BICYCLIC COMPOUNDS AS ATX INHIBITORS

专利摘要:
the invention provides new compounds that are endowed with the general formula (i) in which r1, r2, r9, y, w, m, n, p and q are as defined in this context, compositions that include the compounds and methods of using the compounds.
公开号:BR112018006024A2
申请号:R112018006024-0
申请日:2016-09-20
公开日:2020-05-12
发明作者:Di Giorgio Patrick；Hert Jérôme；Hunziker Daniel；Mattei Patrizio；Rudolph Markus；Schmitz Petra
申请人:F. Hoffmann-La Roche Ag；
IPC主号:

专利说明:

BICYCLIC COMPOUNDS AS ATX INHIBITORS
[001] The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to autotaxin inhibitors (ATX) which are inhibitors of lysophosphatidic acid (LPA) production and, therefore, modulators of LPA levels and associated signaling, for the treatment or prophylaxis of kidney conditions, liver conditions, inflammatory conditions, nervous system conditions, respiratory system conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, eye conditions, metabolic, cholestatic conditions and other forms of chronic itching and acute and chronic rejection of organ transplants.
[002] The present invention provides new compounds of formula (I)
on what
R ¹ is comprised of substituted phenyl, phenyl-C1-
6-substituted alkyl, substituted phenoxy-C1-g-alkyl, substituted phenyl-C2-6 ^_ substituted alkenyl, phenyl-C2-6 ^_ substituted alkynyl, substituted pyridinyl, substituted pyridinyl-C1-alkyl, pyridinyl-C2 -6 ^_ substituted alkenyl, pyridinyl-C2-6 ^_ substituted alkynyl, substituted thiophenyl, substituted thiophenyl-C1-6-alkyl, thiophenyl-C2_6 ^_ substituted alkenyl or thiophenyl-C2-6 ^_ substituted alkynyl, where phenyl substituted, substituted phenyl-C 1 -alkyl, phenoxy
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Substituted C1-6 alkyl, phenyl-C2-6 ^_ substituted alkenyl, substituted phenyl-C2-6 ^_ substituted alkynyl, substituted pyridinyl, substituted pyridinyl-C1-6 alkyl, pyridinyl-C2-6 ^_ substituted alkenyl, pyridinyl-C2 -6 ^_ substituted alkynyl, substituted thiophenyl, substituted thiophenyl-C1-6-alkyl, thiophenyl-C2-
6-alkenyl substituted thiophenyl and substituted alkynyl-C2-6 ^_ are replaced by R, R and R;
Y is comprised of -0C (0) or -C (0)
W is comprised of -C (0) -, -S (0) ₂ ^_ or -CR ⁶ R ⁷ -;
R is selected from the B ring systems,
F, L, Μ, 0, Z, AF, AG, AH, AJ, AN, AO, AP, AQ, AR, AS, AT, AU and AV;
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AQ


AV;
R is comprised of halogen, hydroxy, cyano,
C1-6-alkyl, C1-g-alkoxy, C1-g-alkoxy-C1-6-alkyl, halo-C1-6 alkoxy, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C3-8cycloalkyl, C3 - g-cycloalkyl -Ci-g-alkyl, C3-8cycloalkyl -Ci-g-alkoxy, Cs-s-cycloalkoxy, Cs-s-cycloalkoxyCi-6-alkyl, Ci-g-alkylamino, Ci-g-alkylcarbonylamino , C3-8cycloalkyl carbonylamino, C1-g-alkyl tetrazolyl, C1-alkyl alkyl tetrazolyl-C1-alkyl or heterocycle alkyl-C1-alkoxy;
5
R and R are selected independently from H, halogen, hydroxy, cyano, Ci-g-alkyl, Ci-g
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5/81 alkoxy, C1-6-alkoxy-C1-g-alkyl, halo-C1-alkoxy, halo-C1-alkyl, hydroxy-C1-alkyl, C3 - g-cycloalkyl, C3-8cycloalkyl - C1- g-alkyl, C3-g-cycloalkyl -Ci-g-alkoxy, Cs-g-cycloalkoxy, C3-8-cycloalkoxy -Ci-g-alkyl, Ci-galkylcarbonylamino, Ca-s-cycloalkyl carbonylamino, Ci -tetrazolyl-alkyl, C1-g-alkyl tetrazolyl-C1-g-alkyl or hetero-cycloalkyl -Ci-g-alkoxy;
R ⁶ is comprised of H or C 1 -alkyl;
R is comprised of H, C 1 -alkyl, halogen, halo-C 1 -alkyl or C 1 -alkoxy;
R ⁹ is comprised of halogen, C1-6 alkyl or C1-6 alkoxy;
m, n, p and q are selected independently from 1 or 2;
r is comprised of 1, 2 or 3;
or the pharmaceutically acceptable salts.
