0, sin = 2. these two groups R<sup>2</sup> being chosen independently of one another;
and salts, preferably, its pharmaceutically acceptable salts, its solvates and the solvates of its salts mentioned above.
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Embodiment 5 of the present invention: another embodiment of the invention relates to a compound of general formula (I), in which r ': is a heteroaryl group selected from the group consisting of thiadiazolyl, oxadiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyridyl and pyrimidinyl groups, said heteroaryl group preferably being selected from the group consisting of thiadiazolyl, oxadiazolyl, isoxazolyl, thiazolyl and oxazinidin groups said heteroaryl group possibly being optionally substituted by 1, 2, 3 or 4, preferably by 1 or 2 substituents, said substituents being independently selectable from each other from the group consisting of fluorine, chlorine, bromine, NC-, F3C-, HF2C-, FHC-, methyl, HN- and (CH) 2Ν-;
r2: is selected from the group consisting of fluorine, NC-, FC-, HF2C-, FHC- and a methyl group, preferably fluorine, NC-, F3C- and a methyl group;
D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl, where cyclopentyl and cyclohexyl may be optionally substituted with 1 or 2 substituents, said substituents may be independently selected one of on the other from the group consisting of fluorine, F3C-, HC- and tetrahydrofuranyl and tetrahvdropyranvle which may be optionally substituted with 1 or 2 substituents, said substituents being independently selectable from the group consisting of fluorine, F3C-, HCetFHC-;
the pyridyl group being optionally substituted by 1, 2, 3 or 4, preferably by 1, 2 or 3, more preferably by 1 or 2 substituents, said substituents being independently selected from one another from the group constitutes fluorine, chlorine, bromine, NC-, F3C-, HC-, FHC- F3C-CH2-, a C٠-C alk alkyl group and a C3-C7 cycloalkyl group;
m: is chosen from 1 or 2, m preferably being 1;
n: is chosen from 0, 1 or 2, n preferably being 0 or 1, n being more preferably 0, if n: 2, these two groups r2 are chosen independently of one another;
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Boehringer Ingelheim International GmbH Ρ01-2655 / ΡCT
PC ΕΡ201 063705 and salts, preferably, its pharmaceutically acceptable salts, its solvates and the solvates of its salts mentioned above;
provided that the compound is not the following oxadiazolyl derivative:
<img file="MA35575B1_D0009.tif" />
whether in the form of any possible steoisomer or of a mixture of all or part of these or of one of their salts or of their solvates or of a solvate of one of their salts.
Embodiment 6 of the present invention: another embodiment of the invention relates to a compound of general formula (I), in which r ': is a heteroaryl group selected from the group consisting of thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyridyl and pyrimidinyl groups, said heteroaryl group being preferably selected from the group consisting of thiadiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyridyl and pyrimidinyl groups, said heteroaryl group possibly being optionally substituted with 1, 2, 3 or
4, preferably by 1 or 2 substituents, it being possible for said substituents to be chosen independently of each other from the group consisting of fluorine, chlorine, bromine, NC-, F3C-, HC-, FHC-, a methyl group, HN- and (CH2N-;
R<sup>2</sup> : is selected from the group consisting of fluorine, NC-, F3C-, HC-, FH2C- and a methyl group, preferably fluorine, NC-, FC and a methyl group;
D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl groups,
-15MA
35575Β1
Boehringer Ingelheim International GmbH P01-2655 / PCT
PCT / EP2011 / 063705 where the cvclooentvle and cvclohexyl groups may be optionally substituted with 1 or 2 substituents selected from the group consisting of fluorine, FC-, HFC and FHC-;
the tetrahvdrofuranvle and tetrahvdronvranyl groups being optionally substituted independently of each other by 1 or 2 substituents, said substituents being independently selectable from the group consisting of fluorine, F3C-, HC- and FHC- ;
the pyridyl group being optionally substituted by 1, 2, 3 or 4, preferably by 1, 2 or 3, more preferably by 1 or 2 substituents, said substituents being independently selectable from the group consisting of fluorine, chlorine, bromine, NC-, FC-, HC-, FHC-, F3C-CH2-, a C 1 -C 6 alkyl group and a C3-C7 cycloalkyl group;
m: is chosen from 1 or 2, m preferably being 1;
n: is chosen from 0, 1 or 2, n preferably being 0 or 1, n being more preferably 0, if n = 2, these two groups R<sup>2</sup> being chosen independently of one another;
and salts, preferably, its pharmaceutically acceptable salts, its solvates and the solvates of its salts mentioned above.
Embodiment 7 of the present invention: Embodiment 7 of the invention relates to a compound which corresponds in all respects to Embodiment 6, except that:
Ri: is a heteroaryl group selected from the group consisting of thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isoxazolyl, thiazolyl, oxazolyl and pyrimidinyl groups, said heteroaryl group being preferably selected from the group consisting of thiadiazolyl, isoxazolyl, thiazolyl, oxazolyl and pyrimidinyl groups, said heteroaryl group possibly being optionally substituted by 1, 2, 3 or 4, preferably by 1 or 2 substituents, said substituents being independently selectable from one another from the group consisting of fluorine, chlorine, bromine, NC-, F3C-, HF2C-, FHC-, methyl, HN- and (CH) 2N-.
-16MA
35575Β1
Boehringer Ingelheim International GmbH P01-2655 / PCT
PCT / EP2011 / 063705
Embodiment 8 of the present invention: another embodiment of the invention relates to a compound of general formula (I), in which r ': is a heteroaryl group selected from the group consisting of [1,3,4] thiadiazol-2-yl, isoxazol-5-yl, thiaz01-5-yl, oxazol-2-yfe, pyridin-2-yl and pyrimidin2- yl, said heteroaryl group being preferably selected from the group consisting of [1,3,4] thiadiazol-2-yl, isoxazol-5-yl, thiazol-5-yl, üxazol-2-yl and pyrimidin-2- groups yl, said heteroaryl group possibly being optionally substituted by 1 or 2 substituents, said substituents being independently selectable from the group consisting of fluorine, chlorine, bromine, CN-, a methyl group and
R<sup>2</sup> : is selected from the group consisting of fluorine, NC-, F.٦C-, HC-, FHC- and a methyl group, preferably fluorine, NC-, FC- and a methyl group;
D: is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl, where cyclopentyl and cyclohexyl may be optionally substituted with 1 or 2 substituents, said substituents possibly being independently crystalline. one from the other in the group consisting of fluorine, F3C-, HC- and FHC-; preferably, by fluorine;
the tetrahydrofuranyl and tetrahvdropyranyl groups being optionally substituted with 1 or 2 substituents, said substituents being independently selectable from the group consisting of fluorine, FC-, HCetFHC-;
the pyridine group being optionally substituted with 1, 2, 3 or 4, preferably by 1, 2 or 3, more preferably by 1 or 2, substituents, said substituents being independently selectable from the group consisting of fluorine, chlorine, bromine, NC-, F3C-, HC-, FHC-, F3C-CH2- and a methyl group;
D preferably being selected from the group consisting of 4,4difluorocyclohex-1-yl, tetrahydropyranyl groups, compounds thereof, preferably tetrahydropyran-4-yl group, and 4-methyl-3-pyridyl group;
m: is chosen from 1 or 2, m preferably being 1;
نم '
-17MK
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Boehringer Ingelheim International GmbH PO1-2655 / PC7
PCT / EP2011 / 063705 n: is chosen from 0, ا or 2, n preferably being 0 or 1, n more preferably being 0, if n: 2, these two groups R<sup>2</sup> being chosen independently of one another;
and salts, preferably, its pharmaceutically acceptable salts, its solvates and the solvates of its salts mentioned above.
Embodiments 9 to 16 of the present invention:
In any of the above embodiments 1 to 8, the preferred compounds are represented by the formula (II):
Compounds of formula (II)
<img file="MA35575B1_D0010.tif" />
with r ': as defined in any of the aforementioned embodiments 1 to 8;
D being either a 4,4-difiuorocyclohexyl group, or a tetrahydropyran-4-yl group or else a 4-methyl-3-pyridyl group and neither of these two groups having other substituents;
and salts, preferably their pharmaceutically acceptable salts, their solvates and the solvates of their salts mentioned above, provided that the compound is not the following oxadiazolyl derivative
-18Mk؟ 57 <؟ ٦> Β٩
Boehringer Ingelheim International GmbH P01-2655 / PCT
PC1 / EP2611 / 063705
<img file="MA35575B1_D0011.tif" />
whether it be in the form of any possible seoisomer or else of a mixture of all or part of these or of one of their salts or of their solvates or of a solvate of one of their salts.
Preferred embodiments 9 to 16 of formula (II) follow from the embodiments of formula (I) in that:
m is 1 in formula (I), so that the corresponding cycloalkyl group is a cyclobutyl group;
n is 0 in formula (I);
D, in formula (I), is selected from the group consisting of 4,4difluorocyclohexyl (without other substituents, i.e., unsubstituted) and tetrahydropyran4-yl (without other substituents, i.e. (i.e., unsubstituted) and 4-methyl! -3-pyridyl;
r ', in formula (I), is fixed to said aforementioned cyclobutyl group (m = 1) in its 2 position while position 1 of said cyclobutyl group is the point of attachment at position 6 of the D-substituted pyrazolopyrimidinone.
The corresponding embodiments are referred to as Embodiments 9, 10, 11, 12, 13, 14, 15 and 16, respectively.
Embodiment 9 is derived from Embodiment 1, Embodiment 10 from Embodiment 2, Embodiment 11 from Embodiment 3, Embodiment 12 from Embodiment 4, Embodiment 13 of Embodiment 6, Embodiment 14 of Embodiment 6, Embodiment 15 of Embodiment 7, and Embodiment 16 of Embodiment 7.
Embodiments 17-24 of the present invention:
<img file="MA35575B1_D0012.tif" />
MY
35575Β1
Boehringer Ingelheim International GmbH P01-2655 / PCT
PC ΕΡ2011 / 063705
In each of the aforementioned embodiments 1 to 16, the more preferred compounds are represented by the formula (II):
O
<img file="MA35575B1_D0013.tif" />
with r ': as defined in any of the aforementioned embodiments 1 to 8;
D being either a 4,4-difluorocyclohexyl group or a tetrahydropyran-4-yl group and neither having other substituents;
and salts, preferably their pharmaceutically acceptable salts, their solvates and the solvates of their salts mentioned above.
provided that the compound is not the following oxadiazolyl derivative
<img file="MA35575B1_D0014.tif" />
whether it be in the form of any possible stereoisomer or else of a mixture of all or part of these or of one of their salts or of their solvates or of a solvate of one of their salts.
-20MA
35575Β1
Boehringer Ingelheim International GmbH
P01-2655 / PCT
PCT ΕΡ2011063705
For all embodiments 1 to 24: the configuration of the cycloalkyl group in position 6 of the pyrazolopyrimidinone group relative to said pyrazolopyrimidinone group and of the R substituent<sup>1</sup> can be cis or trans.
With this in mind, the compounds of the invention can have the following configurations:
<td>1 trans configuration</td><td>2 trans configuration</td>
<td>0 ٩ ئيئس ١٢١٦ ا ٦١ ح</td><td>0 حيي ” D لحصد (<sup>2</sup>*)</td>
<td>Configuration 1 cis</td><td>Configuration 2 cis</td>
<td>0 تيبنل ۶ م ١ (R2) n٦ D ٦٧١٦٢١</td><td>0 ؟ بجع</td>
R), R<sup>2</sup>, m, netD being as defined in any of the embodiments
These stereochemically defined embodiments represent a further aspect of the invention.
Embodiment 25 of the present invention:
In the context of the present invention, one or more compound (s) chosen from the group of categories specifically defined as listed in the following table are preferred. The left column contains a letter code to identify the compound family, which is the group of compounds having the same structural chemical formula without taking into account steochemical properties. Members of these families of compounds
-2135575Β1
Mk
Boehringer Ingelheim International GmbH PO1-2655 / PC1
PC٢ / EP2011 / 063705 are given by way of examples in the chapter Embodiments given by way of examples.