[003] Autotaxin (ATX) is comprised of a secreted enzyme that is also called ectonucleotide pyrophosphatase / phosphodiesterase 2 or lysophospholipase D, which is important for converting the lysophosphatidyl choline (LPC) to the lysophosphatidic acid of the bioactive signaling molecule ( LPA). Plasma levels of LPA have been shown to be largely related to ATX activity and, therefore, ATX is believed to be an important source of extracellular LPA. Early experiments with an ATX inhibitor prototype demonstrated that this compound has the ability to inhibit the synthesis activity of LPA in mouse plasma. Studies carried out in the 1970s and early 1980s demonstrated that LPA can cause
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6/81 a wide range of cellular responses; including contraction of smooth muscle cells, platelet activation, cell proliferation, chemotaxis and others. The LPA mediates its effects through signaling to several receptors coupled to protein G (GPCRs); the first limbs were originally referred to as Edg receptors (endothelial cell differentiation gene) or ventricular zone l gene (vzg-l), but are now called LPA receptors. The prototypical group now consists of LPAl / Edg-2 / VZG-1, LPA2 / Edg-4, and LPA3 / Edg-
7. Recently, three additional LPA4 receptors LPA4 / p2y9 / GPR23, LPA5 / GPR92 and LPA6 / p2Y5 have been described which are more closely related to selective purinergic nucleotide receptors than prototype LPA1-3 receptors. The ATX-LPA signaling axis is involved in a wide range of physiological and pathophysiological functions, which include, for example, nervous system function, vascular development, cardiovascular physiology, reproduction, immune system function, chronic inflammation, metastasis and progression of tumors, fibrosis of organs in the same way as obesity and / or other metabolic diseases such as diabetes mellitus. For this reason, increased ATX activity and / or increased LPA levels, altered LPA receptor expression and altered responses to LPA can contribute to the initiation, progression and / or result of a number of different pathophysiological conditions related to the axis of the ATX / LPA.
[004] According to the present invention, the compounds of formula (I) or their salts and esters
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7/81 pharmaceutically acceptable can be used for the treatment or prophylaxis of diseases, disorders or
conditions that They are associated with the activity of autotaxin and / Or the activity biological of acid lysophosphatidic (LPA). [005] The compounds from formula (I) or yours
pharmaceutically acceptable salts and esters in this context inhibit autotaxin activity and therefore inhibit LPA production and modulate LPA levels and associated signaling. The autotaxin inhibitors described in this context are useful as agents for the treatment or prevention of diseases or conditions in which ATX activity and / or LPA signaling participates, is involved in the etiology or pathology of the disease or, otherwise, is associated with at least one symptom of the disease. The ATX-LPA axis is implicated, for example, in angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer and tumor metastasis and progression, eye conditions, metabolic conditions, such as obesity and / or diabetes mellitus, conditions such as cholestatic or other forms. of chronic itching, as well as acute and chronic rejection of organ transplants.
[006] The objectives of the present invention are the compounds of formula (I) and their salts and esters mentioned above and their use as therapeutically active substances, a process for the manufacture of said compounds, intermediates, pharmaceutical compositions, medicaments containing said compounds, their pharmaceutically acceptable salts or esters, the use
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8/81 of said compounds, salts or esters for the treatment or prophylaxis of disorders or conditions that are associated with the activity of ATX and / or the biological activity of lysophosphatidic acid (LPA), with particularity in the treatment or prophylaxis of kidney conditions, liver conditions, inflammatory conditions, nervous system conditions, respiratory system conditions, vascular and cardiovascular diseases, fibrotic diseases, cancer, eye conditions, metabolic, cholestatic conditions and other forms of chronic and acute itching and / or chronic organ transplant rejection , and the use of said compounds, salts or esters for the production of drugs for the treatment or prophylaxis of kidney conditions, liver conditions, inflammatory conditions, nervous system conditions, respiratory, vascular and cardiovascular system conditions, fibrotic diseases, cancer , eye conditions, metabolic, cholestatic and other conditions forms of chronic itching and acute and chronic rejection of organ transplantation. More particularly, the compounds of formula (I) and their salts and esters mentioned above and their use as therapeutically active substances, a process for the manufacture of said compounds, intermediates, pharmaceutical compositions, drugs containing said compounds, their compounds pharmaceutically acceptable salts or esters, the use of said compounds, salts or esters for the treatment or prophylaxis of ocular conditions, in addition, in particular, glaucoma.
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[007] The term C1-g-alkoxy means a group of the formula -0-R ', where R' is comprised of a C1 -6 alkyl group. Examples of the C1- g-alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tercbutoxy. A particular example is understood by methoxy.
[008] The term C2-6 ^- alkenyl means a monovalent linear or branched hydrocarbon group of 2 to 6 carbon atoms with at least one double bond. A particular example is comprised of ethylenyl.
[009] The term Ci-g-alkoxy-Ci-g-alkyl means a Ci-g-alkyl group in which at least one of the hydrogen atoms in the Ci-g-alkyl group is replaced by a Ci-g-alkoxy group . Particular examples are comprised of methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, iso-propoxymethyl and iso-propoxyethyl.
[0010] The term C1-g-alkyl means a monovalent straight or branched saturated hydrocarbon group of 1 to 6 carbon atoms. Examples of C 1 -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. Particular alkyl groups include methyl, ethyl, isopropyl, n-butyl and secbutyl.
[0011] The term Ci-g-alkylamino means a group of the formula -NH-R ', where R' is comprised of a C1-6-alkyl group. The particular C1-g-alkylamino is comprised of a group of the formula -NH-R ', where R' is comprised of tert-butyl.
[0012] The term C1-g-alkylcarbonylamino means a group of the formula -NH-C (O) -R ', where R' is comprised of a C1-6-alkyl group. The Ci-6
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Particular alkylcarbonylamino is comprised of a group of the formula -NH-C (O) -R ', where R' is comprised of terbutyl.
[0013] The term Ci-6-alkylthetrazolyl means the tetrazolyl group substituted by a Ci-galkyl group. The particular C1-g-alkylthetrazolyl is comprised of methyltetrazolyl.
[0014] The term C1-g-alkyltetrazolyl-C1-alkyl means the C1-g-alkyl group in which one of the hydrogen atoms of the C1-g-alkyl group is replaced by a C1-6-alkyltetrazolyl group. A particular example is comprised of methyltetrazolylmethyl.
[0015] The term C2-6 alkynyl ^_ means a linear or branched monovalent hydrocarbon group of 2 to 6 carbon atoms with at least one triple bond.
[0016] 0 term ' 'amino means the group -NH ₂ .[0017] 0 term aminosulfonyl means the group -S (O) ₂ -NH ₂ .[0018] 0 term cyan means a group - C ^ N. [0019] 0 term Cs-g-cycloalkoxy means a
group of the formula -O-R ', where R' is comprised of a C3g-cycloalkyl.
[0020] The term Cs-g-cycloalkoxy-C1-alkyl means a C1-g-alkyl group in which at least one of the hydrogen atoms in the alkyl group is replaced by a Cs-g-cycloalkoxy group.
[0021] The term Cs-g-cycloalkyl means a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic
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11/81 means a ring system that consists of two saturated carbocycles that are endowed with two carbon atoms in common. Examples for monocyclic cycloalkyl are comprised of cyclopropyl, cyclobutanil, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic C3-8cycloalkyl are comprised of heptanil bicycles [2.2.1] or octanyl bicycles [2.2.2]. The particular C3-8cycloalkyl group is comprised of cyclopropyl.
[0022] The term Cs-s-cycloalkyl -Ci-g-alkoxy means a C1-6-alkoxy group in which at least one of the hydrogen atoms in the alkyl group is replaced by a Cs-s-cycloalkyl group.
[0023] The term Cs-s-cycloalkyl -Ci-g-alkyl means a C1-g-alkyl group in which at least one of the hydrogen atoms in the alkyl group is replaced by a Cs-s-cycloalkyl group.