Category table:
<td>AT</td><td>0 لآلآ Compound family A, example explanatory 1</td>
<td>AT at</td><td>0 لآش</td>
<td>AT b</td><td>0 لآبع</td>
<img file="MA35575B1_D0015.tif" />
Family of compounds B, explanatory example 2
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PCT / EP2011 / 063705
<img file="MA35575B1_D0016.tif" />
<td>vs at</td><td> 0</td>
<td>vs b</td><td>0 ٦٨Q نح</td>
<td>vs vs</td><td>0 وم ٩ رح</td>
<td>vs d</td><td>0 ٨١ 0 ء ئردخ</td>
<td>D</td><td><ملآي ه Compound family D, example</td>
-23MA
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P01-2655 / PCT
PCT / EP2011 / 063705
<td colspan="2">Boehringer Ingelheim International GmbH</td>
<td></td><td>explanatory 4</td>
<td>D at</td><td>حم ٦ ح</td>
<td>D b</td><td>اضغ</td>
<td>D vs</td><td>ز</td>
<td>D d</td><td>لأي ي ٦ ةي ٠ ٦F</td>
<td>E</td><td>0 Compound family E, explanatory example 5</td>
<td>E a</td><td> 0</td>
<td>E b</td><td>0 اض -9 تر</td>
<td>E c</td><td>0 ألابي</td>
كل
-24ΜΑ 35575Β1
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P01-2655 / PCT
PCT7EP2011 / 063705
<td>E d</td><td>0 لآع ٩</td>
<td>F</td><td>0 لآير Compound family F, example explanatory 6</td>
<td>F a</td><td> 0</td>
<td>F b</td><td> 0 ٥٩</td>
<td>F c</td><td>0 لآي</td>
<td>F d</td><td> 0 ٥٩</td>
<td>G 1</td><td>0 ٩٩ Gl compound family, example explanatory 7</td>
<td>G the</td><td> 0</td>
-25MA
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Boehringer Ingelheim International GmbH PO1-2655 / PC1
PCT / EP2011 / 063705
<img file="MA35575B1_D0017.tif" />
<img file="MA35575B1_D0018.tif" />
<img file="MA35575B1_D0019.tif" />
<img file="MA35575B1_D0020.tif" />
Family of compounds G2, explanatory example 8
-26ΜΑ 35575Β1
Boehringer Ingelheim International GmbH P01-2655 / PCT
<img file="MA35575B1_D0021.tif" />
<td>H</td><td>حتلم لمغ \ ر<sup>ة</sup>HI compound family, example explanatory?</td>
<td>H the</td><td>0 , 9 تخ</td>
<td>H lb</td><td> 0</td>
<td>H lc</td><td>0 ٦؟ م<sub>ح</sub></td>
-٦٦MA
35575Β1
Boehringer Ingelheim International GmbH
<img file="MA35575B1_D0022.tif" />
P01-2655 / PCT
<img file="MA35575B1_D0023.tif" />
-2835575Β1
MY
Boehringer Ingelheim International GmbH
P01-2655 / PCT
PC ΕΡ2011 / 063705
<img file="MA35575B1_D0024.tif" />
<td>K</td><td>0 خدب 0¾ Compound family K, examples explanatory notes 13, 14 and 15</td>
<td>K at</td><td>0 خلفه زد</td>
<td>K b</td><td> 0 ;</td>
<td>K vs</td><td>0 خنيه زغ</td>
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PO1-2655 / PC1
PCT / EP2011 / 063705
<td>K d</td><td> 0 ٥٧٠</td>
<td>L</td><td>0 5 ٤٠ Family of compounds L, explanatory example 16</td>
<td>The</td><td> 0</td>
<td>L b</td><td> ٢١ ؟٥</td>
<td>L c</td><td>0 ف ؤ و ٦</td>
<td>L d</td><td>0 ؤ ح)</td>
<td>M</td><td>٩ M compounds family, examples explanatory notes 17, 18 and 19</td>
<td>M at</td><td> ٦١'</td>
-30MA
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Boehringer Ingelheim International GmbH P01-2655 / PCT
PC ΕΡ2011 / 063705
<td>M b</td><td>٦٩ ب</td>
<td>M vs</td><td> ٩</td>
<td>M d</td><td>١ ي ١٥ أس ح</td>
<td>NOT</td><td>لأ د ٦ Compound family N, example explanatory 20</td>
<td>NOT at</td><td></td>
<td></td><td></td>
<td>NOT b</td><td> ٦ ١١٨ ١٦۶٥٠</td>
<td>NOT vs</td><td> ١١١١ /٦١</td>
<td>NOT d</td><td>0 ل ١١١ لأ ٦ U ٦ ع''٠</td>
<td> 0</td><td>٠ ٩J١ h Compound family 0, example explanatory 21</td>
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/ د
P01-2655 / PCT
<img file="MA35575B1_D0025.tif" />
Boehringer Ingelheim International GmbH
<td>0 at</td><td>0 ٩٩ ة</td>
<td>0 h</td><td>0 ٦٦٩ h</td>
<td>0 vs</td><td>0 ؛ ٩٦٩ ه</td>
<td>0 d</td><td>0 ٢٢٦ تمت ٦ عمدخ ح</td>
<td>p</td><td>0 ٩ زع ٠۶ ة</td>
-لآ P01-2xxx-Prio
PCT / EP2011 / 063705
UK
35575Β1
Boehringer Ingelheim
<img file="MA35575B1_D0026.tif" />
<img file="MA35575B1_D0027.tif" />
-33PO1-2655 C
PC7 / EP2011 / 063705
UK
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Boehringer Ingelheim International GmbH
<img file="MA35575B1_D0028.tif" />
<td>s</td><td>0 Family of compounds, examples explanatory notes 32, 33 and 34</td>
<td>s at</td><td>Tl</td>
<td>s h</td><td>0 ηνΛ٢١ | حخلراغلآع</td>
<td>s vs</td><td> 0 ؛٠</td>
-34UK
35575Β1
Boehringer Ingelheim International GmbH
PO1-2655 / PC7
<td></td><td></td>
<td>S d</td><td>0 Η | ٢ν خ ٥٨ لا b</td>
<td>T</td><td>0 ع ؤأ b Family of T compounds, examples explanations 26, 27 and 28</td>
<td>T a</td><td>0 ٥; لا ور</td>
PCF / EP2011 / 063705
<td>T b</td><td>0 ع y</td>
<td>T vs</td><td>0 ع</td>
<td>T d</td><td>0 ΗΝ٦Ρν ٠ '، Ν٦٧ لا ئ.</td>
and salts, preferably their pharmaceutically acceptable salts, their solvates and the solvates of their salts mentioned above.
-35MN
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PCI / EP2011 / 063705
In the latter group of compounds, those which exhibit a trans configuration with respect to substitution at the cyclobutyl group may be preferred over compounds having a cis configuration. Among the possible compounds of trans configuration, one of them may have advantages in terms of efficiency. The more effective a compound, the more it is among the preferred compounds. Another criterion which can differentiate the preferred compounds according to the invention is the efficacy / safety balance, for example the selectivity with respect to other members of the PDE family such as PDEIC.
For a pair of compounds of trans configuration according to the experimental part, single crystal stricture by X-ray diffraction revealed that the absolute stereochemistry of the compound less efficient than its enantiomer is R, R. Therefore, the absolute stereochemistry of the most efficient compound is s, s.
For said compound, the s, s configuration is represented by the following structure of general formula (II):
<img file="MA35575B1_D0029.tif" />
By analogy, it can be assumed that among the compounds according to embodiment 25, these compounds exhibiting the same absolute stereochemistry could be the most active compared to other members of the same family of compounds. According to the present invention, in the same family of compounds, the most active compounds are preferred to the less active compounds. The family of compounds is the group of compounds whose chemical structure differs only in steochemical properties.
The different stereoisomers are the subject of individual embodiments according to the invention:
Embodiment 26 of the present invention relates to a compound according to any one of embodiments 1 to 25, the compound having the following stereochemical properties:
-36MA
35575Β1
Boehringer Ingelheim International GmbH
P01-2655 / PCT
PC17EP2011 / 063705 if the compound can be generally represented by the formula (I):
if the compound can generally be represented by formula (II):
O
<img file="MA35575B1_D0030.tif" />
<img file="MA35575B1_D0031.tif" />
(Ha).
Embodiment 27 of the present invention relates to a compound according to any one of Embodiments 1 to 25, the compound exhibiting the following stereochemical properties:
if the compound can be generally if the compound can be generally represented by the formula (I):
represented by formula (II):
<img file="MA35575B1_D0032.tif" />
(Ib),
<img file="MA35575B1_D0033.tif" />
(He b).
Embodiment 28 of the present invention relates to a compound according to any one of Embodiments 1 to 25, the compound having the following stereochemical properties:
-١٩MA
35575Β1
Boehringer Ingelheim International GmbH Ρ01-2655 / ΡCT
PCT / EP2011 / 063705 if the compound can be generally if the compound can be generally represented by the formula (I):
represents by formula (II):
<img file="MA35575B1_D0034.tif" />
<img file="MA35575B1_D0035.tif" />
(Isle).
Embodiment 29 of the present invention relates to a compound according to any one of embodiments 1 to 25, the compound having the following stereochemical properties:
if the compound can be generally if the compound can be generally represented by the formula (I): represented by the formula (II):
<img file="MA35575B1_D0036.tif" />
(Id),
<img file="MA35575B1_D0037.tif" />
(He d).
Embodiment of the present invention: Another set of preferred embodiments of the present invention derive from each of the aforementioned embodiments relating to compounds of formula (I) or (II), including preferences relating to their stereochemical properties , in that :
r 'is a pyrimidinyl or pyridyl group, preferably pyrimidin-2-yl or pyridin2-yl, ml n = 0 and
D is selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl groups.
-38I
35575Β1
Boehringer Ingelheim International GmbH P01-2655 / PCT
PC ΕΡ2011 / 063705 where the cvclopentvle and cyclohexyl groups may be optionally substituted with 1 or 2 substituents, said substituents may be independently selected from the group consisting of fluorine, FC-, HC- and FHC-; preferably, by fluorine;
tetrahydroofuranvle groups. tetrahvdropvranyl may be substituted with 1 or 2 substituents, said substituents may be selected independently of one another from the group consisting of fluorine, F3C-, HC- and FHC-;
the pyridine group being optionally substituted with 1, 2, 3 or 4, preferably 1, 2 or 3, more preferably 1 or 2, substituents, said substituents may be selected independently of each other from the group consisting of fluorine , chlorine, bromine, NC-, FC-, HC-, Fie-, F3C-CH2- and a methyl group;
D being preferably chosen from the group consisting of 4.4difluorocyclohex-1-yl, tetrahydropyranyl and 4-methyl-3-pyridyfe groups and salts, preferably their pharmaceutically acceptable salts, their solvates and the solvates of their aforementioned salts.
For each of embodiments 1 to 30: whenever D can be a tetrahydrofuranyl group, it is preferably a tetrahydrofuran-3-yl group; whenever D may be a tetrahydropyranyl group, it is preferably a tetrahydropyran-3-yl or tetrahydropyran-4-yl group, more preferably a tetrahydropyran-4-yl group.
For each of embodiments 1 to 30: the heteroaryl group r 'is preferably bonded, via one of its carbon ring atoms, to the cycloalkyl group which is attached at position 6 of the pyrazolopyrimidinone ("scaffold") structure. According to general formula (I), said cycloalkyl group may be a cyclobutyl or cyclopentyl group, and according to general formula (II), said cycloalkyl group is a cyclobutyl group.
I
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TERMS AND DEFINITIONS
It is necessary to give the terms not specifically defined herein the meanings which a person skilled in the art would have attributed to them in the light of the description and the context. Examples include that these specific substituents or atoms are shown with their 1 or 2 letter code, such as H for hydrogen, N for nitrogen, c for carbon, 0 for oxygen, s for sulfur and the like. Optionally, but not required, this letter is followed by a hyphen to indicate a link. As used in the description, unless otherwise indicated, the following terms have the meanings indicated and the following conventions are attached thereto.
In the groups, radicals or fragments defined below, the number of carbon atoms is often specified after the group, for example, “C 1 -C 6 alkyl group” denotes an alkyl group or an alkyl radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last group named is the point of attachment of the radical, for example "(CH) 2N-" denotes a monovalent radical of formula (HN- which is fixed via its atom nitrogen (i.e., a dimethylamino substituent). If the substituent term is preceded or followed by a "minus" sign or a hyphen, namely -, this sign highlights the point of attachment as in example (CH) 2Ν above, in which N is bonded to the group of which the dimethylamino group is a substituent. Unless stated otherwise specified below, conventional definitions of term control and conventional stable atom valencies are assumed and obtained in all formulas and groups.
In general, if the terms are defined specifically with a given context, these specific definitions must prevail over the more general definitions as this paragraph underlines.
In general, all “tautomeric forms and isomeric forms and mixtures” are provided for, whether they are individual geometric isomers, optical isomers or else racemic or non-racemic mixtures of isomers, of a structure or of a mixture. chemical compound, unless the specific stereochemistry or isomeric form is specifically indicated in the name or structure of the compound. Specific definitions prevail.
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PC17EP2011 / 063705 "Substitution": the term "substitutes" as it is expressed in the present in an explicit or implicit manner, means that one or more atoms of hydrogen whatever on the designated atom is / are replaced by a member of the indicated group of substituents, provided that it does not exceed the normal valence of the designated atom. In the case where a substituent is linked via a double bond, for example an oxo substituent, that substituent replaces two hydrogen atoms on the designated atom. The substitution should produce a stable compound. In this context, "stable" preferably denotes a compound which, from a pharmaceutical point of view, is sufficiently stable chemically and physically in order to be used as the active principle of a pharmaceutical composition. If a substituent is not defined, it should be hydrogen. By the terms "optionally substituted" is meant that the corresponding group is either substituted or unsubstituted. A feature which is that the substituents of the same group can be "chosen independently of each other" should mean that the corresponding substituents can be the same or different.
The expression “pharmaceutically acceptable” is used herein for the purpose of designating those compounds, products, compositions and / or presentations which are, within the framework of sound medical opinion, suitable for contact with tissue. human or animal origin where appropriate, without causing toxicity, irritation, allergic response or any other serious problem or complication, in proportion to a reasonable benefit / risk ratio.
The “pharmaceutically acceptable salt (s)” of the compounds according to the invention also constitute the subject of the present invention. The terms “pharmaceutically acceptable salt (s) (؟)” refer to derivatives of the disclosed compounds, the parent compound being modified by producing acid or base salts thereof, preferably addition salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic moieties / parts of compounds of the present invention such as amino functions; the acidic residues / moieties in the compounds of the present invention can form salts with alkaline or organic bases. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example from non-toxic organic or inorganic acids. For example, these non-toxic salts
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Conventional PCT / EP2011 / 063705 include those which are derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, acid. tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenz0ic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid and the like.
Physiologically acceptable salts with bases can also include salts with conventional bases such as, for example and preferably, alkali metal salts (eg, sodium and potassium salts), alkaline earth metal salts. (eg, calcium and magnesium salts) and ammonia, organic amines having 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, lethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methyl-morpholine, dehydroabiethylamine, arginine, lysine, ethylenediamine and methylpiperidine analogues.
Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound with acidic or basic properties by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or basic form of these compounds with a stoichiometric amount of the base or of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally preferred are non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
A "prodrug" is considered to be a compound designed to release in vivo a biologically active compound according to the invention when this prodrug is administered to a mammalian subject. Prodrugs of compounds according to
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PCT / EP2011 / 063705 present invention are prepared by modifying the functional groups present in the compound of the invention such that these modifications are transformed back to the original functional groups under physiological conditions. It will be noted that the prodrugs of the compounds according to the present invention are also the subject of the present invention.
The “metabolites” are considered to be derivatives of the compounds according to the present invention which are formed in vivo. Active metabolites are those metabolites which have a pharmacological effect. It will be noted that the metabolites of the compounds according to the present invention are also the subject of the present invention, in particular the active metabolites.
Some of the compounds can form "solvates". For the purposes of the present invention, the term “solvates” refers to those forms of the compounds which constitute, in the solid or liquid state, a complex by coordination with solvent molecules. Hydrates are a specific form of solvates in which coordination takes place with water. According to the present invention, the term is preferably used for solid solvates, for example amorphous solvates or more preferably, for crystalline solvates.
“Structure” (“scaffold”): the structure of the compounds according to the present invention is represented by the following fundamental structure. The numbering of the positions of the ring atoms is indicated in bold:
<img file="MA35575B1_D0038.tif" />
It will be obvious to those skilled in the art that this structure can be described by its tautomeric “enol” form.
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P01-2655 / PCT
PC٢ / EP2011 / 063705
<img file="MA35575B1_D0039.tif" />
In the context of the present invention, the two representations of the structure should be considered as being the object of the present invention, even if only one of the two representations is presented. Without being limited or bound by theory, it is believed that for the majority of compounds under ambient conditions and also under conditions which are the proper conditions for a pharmaceutical composition comprising said compounds, the balance of the tautomeric forms relies on the representation of pyrazolopyrimidin-4-one. Therefore, all embodiments are presented as derivatives of pyrazolopyrimidin-4-one or more specifically, as derivatives of pyrazo [3,4-d] pyrimidin-4-one.
"Bonds": If in a chemical formula of a ring system or a defined group a substituent is directly bonded to an atom or group such as "RyR" in the formula below, it should say that the substituent is only attached to the corresponding atom. If, however, from another substituent such as "RxR", a bond is not specifically linked to an atom of the ring system but drawn towards the center of the ring or group, this means that this "RxR" substituent may be bonded to any relevant atom of the ring / group system, unless otherwise specified.
RyR \ Z \ RxR ^^
The link symbol "-" (= "minus" sign) or the symbol "-٠" (= "minus" sign followed by an asterisk) represents the link by which a substituent is linked to the corresponding remaining part of the molecule. /structure. In cases where the minus sign does not seem sufficiently clear, there is the possibility of adding an asterisk to the symbol of.
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PC17EP2011 / 063705 "-" bond in order to determine the point of attachment of said bond to the corresponding main part of the molecule / structure.
The terms "C 1 -C٥ alkyl" denote a saturated linear or branched hydrocarbon group with 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, i-propyl, ، '.؟ O-propyl, butyl, /. St-butyl,.؟ Ec-butyl, rert-butyl, rr-pentyl, iso-pentyl. , neo-pentyl, ، ert-pentyl, n-hexyl or No-hexyl.
This definition applies to the use of "alkyl" in any reasonable context of the present invention in the absence of any other definition.
The term "C3-C7 cycloalkyl" refers to a saturated monocyclic group having 3 to 7 ring carbon atoms. Preferred are 5- or 6-membered cycloalkyl groups. There are no ring atoms other than carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. This definition applies to "cycloalkyl" in any reasonable context of this specification in the absence of any other definition.
The term "heteroaryl" used in this application denotes a heterocyclic, monocyclic aromatic ring system which comprises, in the ring system proper, in addition to at least one carbon atom, one or more heteroatoms which are independently selected from N , o and / or s. Preferred are heteroaryls having 1 to 3 heteroatoms or 1 or 2 heteroatoms or else 1 heteroatom. The preferred heteroatom is N.
The term "pyridyl" defines a pyridine substituent, sometimes also referred to as pyridinyl.
Expressions such as "prevention", "prophylaxis", "prophylactic treatment" or "preventive treatment" used herein should be understood as being synonymous and in the sense that the risk of developing a disease mentioned above is reduced, especially in a patient at high risk of developing said diseases or having a corresponding history. Thus, the term "disease prevention" as used herein refers to the management
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PC17EP2011 / 063705 and the care of an individual at risk of developing the disease before the clinical onset of the disease. The purpose of prevention is to control the development of the disease, condition or disorder and includes the administration of active compounds to prevent or delay the onset of symptoms or complications and to prevent or delay the development. associated diseases, conditions or disorders. The success of said preventive treatment is statistically reflected by the reduced incidence of said disease in a population at risk for this disease compared to an equivalent patient population not receiving preventive treatment.
The expression “treatment” or “therapy” preferably designates a therapeutic treatment intended for patients (preferably human, for example) who have already developed one or more of said diseases in manifest, acute or chronic form, including symptomatic treatment to alleviate symptoms of the specific indication or causal treatment to reverse or partially reverse the disease or to delay progression of the indication for as long as possible, depending on the disease and its severity. Thus, the term "treatment of a disease" as used herein refers to the management and care of a patient who has developed the disease, condition or disorder. The goal of treatment is to combat the disease, condition, disorder or one of their symptoms. Treatment includes administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate symptoms or complications associated with the disease, condition or disorder.
The following schemes generally illustrate how to prepare the compounds of the present invention by way of example. Abbreviated substituents may be as defined for embodiments of formula (I) if not otherwise defined in the context of the schemes:
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Diagram 1
PO1-2655 / PCÎ
PCT / EP2611 / 063705
<td>OCH</td><td>/ NH<sub>2</sub></td><td rowspan="2">And<sub>3</sub>N / Et0H</td>
<td>NC٧ -٠</td><td>HN</td>
<td>CN</td><td>D</td><td>heat</td>
٢٦N
Η<sub>2</sub>Ν٨? /
<img file="MA35575B1_D0040.tif" />
<td></td><td> 0</td><td></td><td> +</td>
<td></td><td>د ل \ Η</td><td></td><td>NaH / EtOH</td>
<td> 0</td><td></td><td>م</td><td></td>
<td></td><td>Njj HI ٦ رض</td><td>/NOT</td><td></td>
<td>\ r \</td><td></td><td>١Ν</td><td>then NaOH</td>
<td>(R2) n— ،</td><td>ط ر ٢</td><td>D</td><td>(voiel)</td>
See
Diagram 2 (channel 2) νη<sub>3</sub>, η<sub>2</sub>0<sub>2</sub>
Et0H / H<sub>2</sub>0
<img file="MA35575B1_D0041.tif" />
Η<sub>2</sub>Ν 'Γ
D
<img file="MA35575B1_D0042.tif" />
NaHZEtOH
<img file="MA35575B1_D0043.tif" />
Scheme 1: In a first step, 2-ethoxymethylenemalononitrile is condensed with monosubstituted hydrazines by heating in an appropriate solvent (eg ethanol) in the presence of a base (eg triethylamine) to form the corresponding 5-amino-1 H-pyrazole-4-carbonitriles. In a second step, these compounds are converted to the corresponding amides, for example by treating them with an ethanolic solution with ammonia (25٥ / ο in water) and hydrogen peroxide.
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PCT / EP2011 / 063705 (35% in water). In a third step, heating with acid diesters under basic conditions (eg, sodium hydride in ethanol) followed by the addition of aqueous sodium hydroxide produces carboxylic acids. substituted by a 4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl group (lane 1). Their carboxylic acid functional group is converted to a heteroaryl group as described in Scheme 2, yielding pyrazO10 [3,4-d] pyrimidin-4-0nes as end products. Alternatively, nitriles substituted with a 4-oxo-4,5-dihydro-1H-pyrazolo [3,4d] pyrimidin-6-yl group can be synthesized from dinitriles by heating under basic conditions (e.g. (sodium hydride in ethanol) in the third step (route 2). The nitrile functional group is further converted to heteroaryl substituents as described in Scheme 3, yielding pyrazO10 [3,4-d] pyrimidin-4-0nes as end products, [see for example, A. Miyashita et al. , Heterocycles 1990, 31, 1309 et seq.].
Diagram 2
<img file="MA35575B1_D0044.tif" />
Scheme 2; the carboxylic acids substituted with a 4-oxo-4,5-dihydro-1Hpyraz010 [3,4-d] pyrimidin-6-yl group are treated under the conditions listed in the table below to form pyrazo! o [3,4 -d] py'rimidin-4-ones substituted with a heteroaryl group as end products. R<sup>at</sup> is a substituent of R<sup>1</sup>.
<td>Conditions as mentioned in diagram 2</td><td>R '</td><td>R<sup>at</sup></td>
<td>1.) Reaction with HATU and DIPEA followed by a carboxylic acid hydrazide. 2.) Treatment with Lawesson's reagent</td><td>٩/٦ ه 0</td><td>H-, FC-, HC-, FHC-, group methyl</td>
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<td>in THF at high temperature.</td><td></td><td></td>
<td>1.) Reaction with oxalyl chloride in THF followed by treatment with trimethylsilyldiazomethane then hydrochloric acid in dioxane. 2.) Reaction with a thioamide in EtOH.</td><td>أ</td><td>Η-١ F C-, HF2C-, FHC-, group methyl</td>
<td>1.) Reaction with oxalyl chloride in THF followed by treatment with trimethylsilyldiazomethane then hydrochloric acid in dioxane. 2.) Reaction with a thiouee in FEtOH.</td><td></td><td>H-, F3C-, HF2C-, FHC-. group methyl</td>
<td>3.) Reaction with oxalyl chloride in THF followed by treatment with trimethylsilyldiazomethane then hydrochloric acid in dioxane. 4.) Reaction with a thiourea in FEtOH.</td><td>ؤج</td><td>HN-, (CH N-</td>
<td>1.) Reaction with TBTU and DIPEA followed by 2-aminoalcohol. 2.) Oxidation with DessMartin periodinane in dichloromethane. 3.) Treatment with Burgess Reagent in DME at high temperature.</td><td>دج ه 0</td><td>H-, NC-, F3C-, HFC-, FHC-, methyl group</td>
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<td>1.) Reaction with TBTU and DIPEA followed by 2-aminocetone hydrochloride. 2.) Treatment with Burgess's reagent in high temperature DME.</td><td><sup>R</sup>o ٠ د 0</td><td>H-, NC-, F3C-, HC-, FHC-, methyl group</td>
<td>1.) Reaction with TBTU and DIPEA followed by 2-aminoalcohol. 2.) Oxidation with DessMartin periodinane in dichloromethane. 3.) Treatment with Lawesson's reagent in THF at high temperature.</td><td>لآ</td><td>H-, NC-, FC-, HFC, FHC-, methyl group</td>
<td>1.) Reaction with TBTU and DIPEA followed by 2-aminoceton hydrochloride. 2.) Treatment with Lawesson's reagent in THF at high temperature.</td><td>لآ</td><td>H-, NC-, F3C-, HF2C-, FHC-,</td>
<td>1.) Reaction with TBTU and DIPEA followed by drr 1,2-dimethylhydroxylamine hydrochloride. 2.) Reaction with a separately prepared mixture of propan-2-one-oxime and nbutyllithium followed by treatment with sulfuric acid in THF / water.</td><td>Ν١٦ * ن</td><td></td>
<td>1.) Reaction with TBTU and DIPEA followed by hydrazine hydrate. 2.) Treatment with high temperature triethoxymethane.</td><td>لآ</td><td></td>
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Diagram 3
<img file="MA35575B1_D0045.tif" />
1.) Acetyl chloride.
<img file="MA35575B1_D0046.tif" />
ethanol heat
<img file="MA35575B1_D0047.tif" />
<img file="MA35575B1_D0048.tif" />
with
Rx = Me, And
R NC-, F3C-,
HFC-, FH2C-, methyl, HScheme 3: Nitriles substituted with a 4-oxo-4,5-dihydro-1H5 pyraz010 [3,4-d] pyrimidin-6-yl group are mixed with methanol and treated. with acetyl chloride or alternatively they are mixed with a saturated solution of hydrochloric acid in ethanol. The intermediates are treated in a second step with an ammoniacal solution in methanol to form the corresponding amidines. Reaction with 1,1,3,3-tetraalkoxypropane gives pyraz010 [3,4-dJpyrimidin-4-0nes substituted with pyrimidin-2-yl group as end products.
Other alternative procedures for preparing pyraz010 [3,4-d] pyrimidin-4-0nes are known in the art and can likewise be used to synthesize the compounds of the invention (see for example: P. Schmidt el al., Helvetica Chimica Acta 1962, 189, 1620 et seq.).
Diagram 4
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<img file="MA35575B1_D0049.tif" />
P01-2655 / PCT
<img file="MA35575B1_D0050.tif" />
OR
<img file="MA35575B1_D0051.tif" />
is an optionally substituted cyclopentyl OR cyclohexyl group as defined in formula (I). Therefore, n = 1 or 2
Scheme 4: The monosubstituted hydrazine derivatives which are used in step 1 of scheme 1 can be prepared by reductive amination of a ketone with the tert-butyl ester of hydrazinecarboxylic acid followed by a deprotection step. as shown in Scheme 4 for a D which is a cyclopentyl or cyclohexyl group as defined in general formula (I) (see e.g., Jw Timberlake et al., ،، Chemistry of Hydrazo-, Azoand Azoxy Groups ”; Patai, s., Ed .; ATI 5, Chapter 4 '. ، Sc ١٦٠ et at .. Journal of Organic Chemistry 1981, 46, 5413-5414].
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Diagram 5
«.٦٩
ΝΗ3, ΗΟ2 EtOHHO
<img file="MA35575B1_D0052.tif" />
<img file="MA35575B1_D0053.tif" />
Diagram 5: as described in
Scheme 1, 2-ethoxymethylamine 5-malononitrile is condensed with monosubstituted hydrazines by heating in a suitable solvent (eg ethanol) in the presence of a base (eg triethylamine) to form 5-amino-1H -pyrazole-4-carbonitriles corresponding. In a second step, these compounds are transformed into corresponding amides, for example by treating them with an ethanolic solution with ammonia (25٥ / ο in water) and hydrogen peroxide (35٥ / ο in some water). In a third step, heating with the ester of cyclobutylor cyclopentylcarboxylic acid substitutes by r 'and R<sup>2</sup> under basic conditions (eg.
sodium hydride in ethanol) yields pyrazolo [3,4-d] pyrimidm-4-ones as end products, [see, e.g., A. Miyashita et al., Heterocycles 1990, 31, 1309 et al. monitoring.
This procedure is described in more detail with r 'which is a pyridinyl group, m which is equal to 1 and n which is equal to 0 in the experimental chapter (examples 29 to 32).
Further information can also be found in:
wo 2004/099210 (especially page 9, last paragraph through page 14, line 8, incorporated herein by reference).