[0024] The term Cs-s-cycloalkyl carbonylamino means a group of the formula -NH-C (O) -R ', where R' is comprised of a Cs-s-cycloalkyl group.
[0025] The term halo-C1-g-alkoxy means a C1 -6-alkoxy group in which at least one of the hydrogen atoms in the alkoxy group has been replaced by the same or different halogen atoms. Particular examples are comprised of trifluoromethoxy.
[0026] The term halogen and halo are used in this context interchangeably and mean fluorine, chlorine, bromine or iodine. Particular halogens are comprised of chlorine and fluorine.
[0027] The term halo-C1-g-alkyl means a C1-6-alkyl group in which at least one of the atoms of
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12/81 hydrogen of the Ci-g-alkyl group has been replaced by the same or different halogen atoms. Particular examples are comprised of trifluoromethyl.
[0028] The term heterocycloalkyl means a saturated or partially unsaturated, monovalent mono or bicyclic ring system of 4 to 9 ring atoms, comprising 1, 2, or 3 ring hetero atoms selected from N, O and S, the other ring atoms being comprised of carbon. Bicyclic means that it consists of two cycles that have two ring atoms in common, that is, the bridge that separates the two rings is a single bond or a chain of one or two ring atoms. Examples for monocyclic saturated heterocycloalkyl are 4,5-dihydro-oxazolyl, oxetanil, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, pyridine tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanil. Examples for saturated bicyclic heterocycloalkyl are 8aza-bicyclo [3.2.1] octyl, quinuclidinyl, 8-oxa-3-azabicyclo [3.2.1] octyl, 9-aza-bicyclo [3.3.1] nonil, 3 -oxa-
9-aza-biciclo [3.3.1] nonil, or 3-tia-9-aza-biciclo [3.3.1] nonil. Examples for partially unsaturated heterocycloalkyl are comprised of dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydropyridinyl or dihydropyranyl. A particular example of the heterocycloalkyl group is comprised of the hydropyranyl tetra.
[0029] The term heterocycloalkyl-C1-g-alkoxy
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13/81 means a C1-6 alkoxy group in which at least one of the hydrogen atoms in the alkyl group is replaced by a heterocycloalkyl group. A particular example of heterocycloalkyl-C1-6 alkoxy is comprised of tetrahydropyranyl-C1-6 alkoxy, most particularly tetrahydropyranylmethoxy.
[0030] The term hydroxy means an OH group.
[0031] The term hydroxy-C 1-6 alkyl means a C 1-6 alkyl group in which one of the hydrogen atoms of the alkyl group is replaced by a hydroxy group. Particular examples are comprised of hydroxymethyl and hydroxyethyl.
[0032] The term phenoxy means a group of the formula -O-R ', where R' is comprised of a phenyl group.
[0033] The term phenoxy-C 1-6 alkyl means a C 1-6 alkyl group in which one of the hydrogen atoms in the alkyl group is replaced by a phenoxy group.
[0034] The term phenyl-C ₂ -6 ~ alkenyl means a C ₂ -6 ~ alkenyl group in which one of the hydrogen atoms of the alkyl group is replaced by a phenyl group. A particular example of phenyl-C ₂ ^_ -6 alkenyl is understood by phenylethenyl.
[0035] The term phenyl-C1-g-alkyl means a C1-g-alkyl group in which one of the hydrogen atoms of the alkyl group is replaced by a phenyl group. Particular examples of phenyl-C 1 -alkyl are comprised of phenylmethyl and phenylethyl.
[0036] The term phenyl-C ₂ -6 ~ alkynyl means a C ₂ -6 ~ alkynyl group in which one of the hydrogen atoms in the
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14/81 alkyl group is replaced by a phenyl group.
[0037] The term pyridinyl-C2-6 ^_ alkenyl means a C2-6 ^_ alkenyl group in which one of the hydrogen atoms of the alkyl group is replaced by a pyridinyl group.
[0038] The term pyridinyl-C1-g-alkyl means a C1-g-alkyl group in which one of the hydrogen atoms of the alkyl group is replaced by a pyridinyl group. A particular example of pyridinyl-C 1 -alkyl is comprised of pyridinylmethyl, most particularly 2-pyridinylmethyl.
[0039] The term pyridinyl-C2_6 ^_ alkynyl means a C2_6 ^_ alkynyl group in which one of the hydrogen atoms of the alkyl group is replaced by a pyridinyl group.