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PC7 / EP2011 / 063705 concerning the general preparation of the compounds, D being a group 'WO2009 / 121919 discloses other information, in particular on pages 120 to 125 as well as in its experimental part (incorporated herewith by way of reference), concerning D which is a 4,4-difluorocyclohexyl group, wo 2010/026214 discloses other information, in particular on pages 59 to 63 as well as in its experimental part (incorporated herewith by way of reference), and in the experimental part (embodiments given by way of examples) of this description; in particular concerning the preparation of the two structural elements:
<img file="MA35575B1_D0054.tif" />
TREATMENT METHOD
The present invention relates to compounds which are believed to be effective in treating diseases. The compounds according to the invention are both effective and selective inhibitors of phosphodiesterase 9Α and they can be used for drug development. These drugs should preferably be used to treat diseases for which inhibition of PDE9A may provide a therapeutic, prophylactic or disease modifying effect. Medicines should preferably be used in order to improve perception, concentration, cognition, learning or memory, such as those which Ι'οη uses in particular to treat situations / diseases / syndromes such as:
moderate cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, traumatic brain injury, stroke, dementia following stroke (dementia post-stroke), post-traumatic dementia, general concentration disorders, concentration disorders in children with learning and memory disorders, Alzheimer's disease,
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PCT / EP2011 / 063765 Lewy body dementia, dementia with frontal lobe degeneration including Pick's syndrome, Parkinson's disease, progressive supranuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob disease, HIV-related dementia, epilepsy, temporal lobe epilepsy, schizophrenia, schizophrenia (associated with dementia), Korsakoff syndrome or cognitive impairment associated with depression or bipolar disorder.
Another aspect of the present invention may relate to the treatment of a disease which can be achieved by modulating PDE9A, in particular sleep disorders such as insomnia or narcolepsy, bipolar disorders, metabolic syndrome, obesity, diabetes mellitus, including type 1 or 2 diabetes, hyperglycemia, dyslipidemia, glucose intolerance or disease of the testes, brain, small intestine, skeletal muscles, heart, lungs, thymus or spleen.
The medical aspect of the present invention can therefore be summarized in that it is considered that a compound of formula (I) or (II) as defined herein, in particular the compounds of the categories defined in a specific manner, is used as drug.
This medicament is preferably used in a method for treating CNS disease.
In the case of another use, the medicament is for use in a therapeutic or prophylactic method, preferably a therapeutic method, to treat a CNS disease which can be treated by inhibiting PDE9.
In the case of another use, the medicament is intended for use in a therapeutic or prophylactic process, preferably a therapeutic process, in order to treat a disease which can be treated by inhibiting PDE9 and in particular PDE9A.
In another most preferred use, the medicament is for use in a therapeutic or prophylactic method, preferably a therapeutic method, in order to treat, ameliorate and / or prevent cognitive disorders related to the disease. perception, concentration, cognition, learning or memory, preferably
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PCT / EP2011 / 063705 if this type of cognitive impairment is associated with a disease or disorder as described in this chapter.
In the case of another use, the medicament is for use in a therapeutic or prophylactic method, preferably a therapeutic method, in order to treat, improve or prevent age-related cognitive disorders, disorders. age-related learning and memory, age-related memory loss, vascular dementia, traumatic brain injury, stroke, dementia following stroke (post-stroke dementia), post-traumatic dementia, general concentration disorders, concentration disorders in children with learning and memory disorders, Alzheimer's disease, Lewy body dementia, dementia with, degeneration of the frontal lobes, including including Pick's syndrome, Parkinson's disease, progressive supranuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob disease, HIV-related dementia, epilepsy, temporal lobe epilepsy, schizophrenia, schizophrenia (associated with dementia), Korsakoff syndrome or cognitive impairment associated with depression or bipolar disorder.
In the case of another use, the medicament is intended for use in a therapeutic or prophylactic process, preferably a therapeutic process, in order to treat Alzheimer's disease, schizophrenia or cognitive disorders associated with Alzheimer's disease. Alzheimer's or associated with schizophrenia.
In the case of another use, the medicament is for use in a therapeutic or prophylactic method, preferably a therapeutic method, in order to treat sleep disorders, bipolar disorders, metabolic syndrome, obesity, diabetes mellitus, hyperglycemia, dy'slipidemia, glucose intolerance, or disease of the testes, brain, small intestines, skeletal muscles, heart, lungs, thymus or spleen.
According to another aspect of the invention, the present invention relates to a method for treating or preventing a disorder or disease selected from the groups of disorders and
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PC ΕΡ2011 / 063705 diseases listed above, the method comprising the fact of administering to a human being who requires it a therapeutically effective amount of compound according to the invention.
Another aspect of the invention relates to the compounds of the invention for use as a medicament in a therapeutic or prophylactic method, preferably a therapeutic method. If indicated, the therapeutic method or medicament is preferably for treating a disease or disorder selected from the group of disorders and diseases discussed above in this chapter entitled "METHOD OF TREATMENT".
PHARMACEUTICAL COMPOSITIONS
Medicines for administration which are also concerned by the present invention include:
a compound according to the present invention as a pharmaceutically active principle in a therapeutically effective amount and a pharmaceutical vehicle.
By “therapeutically effective amount” is meant that, if the drug is applied via the correct protocol adapted to the patient's condition, the amount of said compound of formula (I) will be sufficient to effectively treat, prevent or slow the progression. of the corresponding disease or otherwise to improve the condition of a patient suffering from that disease. It may happen that the "therapeutically effective amount" in monotherapy differs from the "therapeutically effective amount" in dual therapy with another drug.
The dosage range of compounds of general formula (I) applicable per day may usually be 0.1 to 5000 mg, preferably 0.1 to 1000 mg, preferably 2 to 500 mg, more preferably 5. to 250 mg, most preferably from 10 to 100 mg. A dosage unit (for example, a tablet) can preferably contain between 2 and 250 mg, particularly preferably between 10 and 100 mg of the compounds according to the invention.
The actual pharmaceutically effective amount or therapeutic dosage will depend on factors known to those skilled in the art such as the age, weight, sex or other pathology of the patient, the route of administration, the severity of the disease and analogues.
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The compounds according to the invention can be administered orally, parenterally (intravenously, intramuscularly, etc.), intranasal, sublingually, by inhalation, intrathecally, topically or rectally. Preparations suitable for administering the compounds according to the present invention include, for example, patches (patches), tablets, capsules, pills, lozenges, dragees, powders, lozenges, suppositories, liquid preparations such as solutions, suspensions, emulsions, drops, syrups, elixirs or gaseous preparations such as aerosols, sprays and the like. The amount of the pharmaceutically active compound (s) should be in the range of 0.05 to 90% by weight, preferably 0.1 to 50% by weight of the entire composition. It is for example possible to obtain suitable tablets by mixing for example the active principle (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as starch. corn or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents for delaying release such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also have several layers.
Coated tablets can be prepared accordingly by coating hearts produced analogously to tablets with substances normally used for coating tablets, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or to prevent incompatibility, the heart may also consist of a number of layers. Likewise, the tablet coating may have a number of layers to allow delayed release, possibly using the aforementioned tablet excipients.
The syrups or elixirs containing the active priircipes or their combinations according to the invention can also contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavor enhancer, for example vanillin or extract of 'orange. They can also contain adjuvants or suspension thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide or preservatives such as p-hydroxybenzoates.
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Solutions can be prepared in the usual way, for example by adding isotonic agents, preservatives like p-hydroxybenzoates or stabilizers like alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants then that, if water is used as a diluent, for example, organic solvents can be used as solubilizers or dilution aids and the solutions can be transferred to vials or ampoules for injection or even infusion bottles.
The capsules containing one or more active principles or alternatively combinations of active principles can be prepared, for example, by mixing the active principles with inert vehicles such as lactose or sorbitol and by encapsulating them in gelatin capsules.
Suitable suppositories can be made, for example, by mixing with vehicles provided for this purpose, such as neutral fats or polyethylene glycol or their derivatives.
Excipients which can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (for example, petroleum fractions), vegetable oils (for example, peanut oil or sesame oil) , monofunctional or polyfunctional alcohols (eg ethanol or glycerol), carriers such as natural mineral powders (eg kaolins, clays, talc, chalk), synthetic mineral powders (eg silicic acid and highly dispersed silicates), sugars (eg cane sugar, lactose and glucose), emulsifiers (eg lignin, black liquors, methylcellulose,) starch and polyvinylpyrrolidone) and lubricants (eg, magnesium stearate, stearic acid and sodium lauryl sulfate).
For oral use, the tablets may contain, in addition to the vehicles specified, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various other substances such as starch, preferably sodium starch. potato, gelatin and the like. It is also possible to use lubricants such as magnesium stearate, sodium lauryl sulphate and talc to
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PCEP201 063705 produce the tablets. In the case of aqueous suspensions, the active ingredients can be combined with various flavor enhancers or colorants in addition to the above-mentioned excipients.
The dosage of the compounds according to the invention is naturally strongly dependent on the mode of administration and on the condition to be treated.
COMBINATIONS WITH OTHER ACTIVE INGREDIENTS
According to another aspect, the present invention relates to a dual therapy in which a compound according to the present invention is administered at the same time as another actil 'compound. Therefore, the invention also refers to pharmaceutical formulations providing this combination of pharmaceutically active principles, one of them being a compound of the present invention. These combinations can be combinations at determined doses (the pharmaceutically active ingredients which can be combined are subject to the same pharmaceutical formulation) or combinations at free doses (the pharmaceutically active ingredients are found in separate pharmaceutical formulations).
Therefore, another aspect of the present invention refers to the combination of each of the compounds of the present invention, preferably at least one compound according to the present invention, with another active compound, for example selected from the group of inhibitors of the beta-secretase, gamma-secretase inhibitors, gamma-secretase modulators, amyloid aggregation inhibitors such as Alzhemed, neuroprotective and / or disease-modifying substances acting directly or indirectly, antioxidants such as vitamin E, gingko biloba or gingkolide, anti-inflammatory substances such as Cox inhibitors, NSAIDs having, in addition or exclusively, properties decreasing β (A-beta), HMG-CoA reductase inhibitors, such as statins, acetylcholine esterase inhibitors, such as Donepezil, rivastigmine, tacrine, galantamine, NMDA receptor antagonists such as memantine, AMPA receptor agonists, positive AMPA receptor modulators, AMPkines, glycine type 1 transport inhibitors, monoamine reuptake inhibitors, concentration modulating substances or the release of neurotransmitters, substances inducing the secretion of growth hormone such as ibutamoren mesylate and capromorelin, CB-1 receptor antagonists or reverse agonists, antibiotics such as minocycline or
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PCT ΕΡ2011 / 063705 rifampicin, inhibitors of PDE1, PDE2, PDE4, PDE5 and / or PDEIO, reverse agonists of GAB receptors, reverse agonists of GABAA alpha5 receptors, antagonists of GABAA receptors, agonists, partial or partial agonists positive nicotinic receptor modulators, agonists, partial agonists or positive alpha4beta2 nicotinic receptor modulators, alpha7 nicotinic receptor agonists or partial agonists, histamine Η3 receptor antagonists, 5-ΗΤ4 agonists or partial agonists, 5ΗΤ6 receptor antagonists, alpha2-adrenergic receptor antagonists, calcium antagonists, agonists, partial agonists or modulators positive muscarinic M1 receptors, ant2 muscarinic receptor antagonists, Μ4 muscarinic receptor antagonists, allosteric mGluR5 modulators, mGluR2 antagonists, mGluR2 / 3 agonists, positive allosteric mGluR2 modulators and other substances modulating receptors or enzymes so as to increase the efficacy and / or safety of the compounds according to the invention and / or reduce unwanted effects.
The present invention further relates to pharmaceutical compositions containing one or more active ingredients, preferably just one. At least one active principle is chosen from the compounds according to the invention and / or their corresponding salts. The composition preferably comprises only one of these active compounds. In case there is more than one active compound, the other can be chosen from the above mentioned group of combined elements such as Alzhemed, Vitamin E, Gingkolide, Donepezil, Rivastigmine, Tacrine, galantamine, memantine, ibutamoren mesylate, capromorelin, minocycline and / or rifampicin. The composition optionally further comprises other ingredients such as inert carriers and / or diluents.
The compounds according to the invention can also be used in combination with immunotherapies such as active immunization with A-beta or elements thereof or alternatively as passive immunization with antibodies or fragments of humanized antibodies. anti-A-beta parts for treating the aforementioned diseases and disorders.
The compounds according to the invention can also be combined with Dimebon.
The compounds according to the invention can also be combined with antidepressants such as amitriptyline and imipramine hydrochloride (TOFRANIL),
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ΡΟΙ / ΕΡ2011 / 063705 imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepine (SINEQUAN, ZONALON), trimipramine (SURMONTIL).
Or the compounds according to the invention can also be combined with inhibitors of the reuptake of serotonin (5-ΗΤ) such as alaproclate, citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL), fenfluramine (PONDIMIN), norfenfluramine, fluoxetine (PROZAC), fluvoxamine (LUVOX), Findalpine, milnacipran (IXEL), paroxetine, SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID). bicifadine, desvenlafaxine (PRISTIQ), brasofensin, and tesofensin.
The combinations according to the present invention can be offered at the same time in a single presentation, namely in the form of a combined preparation. The two components can for example be incorporated in a single tablet, for example in different layers of said tablet. The combination can also be offered separately in the form of a free combination, i.e. the compounds of the present invention are offered in a first presentation and one or more of the aforementioned combination elements is / are offered in another presentation. . These two presentations may be equal presentations, for example a co-administration of two tablets, one of which contains a therapeutically effective amount of the compound of the present invention and the other contains a therapeutically effective amount of the aforementioned combination element. If desired, it is also possible to combine different modes of administration. It is possible to provide any type of mode of administration.
The compound according to the invention, or one of its physiologically acceptable salts, combined with another active principle, can be used simultaneously or in a staggered manner but at particularly close time intervals. Administered at the same time, the two active ingredients are administered together to the patient; administered in a staggered manner, the two active principles are administered to the patient successively within a period of less than or equal to 12 hours, preferably less than or equal to 6 hours.
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Presentations OR modes of administration are unlimited and any presentation may be used in the context of the present invention. For example, the presentations can be chosen from preparations in solid form such as patches (stamps), tablets, capsules, pills, lozenges, dragees, powders, tablets, suppositories, liquid preparations such as solutions, suspensions, emulsions, drops, syrups, elixirs or gaseous preparations such as aerosols, sprays and the like.
The presentations are advantageously formulated in dosage units, each dosage unit being adapted to deliver a single dose of each active component present. The ingredients are chosen according to the mode of administration and the presentation.
Suitably, the dosage of the aforementioned combined elements may range from 1/5 of the lowest normally recommended dose to 1/1 of the normally recommended dose.
The presentations are for example administered to the patient 1, 2, 3 or 4 times / day depending on the nature of the formulation. In the case of depot or sustained release formulations or other pharmaceutical formulations, they can be applied differently (eg, once / week, once / month, etc.). It is preferred that the compounds of the invention are administered three times or less, preferably once or twice / day.
EXAMPLES
PHARMACEUTICAL COMPOSITIONS
Examples which may illustrate possible pharmaceutical formulations and which are not intended to be restrictive:
The terms “active principle” denote one or more compounds according to the invention, including their salts. In the case of one of the above-mentioned combinations with one or
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Example A
Tablets containing 100 mg of active ingredient
Composition: compressed
P01-2655 / PCT
PCT / EP2011 / 063705 also include the
<td>active ingredient</td><td>100.0 mg</td>
<td>lactose</td><td>80.0 mg</td>
<td>corn starch</td><td>34.0 mg</td>
<td>polyvinylpyrrolidone</td><td>4.0 mg</td>
<td>magnesium stearate</td><td>2.0 mg</td>
<td></td><td>220.0 mg</td>
Example B
Tablets containing 150 mg of active ingredient
Composition: tablet
<td>active ingredient</td><td>150.0 mg</td>
<td>lactose powder</td><td>89.0 mg</td>
<td>corn starch</td><td>40.0 mg</td>
<td>colloidal silica</td><td>10.0 mg</td>
<td>polyvinylpyrrolidone</td><td>10.0 mg</td>
<td>magnesium stearate</td><td>1.0 mg</td>
<td></td><td>300.0 mg</td>
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Hard gelatin capsules containing 150 mg of active substance
<td>active ingredient</td><td>150.0 mg</td>
<td>lactose</td><td>87.0 mg</td>
<td>corn starch (dried)</td><td>80.0 mg</td>
<td>magnesium stearate</td><td>3.0 mg</td>
<td></td><td>320.0 mg</td>
Example D
Composition: suppository
<td>active ingredient</td><td>150.0 mg</td>
<td>polyethylene glycol 1500</td><td>550.0 mg</td>
<td>polyethylene glycol 6000</td><td>460.0 mg</td>
<td>monostearate</td><td>840.0 mg</td>
<td>polyoxyethylene sorbitan</td><td></td>
<td></td><td>2000.0 mg</td>
Example E
Composition: ampoules containing 10 mg of active principle active principle hydrochloric acid 0.01 N double-distilled water
10.0 mg in sufficient quantity up to 2.0 ml
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Example F
Composition: ampoules containing 50 mg of active principle active principle 50.0 mg hydrochloric acid 0.01 N in sufficient quantity distilled water. Up to 10.0 ml
The preparation of any of the above formulas can be carried out following standard procedures.
BIOLOGICAL ANALYSIS
The in vitro effect of the compounds of the invention can be demonstrated with the following biological analyzes.
ΡΡΕ9Α2 analysis protocol:
Analysis for the enzymatic activity of PDE9A2 was performed as a proximity scintillation (SPA), generally according to the manufacturer's protocol (GE Healthcare, formerly Amersham Biosciences, product number: TRKQ 7100).
A lysate (PBS with I / o of Triton Χ-100 supplemented with protease inhibitors, cell debris removed by centrifugation at 13,000 rpm for 30 min) of SF9 cells expressing human PDE9A2 was used as the enzyme source. . The total protein content included in the assay varied upon infection and production efficiency of SF9 cells and is in the range of 0.1 to 100 ng.
In general, the analysis conditions were as follows:
total analysis volume: 40 microliters protein content: 0.1 to 50 ng substrate concentration (cGMP): 20 nanomolar; approx. 1 mCi / 1 incubation time: 60 min at room temperature final DMSO concentration: 0.2 at I / o
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The analyzes were carried out on 384-well format plates. Test reagents along with enzyme and substrate were diluted in assay buffer. The assay buffer contained 50mM Tris, 8.3mM MgC, 1.7mM EGTA, 0.1٥ / o BSA, 0.05% Tween 20; the pH of the assay buffer was adjusted to 7.5. The reaction was stopped by applying a specific inhibitor for PDE9 (e.g. compounds according to wo 2004/099210 or wo 2004/099211, such as one of the enantiomers of Example 37, e.g. 1- (2) -chlorophenyl) -6 - [(2R) -3,3,3-trifluoro-2-methyl-propyl] -l, 5-dihydro-4Hpyraz010 [3,4-d] pyrimidin-4-one).
References .'
Wunder F, Tersteegen A, Rebmann A, Erb c, Fahrig T, Hendrix M. Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Molecular Pharmacology. 2005 Dec; 68 (6): 1775-81.
van der Staay FJ, Rutten K, Barfacker L, Dev'ry J, Erb c, Heckroth H, Karhaus D, Tersteegen A, van Kampen M, Blokland A, Prickaerts J, Reymann KG, Schroder UH, Hendrix M. The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology. 2008 0ct; 55 (5): 908-18.
PDEIC analysis protocol:
The analysis was carried out in the same way as the analysis for PDE9A2, except for the following differences: instead of using PDE9A2, PDEIC was used and the analysis buffer additionally contained 50 nM calmodulin and 3 mM CaC. The reaction could be stopped by applying the same inhibitor as described above (namely 1- (2chlorophenyl) -6 - [(2R) -3,3,3-trifluoro-2-methyl-propyl] - 1,5-dihydro-4H-pyrazoloj3,4dJpyrimidin-4-one).
Determination of
The IC can be calculated with GraphPadPrism or any other suitable software by setting the positive control to 100 and the negative control to 0. To calculate the IC50, the dilutions of the test compounds (substrates) must be chosen and tested according to the aforementioned protocol.
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Data
In the IC the values of the inhibition of PDE9A2 [nanomolar (nM)] illustrate that the compounds according to the present invention inhibit PDE9, in particular PDE9A2.
This demonstrates that the compounds provide useful pharmaceutical properties. The examples are not meant to be restrictive.
The table also shows selectivity (Selectivity) values which indicate a preference of the compounds for PDE9A over PDEIC. The selectivity is the ratio (CI for inhibition of PDEIC [nanomolar (nM)]) / (CI for inhibition of PDE9A2 [nanomolar (nM)]).
The numbers of the examples refer to the final examples as indicated in the chapter Examples of embodiments and as defined by the table of families of compounds above (embodiment 25).
All data can be measured using the procedure described herein.
The definition "enantiomer 1" or "enantiomer 2" relates to the order of elution of the enantiomers in a chiral CFS and a chiral HPLC.
<td>Family of compounds</td><td>Example no.</td><td>CIso PDE9A2 [nanomolar]</td><td>Selectivity</td>
<td>AT</td><td> 1*</td><td> 450</td><td> 3</td>
<td>B</td><td> 2*</td><td> 5</td><td> 143</td>
<td>VS</td><td> 3*</td><td> 23</td><td> 34</td>
<td>D</td><td> 4*</td><td> 242</td><td> 22</td>
<td>E</td><td> 5*</td><td> 60</td><td> 14</td>
<td>F</td><td> 6*</td><td> 58</td><td> 15</td>
<td>Gl</td><td> 7*</td><td> 31</td><td> 15</td>
<td>G2</td><td> 8*</td><td> 85</td><td> 63</td>
<td>Hl</td><td> 9*</td><td> 19</td><td> 46</td>
<td>Η2</td><td> 10*</td><td> 13</td><td> 120</td>
<td>I</td><td> 11*</td><td> 233</td><td> >43</td>
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<td>Family of compounds</td><td>Example no.</td><td>CI PDE9A2 [nanomolar]</td><td>Selectivity</td>
<td>ل</td><td> 12*</td><td> 80</td><td> 38</td>
<td>K</td><td> 13*</td><td> ٦</td><td> 328</td>
<td>K</td><td>14 (enantiomer 1)</td><td> 473</td><td> 4,3</td>
<td>K</td><td>15 (enantiomer 2)</td><td> 4</td><td> 424</td>
<td>L</td><td> 16*</td><td> 5</td><td> 245</td>
<td>M</td><td> 17*</td><td> 16</td><td> 78</td>
<td>M</td><td>18 (enantiomer 1)</td><td> 5</td><td> 255</td>
<td>M</td><td>19 (enantiomer 2)</td><td> 1345</td><td> 0,61</td>
<td>NOT</td><td> 20*</td><td> 31</td><td> 68</td>
<td> 0</td><td> 21*</td><td> 433</td><td> 10</td>
<td>P</td><td> 22*</td><td> 21</td><td> 49</td>
<td>Q</td><td> 23</td><td> 23</td><td> 187</td>
<td>Q</td><td>24 (enantiomer 1)</td><td> 218</td><td> 8,9</td>
<td>Q</td><td>25 (enantiomer 2)</td><td> ٦</td><td> 197</td>
<td>R</td><td> 29*</td><td> 11</td><td> 117</td>
<td>R</td><td>30 (enantiomer 1)</td><td> 304</td><td> 4,95</td>
<td>R</td><td>31 (enantiomer 2)</td><td> ٦</td><td> 186</td>
<td>S</td><td> 32*</td><td> 7</td><td> 117</td>
<td>S</td><td>33 (enantiomer 1)</td><td> 4</td><td> 181</td>
<td>S</td><td>34 (enantiomer 2)</td><td> 388</td><td> 1,68</td>
<td>T</td><td> 26*</td><td> 32</td><td> >400</td>
<td>T</td><td>27 (enantiomer 1)</td><td> 11</td><td> 250</td>
<td>T</td><td>28 (enantiomer 2)</td><td> 360</td><td> ٦</td>
* trans racemic
Effect in vivo:
It is believed that positive efficacy in vitro results from the fact that the compounds of the present invention change to positive efficacy in vivo.
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The in vivo effect of the compounds of the present invention can be tested during the new object recognition test according to the protocol of Prickaerts et al. (. Neuroscience 2002, 113, 351-361), the social recognition test or the spontaneous alternation test in a T-maze according to the protocols described by van der Staay et al. (. Neuropharmacology 2008, 55, 908-918). These two citations are also referred to for further information regarding bioassays.
Besides the property of inhibition towards the target PDE 9, the compounds according to the present invention can provide other advantageous pharmacokinetic properties.
The compounds according to the invention can for example have one or more advantages in terms of safety, balanced metabolism, low risk of drug interaction and / or balanced clearance.
The compounds could also have one or more other advantages in terms of bioavailability, large fraction absorbed, transport properties to the blood brain barrier, favorable residence time (mrt) (eg, medium high).
favorable exposure in the effect compartment and so on.
MANUFACTURING OF CHEMICALS
Abbreviations:
Burgess Reagent
Lawesson's reagent
APCI
ACN
CDI
DEA
DIPEA (methoxycarbonylsulfamoylftriethylammonium-N-betaine
2,4-bis- (4-methoxy-phenyl) - [l, 3,2,4] dithiadiphosphetane-2,4disulfide chemical ionization at atmospheric pressure acetonitrile
1,1 '-carbonyldiimidazole diethylamine diisopropylethylamine
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DME 1,2-dimethoxyethae
DMF dimethylformamide
ESI ionization by electronebulizer (in a SM)
EtOH ethanol
Exp. example h hour (s)
HATU hexafluorophosphate of O- (7-azabenzotriazol-1-yl) -N, N, N ', N'tetramethyluronium
HPLC high performance liquid chromatography
CHLP-SM high performance liquid chromatography coupled with mass spectrometry
M molar (mol / 1)
MeOH methanol min minutes
MS mass spectrometry
NMP l-methyl-2-pyrrolidinone
Rt retention time (in an HPLC)
CFS supercritical fluid chromatography
TBTU O- (benzotriazol-1-yl) -N, N, N ', N'tetramethyluronium tetrafluoroborate
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
CSM methods:
Method 1
Device Type for SM: Waters Micromass ZQ; device type for HPLC: Waters Alliance 2695, Waters 2996 diode array detector; column: Varian Microsorb 100 C18, 30 x 4.6 mm, 3.0 µm; eluent A: water + 0.13٥ / ο TFA, eluent B: ACN;
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PC ΕΡ201 063705 gradient: 0.0 min 5% B -0.18 خ min 5% B -> 2.0 min 98٥ / ο B 2.2 ب min 98٠ / ο B 2.3 ب min 5% B 2, 5 min 5% B; flow rate: 3.5 ml / min; uv detection: 210-380 nm.
Method 2
Device Type for SM: Waters Micromass ZQ; device type for HPLC: Waters Alliance 2695, Waters 2996 diode array detector; column: Varian Microsorb 100 C18, 30 X 4.6 mm, 3.0 µm; eluent A: water + 0.13٥ / ο TFA, eluent B: MeOH; gradient: 0.0 min 5% B 0.35 ب min 5% B 3.95 ب min 100٥ / ο B 4.45 ب min 100٥ / ο B 4.55 ب min 5% B 4.9 ب min 5% B; flow rate: 2.4 ml / min; uv detection: 210-380 nm.
Method 3
Device Type for SM: Waters Micromass ZQ; device type potrr HPLC: Waters Alliance 2695, Waters 2996 diode array detector; column: Varian Microsorb C18, 20 X 4.6 mm, 5.0 µm; eluent A: water t-0.15% TFA, eluent B: MeOH; gradient: 0.0 min 5% B 0.25 ب min 5% B »1.90 min 100 / ο B 2.05 ب min 100% B -٦ 2.15 min 5% B 2.25 ب min 5% B; flow rate: 5.2 ml / min; uv detection: 210-400 nm.
IE hydro method
Instrument: CL / SM ThermoFinnigan. Hplc Surveyor DAD, MSQ Quadrupole; column: Synergi Hydro-RP80A, 4 µm, 4.60 X 100 mm; eluent A: 90٥ / ο water 10٥ ا / ο acetonitrile + 10 mM ammonium formate; eluent B = 90% ACN ٠10% HO t 10 mM NHCOOH; gradient: A (100) for 1 minute and a half, then in B (100) in 10 minutes for 1 minute and a half; flow rate: 1.2 ml / min; uv detection: 254 nm; ion source: APCI.