[0040] The term thiophenyl-C2_6 ^_ alkenyl means a C2_6 ^_ alkenyl group in which one of the hydrogen atoms in the alkyl group is replaced by a thiophenyl group.
[0041] The term thiophenyl-C1-g-alkyl means a C1-g-alkyl group in which one of the hydrogen atoms of the alkyl group is replaced by a thiophenyl group.
[0042] The term C2-6-thiophenyl phenyl ^{_ _} C2-6 alkynyl means an alkynyl group in which one of the hydrogen atoms of the alkyl group is substituted by a phenylthio group.
[0043] The term pharmaceutically acceptable salts refers to those salts that retain the efficiency and biological properties of free bases or acids
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15/81 free, which are biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition, these salts can be prepared by adding an inorganic base or an organic base or free acid. Salts derived from an inorganic base include, but are not limited to, the salts of sodium, potassium, lithium, ammonium, calcium, magnesium and the like. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amine salts, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. The pharmaceutically acceptable salts of the compounds of formula (I) are comprised of the hydrochloride salts, the methanesulfonic acid salts and the citric acid salts.
[0044] Pharmaceutically esters
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Acceptable 16/81 means that the compounds of general formula (I) can be derived in functional groups to provide derivatives that are capable of conversion back to the original compounds in vivo. Examples of such compounds include those derived from physiologically acceptable metabolically labile esters, such as methoxymethyl esters, methyl thiomethyl esters and pivaloylmethyl esters. In addition, the physiologically acceptable equivalents of the compounds of the general formula (I), similar to the metabolically labile esters, which are capable of producing the original compounds of the general formula (I) in vivo, are within the scope of the present invention.
[0045] The term protecting group (PG) means a group that selectively blocks a reactive site in a multifunctional compound in such a way that a chemical reaction can be carried out selectively at another unprotected reactive site in the sense conventionally associated with it in synthetic chemistry . Protection groups can be removed at the appropriate point. Exemplary protection groups are comprised of amino protection groups, carboxy protection groups or hydroxy protection groups. Particular protecting groups are comprised of the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxy carbonyl (Fmoc) and benzyl (Bn) groups. Other particular protection groups are comprised of the tert-butoxycarbonyl (Boc) and fluorenyl methoxycarbonyl (Fmoc) groups. A more particular protecting group is comprised of the tert-butoxycarbonyl (Boc) group.
[0046] The abbreviation μΜ stands for micro Molar
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and is equivalent to pM symbol. [0047]The abbreviation pL means micro liter and is equivalent to pL symbol. [0048]The abbreviation pg means micro grass and is equivalent to symbol pg. [0049]The compounds gives formula (I) can
contain several asymmetric centers and may be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
[0050] According to the Cahn-IngoldPrelog Convention, the asymmetric carbon atom can be of the R or S configuration.
[0051] Also, an embodiment of the present invention is comprised of the compounds according to formula (I) as described in this context and the pharmaceutically acceptable salts or esters, in particular the compounds according to formula (I) as described in this context and their pharmaceutically acceptable salts, more particularly the compounds according to formula (I) as described in this context.
[0052] A particular embodiment of the present invention provides the compounds according to formula (I) as described in this context, wherein
R ¹ is comprised of substituted phenyl-C 1 -alkyl or substituted pyridinyl, wherein substituted phenyl-C 1 -alkyl and substituted pyridinyl-C 1 -alkyl are replaced by R, R and R;
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Y is comprised of -0C (0) - or -C (0) -;
W is comprised of -C (0) -;
R is selected from the 0, AJ, AN and AO ring systems;
the _z
R is comprised of halo-C 1 -g-alkoxy or tetrahydropyranyl-C 1 -6-alkoxy;
R ⁴ is comprised of H or C3 - g-cycloalkyl;
R is comprised of H;
R ⁶ is comprised of C 1 -g-alkyl;
R ⁹ is comprised of halogen, C1-g-alkyl or C1-6-alkoxy;
m, n, p and q are comprised of 1;
or the pharmaceutically acceptable salts.
[0053] Another embodiment of the present invention provides the compounds according to formula (I) as described in this context, wherein R ¹ is comprised of substituted phenyl-C 1 -alkyl or substituted pyridinyl, wherein f-enyl-C 1 -g-alkyl and substituted CI-6 ^_ prrrdrnrl alqurla substrturdo are replaced by R, R ⁴ and R ^5.