Chiral CFS Methods:
Method 4
Device type for CFS: Berger "Analytix"; column: Daicel IC, 250 mm X
4.6 mm, 5.0 µm; eluent: 0/25% MeOH / 0.2٥ / o DEA (isocratic); flow rate: 4.0 ml / min, 10 min; temperature: 4O٥C; uv detection: 210/220/254 nm.
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Method 5
Device type for CFS: Berger "Analytix"; column: Daicel ADH, 250 mm x
4.6 mm, 5.0 µm; eluent: Ο / 25٥ / ο MeOH / 0.2% DEA (isocratic); flow rate: 4.0 ml / min, 10 min; temperature: 4O٥C; uv detection: 210/220/254 nm.
Chiral HPLC methods:
Method 6:
Instrument type for HPLC: Agilent 1100; column: Daicel chiralcel 0J-H, 250mm X 4.6mm, 5.0 µm; eluent: hexane / 12tOH80:20; flow rate: 1 ml / min, temperature: 25 ° c; uv detection: variable (200-500 nm).
Method 6.1:
Instrument type for HPLC: Agilent 1100; column: Daicel chiralcel 0J-H, 250mm X 4.6mm, 5.0 µm; eluent: hexane / EtOH 85/15; flow rate: 1 ml / min, temperature: 25٥c; uv detection: variable (200-500 nm).
Method 7:
Instrument type for HPLC: Agilent 1100; column: Chiralpak AD-H, 250 mm X
4.6 mm, 5.0 µm; eluent: hexane / isopropanol 80:20; flow rate: 1 ml / min, temperature: 25 ° c; uv detection: variable (200-500 nm).
Instrument type for HPLC: Agilent 1100; column: Chiralpak AD-H, 250 mm X
4.6 mm, 5.0 µm; eluent: hexane / isopropanol 80:20; flow rate: 1 ml / min, temperature: 25 ° c; uv detection: variable (200-500 nm).
Microwave heating:
CEM Discover® instruments teams of 10 and 35 ml containers;
Biotage Initiator Sixty.
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General comment concerning the presentation of the structures
Compounds having one or more stereogenic centers: the structures illustrated in the experimental chapter below do not necessarily indicate all the stereochemical possibilities of the compounds, but only one. However, in these cases, terms such as "trans racemic" or "cis racemic" are added next to the structure to indicate other steochemical options.
An example is given below. The structural formula presented is, 'Xx
٩٠
Racemic trans
The added terms "trans racemic" denote the second steochemical option:
XX
٩
Thus, the prepared compound is a mixture of
Xx <.i٩y and
This principle also applies to the other structures illustrated.
Starting compounds:
Example IA (trans racemic)
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Hk دي
0
Racemic trans
2.00 g (13.9 mmol) of trans-cyclobutan-1,2-dicarboxylic acid was mixed with 16 ml of EtOH at o٥c and 2.21 ml (30.5 mmol) of thionyl chloride was slowly added. . The mixture was allowed to warm to room temperature and stirred for 1 hour. The solvent was removed under reduced pressure and the product was filtered through a pad of basic activated alumina. 2.71 g (98%) of product were obtained.
HPLC-MS (method 1): R (= 1.34 min
MS (ESI pos): m / z = 201 (M + H) ٠
The following example was synthesized in a manner analogous to the preparation of Example 1A using the corresponding diacid as starting material.
<td>Example</td><td>Structure</td><td>Starting period</td><td>R, [min]</td><td>SM (ESI pos, m / z)</td>
<td>Exp. IB Racemic cis</td><td>حهؤ ٣٧</td><td>O لأر OH y<sub>O</sub>H T</td><td>1.12 (method 3)</td><td>201 (Μ + Η) '</td>
Example 2Α (racemic)
X
8.00 g (89.7 mmol) of 2-amino-propionic acid were mixed with 88.0 ml (0.93 mol) of acetic anhydride and 88.0 ml of pyridine. The reaction mixture was stirred at 100 ° C for 135 min. The solvent was removed under reduced pressure. Toluene was added to the
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PC17EP2011 / 063705 residue and the solvent was removed under reduced pressure then 204 ml (816 mmol) of HCl (4M aqueous solution) were added and the mixture was refluxed for 3 h. The solvent was removed under reduced pressure. 1-Butanol (20 mL) was added to the residue and the solvent was removed under reduced pressure. 11.6 g of the title compound were obtained as the hydrochloride salt.
MS (ESIpos): m / z = 88 (M ؛ H) ٠
Example 3Α (racemiaue man.؟)
<img file="MA35575B1_D0055.tif" />
Racemic trans
1.00 g (4.09 mmol) of 5-amino-1- (4,4-difluorocyclohexyl) -1H-pyrazole-4-carboxylic acid amide was mixed (see PCT patent application wo 2010 / 026214, Example 8Α) to 15 ml of anhydrous EtOH and 2.46 g (12.3 mmol) of the product of Example IA and 0.66 g (16.4 mmol) of sodium hydride ( suspension at 60٥ / ο in mineral oil). The reaction mixture was heated at 14O٥C for 30 min in a microwave oven. The mixture was cooled to room temperature and sodium hydroxide solution (4M aqueous solution) was added. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (eluent A: water 0.13 ا / ο TFA, eluent B: MeOH). 0.70 g (49%) of product was obtained.
HPLC-MS (method 1): Ri = 1.24 min
MS (ESIpos): m / z = 353 (M٠H) ٠
The following examples were synthesized in a manner analogous to the preparation of Example 3Α using the corresponding amide and ester as starting materials (for the starting materials, reference is made to PCT patent publications wo 2010/026214 , WO 2009/121919 and wo 2004/09921).
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<td>Example</td><td>Structure</td><td>Product of start: amide</td><td>Starting product: ester</td><td>R ([min]</td><td>SM (ESI pos, m / z)</td>
<td>Exp. 3Β (trans racemic)</td><td>هنيلآ ري</td><td>Amide of 5 amino-1 (tetrahydropyran-4-yl) ٠ 1H-pyrazol-4-carboxylic acid (see wo 2009/121919, example 11 B)</td><td>Exp. IB</td><td>1.07 (method 3)</td><td>319 (MH *</td>
<td>Exp. 3C (trans racemic)</td><td></td><td>Amide of 5 amino-l- (4methylpyridin-3-yl) 1H-pyrazol-4carboxylic acid (see WO 2004/099211, example 35Α)</td><td>Exp. AI</td><td>0.81 (method 1)</td><td>326 (MtH) ٠</td>
Example 4Α (trans racemic)
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<img file="MA35575B1_D0056.tif" />
0.200 g (0.568 mmol) of the product of Example 3Α was mixed with 0.157 ml (1.14 mmol) of triethylamine and 5 ml of DMF. 0.237 g (0.624 mmol) of HATU was added to the mixture and the reaction mixture was then stirred at room temperature for 10 min. To the mixture was added 0.042 g (0.568 mmol) of acetic acid hydrazide and the reaction mixture was stirred at room temperature for 1 h. The mixture was purified by preparative HPLC (eluent A: water ٠ 0.13% TFA, eluent B: MeOH). 30 mg of product were obtained.
HPLC-MS (method 1): R = 1.03 min
MS (ESI pos): m / z - 409 (MH) *
Example 5Α (racemic / ra »٠H
<img file="MA35575B1_D0057.tif" />
0.150 g (0.426 mmol) of the product of Example 3Α was mixed with 2 ml of THF. The mixture was cooled to 0 ° C and 0.036 ml (0.426 mmol) of oxalyl chloride was added along with a drop of DMF. The reaction mixture was stirred at 0 ° C for 1 h. 2 ml of ACN and 0.426 ml (0.851 mmol) of trimethylsilyldiazomethane (2Μ in hexane) were added to the reaction mixture. The mixture was stirred for 2 h then slowly stirred 0.213 ml of HCl (4M in dioxane). The reaction mixture was stirred for 3 h. We added to
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HPLC-MS (method l): Ri = 1.40 min
MS (ESI pos): m / z = 385/387 (Cl)
The following example was synthesized analogously to the preparation of Example 5Α using the corresponding acid as the starting material.
<td>Example</td><td>Structure</td><td>Starting product</td><td>R [[min]</td><td>SM (ESI pos, m / z)</td>
<td>Exp. 5Β Racemic sorting</td><td>at : Cl زح</td><td>Exp. 3Β</td><td>1.12 (method 1)</td><td>351/353 (Cl)</td>
Example 6Α (mixture of stereoisomers اكد
<img file="MA35575B1_D0058.tif" />
Mixture of trait stereoisomers
0.200 g (0.628 mmol) of the product of Example 3Β was mixed with 1 ml of DMF. 0.261 ml (1.89 mmol) of triethylamine and 0.222 g (0.691 mmol) of TBTU were added. The û-79UK
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0.078 g (0.628 mmol) of the product of Example 2Α and the mixture was stirred at room temperature for 1 h. The mixture was purified by preparative HPLC (eluent A: water 0.13٥ ا / ο
TFA, eluent B: MeOH). 190 mg of product were obtained.
HPLC-MS (method 3): R (= 1.03 min
MS (ESIpos): m / z = 388 (M٠H) '
Example 7Α (trans racemic}
Racemic trans
0.200 g (0.628 mmol) of the product of Example 3Β was mixed with 1 ml of DMF. 0.174 ml (1.26 mmol) of triethylamine and 0.222 g (0.691 mmol) of TBTU were added. The reaction mixture was stirred at room temperature for 10 min. Then 0.066 g (0.628 mmol) of 2,2-dimethoxy-ethylamine was added and the mixture was stirred at room temperature for 1 h. Then HCl (2Μ aqueous solution) was added and the mixture was purified by preparative HPLC (eluent A: water t 0.13٥ / ο TFA, eluent B: MeOH). The residue was mixed with 5 ml of acetone and 1 ml of HCl (2Μ aqueous solution) and stirred under nitrogen atmosphere overnight. Then the mixture was extracted with DCM. The organic layer was evaporated and purified by preparative HPLC (eluent A: water 0.13٥ ا / ο
TFA, eluent B: MeOH). 170 mg of product were obtained.
HPLC-MS (method 3): R [= 1.01 min
MS (ESIpos): m / z = 360 (M٠H) ٠
Example 8Α (mixture of steeoisomers / ranA
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<img file="MA35575B1_D0059.tif" />
0.200 g (0.568 mmol) of the product of Example 3Α was mixed with 1.0 ml of DMF, 0.432 ml (2.84 mmol) of DIPEA and 0.200 g (0.624 mmol) of TBTU were added. The reaction mixture was stirred at room temperature for 10 min. Then 0.140 g (1.14 mmol) of the product of Example 2Α was added and the mixture was stirred at room temperature for 2 h. The mixture was purified by preparative HPLC (component A: water t 0.13٥ / ο TFA, eluent B: MeOH). 70 mg (29٥ / ο) of product were obtained.
HPLC-MS (method 1): R = 1.23 min
MS (ESI pos): m / z = 422 (Μ + Η) ♦
The following examples were synthesized in a manner analogous to the preparation of Example 8Α using the corresponding nucleophiles as starting materials.
<td>Example</td><td>Structure</td><td>Starting product</td><td>R, [min]</td><td>SM (ESI pos, m / z)</td>
<td>Exp. 8Β Racemic trans</td><td>؛ ه</td><td>بر Hydrochloride</td><td>1.31 (method 1)</td><td>396 (M + H)<sup>+</sup></td>
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<td>Exp. 8C Mix of irans stereoisomers</td><td> ١٩</td><td>Η٠Ύ ”1</td><td></td><td>410 (M + H) <sup>+</sup></td>
<td>Exp. 8D Mix of trans stereoisomers</td><td>٠h٩</td><td>ئر</td><td>1.12 (method 1)</td><td>410 (MtH) *</td>
<td>Exp. 8Ε Racemic trans</td><td> ٦٩</td><td>hydrazine hydrate</td><td>0.99 (method 1)</td><td>٦6٦ (MtH) ٠</td>
Example 9Α (trans racemiaue)
<img file="MA35575B1_D0060.tif" />
Racemic trans
0.182 g (0.430 mmol) of Dess-Martin periodinane was mixed with 2.5 ml of DCM. 0.160 g (0.391 mmol) of the product of Example 8D was added at room temperature.
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PC / ΕΡ2011 / 063705 in 2.5 ml of DCM. The reaction mixture was stirred at room temperature for 30 min and at 3O٥C for 30 min. 10 ml of sodium thiosulfate solution (10% in water) and 10 ml of saturated sodium hydrogencarbonate solution were added to the mixture and the mixture was stirred for 20 min. The organic layer was separated and the aqueous layer was extracted with DCM. The organic layer was washed with saturated sodium hydrogencarbonate solution, dried and evaporated. 93 mg (58%) of product were obtained.
HPLC (method 1): Ri = 1.18 min
MS (ESI pos); m / z = 408 (M + H)<sup>+</sup>
The following example was synthesized analogously to the preparation of Example 9Α using the corresponding alcohol as the starting material.
<td>Example</td><td>Structirre</td><td>Product of departure</td>
<td>Exp. 9Β Mixture of trans stereoisomers</td><td> ٦٩</td><td>Exp. 8C</td>
Example 10Α (mixture of stereoisomers / rare)
<img file="MA35575B1_D0061.tif" />
0.450 g of the product of Example 3C was mixed with 3.5 ml of DMF and 0.273 g (2.21 mmol) of the product of Example 2Α. 1.00 ml (6.64 mmol) of DIPEA was added and
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0.390 g (1.22 mmol) of TBTU and the mixture was stirred for 1 h. The mixture was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: MeOH). 360 mg (83%) of product were obtained.
HPLC-MS (method 1): Ri = 0.85 min
MS (ESI pos): m / z = 395 (MtH) (
Example 1 IA (racemic برا)
<img file="MA35575B1_D0062.tif" />
Racemic لد
300 mg (1.23 mmol) of 5-amin0-1 - (4,4-difluorocyclohexyl) -1H-pyrazole-4-carboxylic acid amide (see wo 2010/026214, example 8Α) were mixed with 4 ml of anhydrous EtOH, 326 mg (3.07 mmol) of trans-cyclobutane-1,2-dicarbonitrile and 0.197 g (4.91 mmol) of sodium hydride (60 à / ο suspension in oil mineral) under a nitrogen atmosphere. The reaction mixture was heated at 140 ° C for 45 min in a microwave oven. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (eluent A: water 0.13٥ ا / ο TFA, eluent B: MeOH). 210 mg (51%) of the title compound were obtained.
HPLC-MS (method 3): Ri = 1.19 min
MS (ESI pos): m / z = 334 (MtH) '
Example 1 IB (racemic irans)
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<img file="MA35575B1_D0063.tif" />
Racemic trans
0.457 g (19.6 mmol) of sodium hydride (60٥ / ο suspension in mineral oil) was added at room temperature under a nitrogen atmosphere to a solution of 0.8 g (3.805 mmol) d 5-Amino-1- (Tetrahydro-pyran-4-yl) -1H-pyrazol-45 carboxylic acid amide (see PCT patent application WO2010 / 026214) in 8 ml of anhydrous EtOH.
After 1 h of stirring, 1.2 g (11.42 mmol) of trans-cyclobutane-1,2-dicarbonitrile were added and the reaction mixture was heated at 14O٥C for 45 min in a microwave oven. The solvent was removed under reduced pressure. The residue was dissolved in DCM, water was added and the layers were separated. The organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash chromatography (Cy / EtOAc 80/20 to 100٥ / ο) to obtain the title compound as a yellow solid. (O, 64g, 55٥ / ο).
HPLC-MS (lEh method): Rt = 6.21min
MS (APCI): m / z = 300 (M٠H) ٠
Example 1 IC (racémiaue / raws)
<img file="MA35575B1_D0064.tif" />
Racemiqueras
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0١47 g (11.74 mmol) of sodium hydride (suspension at 6O٥ / o in mineral oil) were added at room temperature under a nitrogen atmosphere to a solution of 0.85 g (3.91 mmol). ) amide of 5-amino-1- (4-methyl-pyridin-3-yl) -lH-pyrazol-4carboxylic acid (see PCT patent application wo 2004/09921) in 10 ml of anhydrous EtüH. After 1 h of stirring, 1.28 g (11.74 mmol) of trans-cyclobutane-1,2-dicarbonitrile were added and the reaction mixture was heated at 14O٥C for 45 min in a microwave oven. The reaction mixture was then loaded onto an scx cartridge, the ammoniacal fractions were collected and evaporated and the residue was purified by flash chromatography (DCM / MeOH 90/10) to obtain the title compound as a white solid. . (0.63 g, 52٥/٥).
HPLC-MS (lEh method): R<sub>t</sub> = 5.92 min
MS (APCIpos): m / z = 307 (M٠H) ٠
Example 12Α (trans racemic}
<img file="MA35575B1_D0065.tif" />
Racemic trans
190 mg (0.570 mmol) of the product of Example 11Α were mixed with 0.281 ml of toluene and 0.093 ml (2.30 mmol) of anhydrous MeOH. Acetyl chloride 0.103 mL (1.45 mmol) was slowly added at 0 ° C. The mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. To the residue was added 0.5 ml of MeOH. Then 0.407 ml (2.85 mmol) of ammonia (7Μ in MeOH) was added at o٥c and the mixture was allowed to warm to room temperature. After 30 min, the reaction mixture was treated with water and the pH was adjusted to ρΗ = 1 by adding TFA. The mixture was
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HPLC-MS (method 3): R 1.04 min
MS (ESI pos): m / z = 351 (MH) *
Example 12 B tracemic / rrmx)
<img file="MA35575B1_D0066.tif" />
Racemic trans
Acetyl chloride (2.27ml, 30.82mmol) was slowly added to a mixture of dry EtOH (5ml) and dry CHCl (5ml) cooled to oc and the mixture was allowed to stir. for 20 min. A solution of the product of Example 11Β (0.410g, 1.027mmol) in dry CHCl (5ml) was added dropwise and the mixture was stirred at room temperature overnight. The solvents were evaporated under reduced pressure, the residue was dissolved in dry EtOH (5ml) and 6.4ml of a 7.5M ammoniacal solution in MeOH (30.82mmol) was added. . The mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The final product was obtained as the hydrochloride which was used in the next step without further purification. (0.37 g, 50% content estimated by HPLC-MS).
HPLC-MS (lEh method): R5.38 = ؛ min
MS (APCI pos): m / z = 317 (M٠H) ٠
Example 12c (racemic / ratts)
<img file="MA35575B1_D0067.tif" />
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<img file="MA35575B1_D0068.tif" />
Racemic trans
Acetyl chloride (4.38ml, 61.7mmol) was slowly added to a mixture of dry EtOH (4ml) and dry CHCl (10ml) cooled to o ° C and the mixture was allowed to stir for 20 min to o٥c. A solution of the product of Example UC (0.63 g, 2.057 mmol) in dry CHCl (5 ml) was added dropwise and the mixture was stirred at room temperature overnight. The solvents were evaporated under reduced pressure, the residue was dissolved in dry MeOH (10ml) and 10.3ml of a 7.5M ammoniacal solution in MeOH (72mmol) was added. The mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The final product, obtained as the hydrochloride salt, was used. The final product was obtained as the hydrochloride salt which was used in the next step without further purification. (0.85 g, 84٥ / ο content estimated by 1 H NMR).
HPLC-MS (lEh method): Ri = 5.15 min
MS (APCI pos): m / z = 324 (M٠H) ٠
Example 13Α (racemic Ira ".?)
<img file="MA35575B1_D0069.tif" />
Propargylamine (1.4 ml, 20.4 mmol) was added to a solution of 1.6 g (10.24 mmol) of 2-acetyl-cyclobutanecarboxylic acid methyl ester (prepared as described in J Med. Chem, 25, 109, 1982) in dry EtOH (12 ml) followed by
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0.122 g (0.307 mmol) of aurico-sodium trichloride. The reaction mixture was heated at 14O٥C for 45 min in a microwave oven, the solid material was filtered off and the organic layer was evaporated. The crude material was purified by flash chromatography (Cy / EtOAc 70/30) to obtain the title compound as a green-yellow oil. (0.18 g, 9.2٥ / ο).
HPLC-MS (lEh method): Ri = 0.87 min
MS (APCIpos): m / z = 192 (M٠H) ٠
Embodiments given by way of example
Example 1 (racemiaue Iraw)
<img file="MA35575B1_D0070.tif" />
Racemic trans
22.0 mg (0.306 mmol) of propan-2-one-oxime was mixed with 2 ml of anhydrous THF and to the mixture was gently added 0.471 ml (1.22 mmol) of n-butyllithium (2.6 mol / 1 in toluene). The reaction mixture was stirred at room temperature for 30 min. 0.110 g (0.278 mmol) of the product of Example 8Β in 1 ml of anhydrous THF was gently added over 10 min. After 30 min, the reaction mixture was added in a mixture of 0.28 ml of H2SO4 and 4 ml of THF / water (4/1). The mixture was refluxed for an hour and a half. A saturated aqueous solution of sodium hydrogencarbonate was added and extracted with ethyl acetate. The organic layer was dried and the solvents were evaporated. The residue was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: MeOH). 8 mg (8%) of product were obtained.
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CEHP-SM (method 1): RIO min
MS (ESIpos): m / z = 390 (M٠H) ٠
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Example 2 (racemic rrart.?)
<img file="MA35575B1_D0071.tif" />
Racemic trans
0.190 g of the product of Example 6Α was mixed with 3 ml of DME and 0.273 g (1.14 mmol) of Burgess reagent. The reaction mixture was heated at 13O٥C for 1 hour 10 minutes in a microwave oven. The solvent was evaporated and the residue purified by preparative HPLC (eluent A: water + 0.13 / ο TFA, eluent B: MeOH). 70 mg (55٥ / ο) of the product were obtained.
HPLC-MS (method 1): R ، = 1.11 min
MS (ESI pos): m / z = 370 (MH) *
The following examples were synthesized analogously to the preparation of Example 2 using the corresponding amides as starting materials.
<td>Example</td><td>Structure</td><td>Product of departure</td><td>Rt [min]</td><td>SM (ESI pos, m / z)</td>
<td>Exp. 3 Racemic trans</td><td>٩ زي</td><td>Exp. 7Α</td><td>1.17 (method 3)</td><td>342 (MtH) '</td>
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<td>Exp. 4 Racemic tans</td><td> ٩</td><td>Exp. 4Α</td><td>1.20 (method 1)</td><td>391 (Μ + Η</td>
<td>Exp. 5 Racemic tans</td><td>ه</td><td>Exp. 8Α</td><td>1.38 (method 1)</td><td>404 (MH) '</td>
<td>Exp. 6 Racemic tans</td><td> *</td><td>Exp. 9Α</td><td>1.37 (method 1)</td><td>390 (M٠H) ٠</td>
<td>Exp. 7 Racemic trans</td><td> ٠</td><td>Exp. 9Β</td><td>1.42 (method 3)</td><td>390 (M + H) ٠</td>
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<img file="MA35575B1_D0072.tif" />
<img file="MA35575B1_D0073.tif" />
Racemic trans
0.062 g (0.832 mmol) of thioacetamide in 2 ml of EtOH was added dropwise to a solution of Example 5A, synthesized from 0.426 mmol of the product of Example 3Α as described above. The reaction mixture was stirred overnight. The mixture was purified by preparative HPLC (eluent A: water + 0.13% TFA, eluent B: 10 MeOH). 62 mg of the title compound were obtained.
HPLC-MS (method 1): R (= 1.37 min
MS (ESI pos): m / z = 406 (M + H) <sup>+</sup>
The following examples were synthesized analogously to the preparation of Example 9 using the corresponding starting materials.
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<td>Example</td><td>Structure</td><td>Starting product: nucleophile</td><td>Starting product: chloroketone</td><td>R, [min]</td><td>SM (ESI pos, m / z)</td>
<td>Exp. 10 Racemic trans</td><td>ق</td><td>thioacetamide</td><td>Exp. 5Β</td><td>1.21 (method 3)</td><td>372 (MH) (</td>
<td>Exp. 11 Racemic trans</td><td>ج</td><td>1,1-dimethyl- thiourea</td><td>Exp. 5Α</td><td>1.15 (method 3)</td><td>435 (MH *</td>
<td>Exp. 12 Racemic trans</td><td>ί</td><td>thiourea</td><td>Exp. 5Α</td><td>1.15 (method 3)</td><td>407 (MH *</td>
Example 13 (racemiaue / TOM.؟.
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<img file="MA35575B1_D0074.tif" />
100 mg (0.215 mmol) of the product of Example 12Α were mixed with 1.00 ml (6.07 mmol) of 1,1,3,3-tetramethoxypropane. The reaction mixture was heated at 175٥c for 1 hour in a microwave oven. The reaction mixture was treated with a mixture of DCM / MeOH and a drop of triethylamine. The solvents were removed under reduced pressure. The mixture was purified by preparative HPLC (eluent A: water 0.13٥ ا / ο TFA, eluent B: MeOH) to give 45 mg (54%) of the title compound.
HPLC-MS (method 3): R = 1.36 min
MS (ESIpos): m / z- 387 (M٠H) '
The enantiomers of the title compound were separated by HPLC with a chiral stationary phase.
Enantioseparation method:
Device type for HPLC: Berger Minigram; column: Daicel IC, 5.0 pm,
250 mm X 10 mm; method: eluent 0/30% MeOH / 0.2% DEA (isocratic); flow rate: 10 ml / min, temperature: 40 ° C; pressure: 100 bar; uv detection: 210 nm
<td>Example</td><td>Structure</td><td>R<sub>t</sub> [min]</td>
<td>Exp. 14 Enantiomer 1 trans</td><td></td><td>3.15 (method 4)</td>
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<img file="MA35575B1_D0075.tif" />
The following example was synthesized analogously to the preparation of Example 13 using the corresponding dialdehyde diacetal as the starting material.
<td>Example</td><td>Structure</td><td>Starting product</td><td>Rt [min]</td><td>SM (ESl pos, m / z)</td>
<td>Exp. 16 Racemic trans</td><td> ;</td><td>1,1,3,3tetraethoxy-2-methylpropane</td><td>1.42 (method 3)</td><td>401 (M٠H) ٠</td>
Example 17 (racemic Irans)
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<img file="MA35575B1_D0076.tif" />
176 mg (0.431 mmol) of the product of Example 4Α were mixed with 3 ml of THF and
122 mg (0.302 mmol) of Lawesson's reagent at room temperature. Then the mixture was stirred for 6h at 6O٥C. The reaction mixture was worked up and diluted with DCM. The mixture was filtered through basic alumina and eluted with DCM and EtOH. The solvents were removed under reduced pressure. The residue was purified by preparative HPLC (eluent A: water 0.13٥ ا / ο TFA, eluent B: MeOH). 45 mg (26٥ / ο) of product were obtained.
HPLC-MS (method 3): R (= 1.37 min
MS (ESI pos): m / z = 407 (MUI) ؛
The enantiomers of the title compound were separated by HPLC with a chiral stationary phase.
Enantioseparation method:
Device type for HPLC: Berger Minigram; column: Daicel ADH, 5.0 µm,
250 mm X 10 mm; method: eluent Ο / 30٥ / ο MeOH / 0.2٥ / o DEA (isocratic); debit :
ml / min, temperature: 4O٥C; pressure: 100 bar; uv detection: 210 nm
<td>Example</td><td>Structure</td><td>R, [min]</td>
<td>Exp. 18 Enantiomer 1 trans (SS)</td><td> ٥٩'</td><td>2.47 (method 5)</td>
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<img file="MA35575B1_D0077.tif" />
The individual crystals of Example 19 were prepared by recrystallization from ethyl acetate and subjected to x-ray analysis. The data determined the absolute configuration of Example 19 to be (R, R ).
Experiment: data collection and reduction: data collected on CCD detector
Saturn 944 mounted on an AFCllK goniometer, radiation: Cu Ka from a RU200 rotating anode and a RIGAKU VARIMAX optical system, temperature: 100Κ.
Summary of statistics on data collection
Space group
Unit cell dimensions
Resolution range
Total number of reflections
Ρ21
8,560(2) 6,844(1) 15,603(3) 90,00 98,82(3) 90,00
15,42-0,85 (0,88-0,85)
10857
Number of unique reflections
Average redundancy% complete
1588
6,84
٩5١٦ (2,46) (79,1) (0,118) (7,9)
0,064
٦٦١٦ are given for the last layer of resolution.