[0054] A particular embodiment of the present invention provides the compounds according to formula (I) as described in this context, where Y is comprised of -C (0).
[0055] Another embodiment of the present invention provides the compounds according to formula (I) as described in this context, wherein R is selected from the 0, AJ, AN and AO ring systems.
[0056] A particular embodiment of the present invention provides the compounds according to
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19/81 z 2 Z formula (I) tars as described in this context, where R is selected from the AJ and AO ring systems.
Another embodiment of the present invention provides the compounds according to formula (I) as described in this context, wherein R is comprised of halo-C 1 -alkoxy or tetrahydropyranyl-C 1 -coxy.
[0058] Another embodiment of the present invention provides the compounds according to formula (I) as described in this context, wherein R ⁴ is comprised of H or C ₄ a-cycloalkyl.
[0059] Another embodiment of the present invention provides the compounds according to formula (I) as described in this context, wherein R is comprised of H.
[0060] Another embodiment of the present invention provides the compounds according to formula (I) as described in this context, wherein R ⁶ is comprised of C 1 -alkyl.
[0061] Another embodiment of the present invention provides the compounds according to formula (I) as described in this context, wherein R ⁷ is comprised by H.
[0062] Another embodiment of the present invention provides the compounds according to formula (I) as described in this context, wherein R ⁹ is comprised of C 1 -g-alkoxy.
[0063] Another embodiment of the present invention provides the compounds according to formula (I) as described in this context, wherein m, n, p and q
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20/81 are comprised of 1.
[0064] A particular embodiment of the present invention provides the compounds according to formula (I) as described in this context, wherein
R ¹ is comprised of substituted phenyl-C 1 -alkyl or substituted pyridinyl, wherein substituted phenyl-C 1 -alkyl and substituted pyridinyl-C 1 -alkyl are replaced by R, R and R;
Y is comprised of -C (O) -;
W is comprised of -C (O) -;
R is selected from the AJ and AO ring systems;
R is comprised of halo-C1-g-alkoxy or tetrahydropyranyl-C1-6-alkoxy;
R ⁴ is comprised of H or C ₃ _3-cycloalkyl;
R is comprised of H;
R ⁶ is comprised of C 1 -g-alkyl;
R ⁷ is comprised of H;
R ⁹ is comprised of Ci-g-alkoxy;
m, n, p and q are comprised of 1 or the pharmaceutically acceptable salts.
[0065] Particular examples of the compounds of formula (I) as described in this context are selected from:
-trifluoromethoxy-benzyl ester of trans 5 - (1H-benzotriazole-5-carbonyl) -3a-fluoro-hexahydro pyrrolo [3,4-c] pyrrole -2-carboxylic;
-trifluoromethoxy-benzyl ester of trans 5 - (1H-benzotriazole-5-carbonyl) -3a-methoxy-hexahydro pyrrolo [3,4-c] pyrrole -2-carboxylic;
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21/81 trans -1 - [5 - (1H-benzotriazole -5-carbonyl) -3a-methoxy -3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -il] -3 - [4 - (trifluoromethoxy) phenyl] propan -1 -one;
trans - [5 - [2 -cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] -3a-methoxy -3,4,6,6a tetrahydro -1H -pyrrole [3,4 -c] pyrrole - 2-yl] - (1H benzotriazole -5-yl) methanone;
-trifluoromethoxy-benzyl ester of trans 5 - (1H-benzotriazole-5-carbonyl) -3a-methyl-hexahydro pyrrolo [3,4-c] pyrrole -2-carboxylic;
trans -5 - [3a-methoxy -2 - [3 - [4 (trifluoromethoxy) phenyl] propanoyl] -3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -5 -carbonyl] -3-methyl -1H benzimidazole -2 -one;
trans -5 - [5 - [2 -cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] -3a-methoxy -3,4,6,6a tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2-carbonyl] -3 methyl -1H -benzimidazole -2 -one;
trans - [3a-methoxy -5 - (1,4,6,7tetrahydrotriazolo [4,5 -c] pyridine -5 -carbonyl) -3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c ] pyrrole-2-yl] - [2-cyclopropyl-6 - (oxan-4-ylmethoxy) pyridin-4-yl] methanone;
trans -1 - [3a-methoxy -5 - (1,4,6,7tetrahydrotriazolo [4,5 -c] pyridine -5 -carbonyl) 3,4,6,6a -tetrahydro -1H -pyrrole [3, 4 - c] pyrrole -2 -yl] -3 - [4 - (trifluoromethoxy) phenyl] propan -1 -one;
trans -1 - [5 - (3-hydroxy -5,7-dihydro -4H [1,2] oxazolo [5,4 -c] pyridine -6 -carbonyl) -3a-methoxy 3,4,6,6a - tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] -3
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- [4 - (trifluoromethoxy) phenyl] propan -1 -one;
trans - [5 - (3-hydroxy -5,7-dihydro -4H - [1,2] oxazolo [5,4 -c] pyridine -6-carbonyl) -3a-methoxy 3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4 -yl] methanone;
trans - [3a-methoxy -5 - (1,4,6,7tetrahydrotriazolo [4,5 -c] pyridine -5 -carbonyl) 3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2-yl] - [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4yl] methanone;
trans - [5 - (3-hydroxy -5,7-dihydro -4H - [1,2] oxazolo [5,4 -c] pyridine -6-carbonyl) -3a-methoxy 3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2-yl] [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4yl] methanone;
-trifluoromethoxy-benzyl (+) trans -5 - (1H-benzotriazole -5-carbonyl) -3a-methyl hexahydro-pyrrole [3,4-c] pyrrole -2-carboxylic acid ester;
-trifluoromethoxy-benzyl (-) trans -5 - (1H-benzotriazole -5-carbonyl) -3a-methoxy hexahydro-pyrrole [3,4-c] pyrrole -2-carboxylic acid ester;
trans - [5 - (3-hydroxy -5,7-dihydro -4H - [1,2] oxazolo [5,4 -c] pyridine -6-carbonyl) -3a-methoxy 3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4 -yl] methanone;
-trifluoromethoxy-benzyl (-) trans -5 - (1H-benzotriazole -5-carbonyl) -3a-methyl hexahydro-pyrrole [3,4-c] pyrrole -2-carboxylic acid ester;
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-trifluoromethoxy-benzyl (+) trans -5 - (1H-benzotriazole -5-carbonyl) -3a-methoxy hexahydro-pyrrole [3,4-c] pyrrole -2-carboxylic acid ester;
and their pharmaceutically acceptable salts.
[0066] Other particular examples of compounds of formula (I) as described in this context are selected from:
trans -1 - [5 - (1H -benzotriazole -5 -carbonyl) -3a -methoxy -3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] -3 - [4 - (trifluoromethoxy) phenyl] propan -1 -one;
trans - [5 - [2 -cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] -3a-methoxy -3,4,6,6a tetrahydro -1H -pyrrole [3,4 -c] pyrrole - 2-yl] - (1H benzotriazole -5-yl) methanone;
trans - [5 - (3-hydroxy -5,7-dihydro -4H - [1,2] oxazolo [5,4 -c] pyridine -6-carbonyl) -3a-methoxy 3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4 -yl] methanone;
and their pharmaceutically acceptable salts.
[0067] Processes for the manufacture of the compounds of formula (I) as described in this context are an objective of the present invention.
[0068] The preparation of compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The syntheses of the invention are set out in the following general schemes. The practices necessary to carry out the reactions and the purifications of the resulting products are known to those skilled in the art. In case of
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24/81 a mixture of enantiomers or diastereoisomers is produced during a reaction, these enantiomers or diastereoisomers can be separated by methods described in this context or by the knowledge of the person skilled in the art, such as, for example, chromatography, (chiral) or crystallization . The substituents and indices used in the following description of the processes have the meaning given in this context.
[0069] The compounds of general formula (I) can be synthesized from the amine precursor 1 and appropriate reagents, using methods that are widely known in the art.
[0070] The preparation of compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The syntheses of the invention are set out in the following general schemes. The practices necessary for carrying out the reactions and the purification of the resulting products are known to those skilled in the art. In the event that a mixture of enantiomers or diastereoisomers is produced during a reaction, these enantiomers or diastereoisomers can be separated by methods described in this context or by the knowledge of the person skilled in the art, such as, for example, chromatography, (chiral) or crystallization . The substituents and indices used in the following description of the processes have the meaning given in this context.