Rmerge value
Output <I / sigI>
Values in parentheses
Refinement statistics:
Calculation of the final structural factor for example of 19 in Ρ21
Total number of parameters ls = 255
GooF == S = 1.154
Weight = l / [sigma٨2 (Fo٨2) 0.0421) ؛ * Ρ) ٨2 0.38 ا * P] where P = (Max (Fo٨2, 0) t 2 *
Bc2) / 3
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Rl = 0.0695 for 2207 Fo> 4sig (Fo) and 0.0829 for all 2334 data, wR2 = 0.1646,
Flack parameter x = 0.09 (3).
Example 20 (racemic transi
<img file="MA35575B1_D0078.tif" />
0.060 g of the product of Example 10Α was mixed with 4 ml of anhydrous dioxane and 0.074 g (0.180 mmol) of Lawesson's reagent. The reaction mixture was heated at 12O٠C 10 for 1 hour in a microwave oven. The mixture was filtered through basic alumina and eluted with DCM and MeOH. The solvents were removed under reduced pressure. The residue was purified by preparative HPLC (eluent A: water t 0.13% TFA, eluent B: MeOH). 22 mg of the product was obtained as a salt with TFA.
HPLC-MS (method 1): Rt = 0.94 min
MS (ESIpos): m / z = 393 (M٠H) ٠
Example 21 (racemic transi
<img file="MA35575B1_D0079.tif" />
Racemic Iran
-98MA
35575Β1
Boehringer Ingelheim International GmbH
P01-2655 / PCT
PC ΕΡ2011 / 063705
0.190 g (0.519 mmol) of the product of Example 8Ε was mixed with 1.38 ml (8.31 mmol) of triethoxymethane. The mixture was stirred for an hour and a half at 15O٥C. The reaction mixture was allowed to cool to room temperature and purified by preparative HPLC (eluent A: water t-0.13٥ / ο TFA, eluent B: MeOH). 90 mg (46%) of product were obtained.
HPLC-MS (method 1): R ، = 1.19 min MS (ESI pos): m / z = 377 (MH *
Example 22 (racemic mansd
Racemic trans
13 mg (0.10 mmol) of CuCl and 26 ml (0.22 mmol) of tert-butyl-nitrite were mixed with ACN. A mixture consisting of 22 mg (0.05 mmol) of the product of Example 12C was gently added to o٥c. The mixture was stirred for 1 h at 25٥c. In addition, 9 mg (0.07 mmol) of CuCl and 13 ml (0.11 mmol) of tert-butyl-nitrite were added which were stirred for a further 20 minutes. The solvents were removed under reduced pressure. The residue was taken up in DCM and extracted with HCl and water. The mixture was purified by preparative HPLC (eluent A: water د Ο, 13٥ / ο TFA, eluent B: MeOH) to give 2.1 mg (9%) of product.
HPLC-MS (method 3): R1.46 = ؛ min
MS (ESIpos): m / z - 426/428 (Cl) (M٠H)
Example 23 racemia
-99P01-2655 / PCT
PC ΕΡ2011 / 063705
MA 35575Β1
Boehringer Ingelheim International GmbH
<img file="MA35575B1_D0080.tif" />
Racemic trans
180 mg (0.26 mmol, content of 50 / ο estimated by HPLC-MS) of the product of Example 12b were mixed with 1.00 ml (6.07 mmol) of 1,1,3,3-tetramethoxypropane . The reaction mixture was heated at 175 ° C for 1 hour with a microwave oven. The reaction mixture was treated with DCM and washed with water. The organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash chromatography (Cy / EtOAc from 80/20 to AcOEt / MeOH 96/4) and then by a second flash chromatography (DCM 100٥ / ο to DCMZEtOH 96/4) in order to obtain the compound of the title as a beige solid. (O, O34g).
HPLC-MS (lEh method): R ،: 6.57 min
MS (APCI pos): m / z = 353 (MH) '
The enantiomers of the title compound were separated by HPLC with a chiral stationary phase.
Enantioseparation method:
Semi-preparative conditions:
Semi-preparative HPLC system: Waters 600 pump; column: Daicel chiralcel 0J-H, 250mm x 20mm, 5.0 µm; eluent: hexane / EtOH: 80/20; flow rate: 15 ml / min, temperature: 25٥c; uv detection: 254 nm
-100ΜΑ 35575Β1
<td>Boehringer Ingelheim International GmbH</td><td>PO1-2655 / PC1 PC7 / EP2011 / 063705</td>
<td>Example</td><td>structure</td><td>R [min]</td>
<td>Exp. 24 Enantiomer 1 trans</td><td> ٠</td><td>15.604 (method 6)</td>
<td>Exp. 25 Enantiomer 2 trans</td><td>ه</td><td>20,119 (method 6)</td>
Analysis conditions
Instrument type for HPLC: Agilent 1100; method 6; column: Daicel chiralcel
0J-H, 250mm X 4.6mm, 5.0 µm; eluent: hexane / EtOH 80/20; flow rate: 1 ml / min, temperature: 25٥c; uv detection: 254 nm
Example 26 (trans racemic)
-101MA
35575Β1
Boehringer Ingelheim International GmbH
P01-2655 / PCT
PC ΕΡ2011 / 063705
<img file="MA35575B1_D0081.tif" />
Racemic trans
140 mg (84% content, 0.33 mmol) of the product of Example 12C were mixed with 1.4 ml of 1,1,3,3-tetramethoxypropane and 1.4 ml of NMP. The reaction mixture was heated at 175٥c for 1 hour with a microwave oven. The reaction mixture was then diluted with MeOH and then loaded onto a scx cartridge. The ammoniacal fractions were collected and the residue was purified by flash chromatography (Cy / EtOAc 90/10 to 100٥ / ο) to obtain the title compound as a white solid (30 mg).
HPLC-MS (lEh method): Ri = 6.72 min
MS (APCIpos): m / z = 370 (MtH) *
The enantiomers of the title compound were separated by HPLC with a chiral stationary phase.
Enantioseparation method:
Semi-preparative conditions:
Semi-preparative HPLC system: Waters 600 pump; column: Daicel chiralcel
0J-H, 250mm X 20mm, 5.0 µm; eluent: hexane / EtOH: 80/20; flow rate: 15 ml / min, temperature: 25٥c; uv detection: 230 nm
-102UK
35575Β1
Boehringer Ingelheim International GmbH P01-2655 / PCT
PCT / EP2O11 / O637O5
<td>Example</td><td>structure</td><td>R [[min]</td>
<td>Exp. 27 Enantiomer 1 trans</td><td> *</td><td>1.748 (method 6)</td>
<td>Exp. 28 Enantiomer 2 trans</td><td> *</td><td>20,475 (method 6)</td>
Analysis conditions
Instrument type for HPLC: Agilent 1100; method 6; column: Daicel chiralcel 0J-H, 250mm X 4.6mm, 5.0 µm; eluent: hexane / EtOH: 80/20; flow rate: I ml / min, temperature: 25٥c; uv detection: 254 nm
Example 29 (racemiaue JranM
-103I
35575Β1
Boehringer Ingelheim International GmbH PO1-2655 / PC
PCL / EP2011 / 063705
<img file="MA35575B1_D0082.tif" />
Racemic trans
0.066 g (1.66 mmol) of sodium hydride (60% suspension in mineral oil) was added to a suspension of 0.132 g (0.63 mmol) of 5-amino acid amide. -1 (tetrahydro-pyran-4-yl) -1H-pyrazol-4-carboxylic acid (see PCT patent application WO2010 / 026214) in dry EtOH (1.5 ml) at room temperature under a nitrogen atmosphere. After 10 min, 0.181 mg (0.945 mmol) of the product of Example 13Α was added and the reaction mixture was heated at 14O٥C for 40 min in a microwave oven (power: 100 W). The reaction mixture was then diluted with DCM, the organic layer was separated and dried over sodium sulfate. The organic layer was evaporated under reduced pressure and the crude product was purified by flash chromatography (DCM / IPA: 98/2) to obtain the title compound as a white solid (54 mg, 32%).
HPLC-MS (lEh method): Ri = 8.01 min
MS (APCI pos): m / z = 352 (MH) ؛
The enantiomers of the title compound were separated by HPLC with a chiral stationary phase.
Enantioseparation method:
Semi-preparative conditions:
Semi-preparative HPLC system: Waters 600 pump; column: Daicel chiralcel 0J-H, 250mm X 20mm, 5.0 µm; eluent: hexane / EtOH: 85/15; flow rate: 15 ml / min, temperature: 25٥c; uv detection: 254 nm
-104Mk
35575Β1
Boehringer Ingelheim International GmbH P01-2655 / PCT
PCT / EP2011 / 063705
<td>Example</td><td>structure</td><td>Rt [min]</td>
<td>Exp. 30 Enantiomer 1 trans</td><td></td><td>14,754 (method 6.1)</td>
<td>Exp. 31 Enantiomer 2 trans</td><td> *</td><td>16.834 (method 6.1)</td>
Analysis conditions
Instrument type for HPLC: Agilent 1100; method 6.1; column: Daicel chiralcel 0J-H, 250mm X 4.6mm, 5.0 µm; eluent: hexane / EtOH: 85/15; flow rate: 1 ml / min, temperature: 25٠c; uv detection: 254 nm
Example 32 (racemiaue / TOM.؟)
-105MK
35575Β1
Boehringer Ingelheim International GmbH P01-2655 / PCT
PCT / EP2611 / 063705
<img file="MA35575B1_D0083.tif" />
0.066 g (1.66 mmol) of sodium hydride (60% suspension in mineral oil) was added to a suspension of 0.135 g (0.0553 mmol) of 5-amino acid amide. -1 (4,4-diflu0r0-cycl0hexyl) -1H-pyraz01e-4-carboxyl (see PCT patent application WO2010 / 026214) in dry EtOH (1.5 ml) at room temperature under a nitrogen atmosphere. After 10 min, 0.161 mg (0.837 mmol) of the product of Example 13Α was added and the reaction mixture was heated at 14O٥C for 40 min in a microwave oven (power: 100 w). The reaction mixture was then diluted with DCM, the organic layer was separated and dried over sodium sulate. The organic layer was evaporated under reduced pressure and the crude product was purified by flash chromatography (Cy / ΕΑ from 50/50 to 10/90) to obtain the title compound as a white solid (54 mg, 25 %).
HPLC-MS (lEh method): R ، = 9.63 min
MS (APCI pos): m / z = 386 (M + H)<sup>+</sup>
The enantiomers of the title compound were separated by HPLC with a chiral stationary phase.
Enantioseparation method:
Semi-preparative conditions:
Mk
35575Β1
Boehringer Ingelheim International GmbH
PO1-2655 / PCÏ
PC٢ / EP2011 / 063705
Semi-preparative HPLC system: Waters 600 pump; column: Daicel chiralpak
ADH, 250mm X 20mm, 5.0 µm; eluent: hexane / isopropanol: 80/20; flow rate: 10 ml / min, temperature: 25٥c; uv detection: 260 nm
<td>Example</td><td>structure</td><td>Rt [min]</td>
<td>Exp. 33 Enantiomer 1 trans</td><td></td><td>14.80 (method 7)</td>
<td>Exp. 34 Enantiomer 2 trans</td><td>Λ</td><td>20.40 (method 7)</td>
Analysis conditions
Instrument type for HPLC: Agilent 1100; method 7; column: Daicel chiralcel AD-H, 250mm X 4.6mm, 5.0 µm; eluent: hexane / isopropanol: 80/20; flow rate: 1 ml / min, temperature: 25٥c; uv detection: 260 nm.
-107Mk
Boehringer Ingelheim International GmbH
P01-2655 / PCT
PCT / EP2611 / 063705
Contents161
83 sheets
Sheet 1 Sheet 2 Sheet 3 Sheet 4 Sheet 5 Sheet 6 Sheet 7 Sheet 8 Sheet 9 Sheet 10 Sheet 11 Sheet 12 Sheet 13 Sheet 14 Sheet 15 Sheet 16 Sheet 17 Sheet 18 Sheet 19 Sheet 20 Sheet 21 Sheet 22 Sheet 23 Sheet 24 Sheet 25 Sheet 26 Sheet 27 Sheet 28 Sheet 29 Sheet 30 Sheet 31 Sheet 32 Sheet 33 Sheet 34 Sheet 35 Sheet 36 Sheet 37 Sheet 38 Sheet 39 Sheet 40 Sheet 41 Sheet 42 Sheet 43 Sheet 44 Sheet 45 Sheet 46 Sheet 47 Sheet 48 Sheet 49 Sheet 50 Sheet 51 Sheet 52 Sheet 53 Sheet 54 Sheet 55 Sheet 56 Sheet 57 Sheet 58 Sheet 59 Sheet 60 Sheet 61 Sheet 62 Sheet 63 Sheet 64 Sheet 65 Sheet 66 Sheet 67 Sheet 68 Sheet 69 Sheet 70 Sheet 71 Sheet 72 Sheet 73 Sheet 74 Sheet 75 Sheet 76 Sheet 77 Sheet 78 Sheet 79 Sheet 80 Sheet 81 Sheet 82 Sheet 83
80 members in 33 offices
Priority claims6
| Document | Office | Kind | Date |
|---|---|---|---|
| 10172597 | European Patent Office (EPO) | A | |
| 2011063705 | European Patent Office (EPO) | W | |
| 101725976 | – | – | – |
| EP20100172597 | – | – | – |
| PCTEP2011063705 | – | – | – |
| WO2011EP63705 | – | – | – |
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Numbers
- Publication
- 35575
- Publication, DOCDB
- 35575
- Publication, EPODOC
- MA35575
- Application
- 35623
- Application, DOCDB
- 35623
- Application, EPODOC
- MA20130035623
Titles2
- French
- Derives de 6-cycloalkyl-pyrazolopyrimidinones et leur utilisation comme inhibiteurs de la pde9a
- English
- Derivatives of 6-cycloalkyl-pyrazolopyrimidinones and their use as inhibitors of PDE9A
Classification
- CPC, 1
- C07D487/04
- IPC, 3
- A61K31 519
- A61P25 28
- C07D487 04