[0071] The present invention provides new compounds of formula (I)
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[0072]
R ⁹
R ²
A — W 'q' η
The compounds of the general formula (I) can be synthesized from the amine precursor 1 and appropriate reagents, using methods that are widely known .9
HN
A W
[0073]
For example, amine 1 R ¹ -COOH (2) is reacted with a suitable carboxylic acid of the formula which leads to a compound of the formula in which Y is comprised of —C (O) -. The reaction The reaction is carried out in the presence of a coupling agent such as 1,1'carbonildiimidazole
Ν, Ν'-dicyclohexylcarbodiimide 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride
O- (benzotriazol-l-yl) -Ν, Ν, Ν ', Ν'-tetramethyluronium hexafluoro-phosphate
O- (7-azabenzotriazol-l-yl) -Ν, Ν, Ν ', Ν' tetramethyluronium hexafluoro-phosphate or bromo-trispyrrolidine-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N, Ndimethylformamide and their mixtures at temperatures between -40 ° C and 80 ° C in the presence or absence of a base such as triethylamine, diisopropylethylamine,
4-methylmorpholine and / or 4- (dimethylamino) pyridine.
[0074] Amine 1 can also be caused to react with suitable acylating reagents, such as acyl chlorides of the formula R ¹ -COC1 (3) to lead to
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26/81 compounds of formula (I), where Y is comprised of C (0) -. The reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran, or N, N-dimethylformamide, in the presence of a base such as triethylamine or 4methylmorpholine, at temperatures between 0 ° C and 80 ° C.
[0075] Alternatively, amine 1 is reacted with a chloroformate ester of the formula R ¹ -OC (O) -Cl (4), or with an imidazole-1-carboxylate ester of the formula (3) , which leads to a compound of formula (I) in which
Y is comprised of -OC (O) -.
[0076] The relationship is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N, Ndimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, for example, triethylamine, diisopropylethylamine, pyridine, potassium hydrogen carbonate, potassium carbonate, at temperatures between 0 ° C and the boiling point of the solvent or mixture of solvents.
[0077] Chloroformate esters 4 are found commercially available or can be synthesized from the corresponding alcohol of formula R ¹ -OH, by reaction with phosgene or a phosgene equivalent (eg diphosgene, triphosgene), as if is described in the literature.
[0078] The imidazole-1-carboxylate esters 5 are synthesized from the corresponding alcohols of the formula R ¹ -OH, by means of reaction with 1.1 '
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27/81 carbonyldiimidazole. The reaction is carried out at room temperature, in a solvent, such as dichloromethane, tetrahydrofuran or acetonitrile. Typically, the imidazole-1-carboxylate esters 5 are not isolated, but caused to react directly with amines 1 as previously described in this context.
[0079] Alcohols of the formula R ¹ -OH - or can be produced using methods described in this context or known in the art.
[0080] Carboxylic acids (2) and acyl halides (3) - or can be prepared as described in this context or in the literature.
[0081] Amines of general formula 1 are synthesized from precursors 6 suitably protected.
[0082] Suitable protection groups (PG) are tert-butoxycarbonyl or benzyloxycarbonyl. Deprotection of intermediates 6 can be accomplished using methods and reagents that are known in the art.
[0083] For example, in the case where PG is comprised of benzyloxycarbonyl, deprotection can be carried out by hydrogenation under pressures between 1 bar and 100 bar, in the presence of a suitable catalyst, such as palladium on activated carbon, at temperatures between 20 ° C and 150 ° C in solvents such as methanol or ethanol.
[0084] Alternatively, in case PG is understood as tert-butoxycarbonyl, deprotection
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28/81 can be carried out in the presence of a suitable acid, for example hydrochloric acid or trifluoroacetic acid, in a solvent such as water, 2-propanol, dichloromethane or 1,4dioxane at temperatures between 0 ° C and 30 ° C.
[0085]
Intermediaries 6 where understood by are represented by the general structure
6A.
R ⁹
PG-N: ^m i N — W
R ²
6A
PG is a suitable protecting group, for example tert-butoxycarbonyl or benzyloxycarbonyl.
Intermediates 6A can be produced from amine precursors of the general formula 7 by reaction with appropriate reagents, using methods as are known in the art.
R ⁹ agents
X ^y P PG-N 'm
NH
For example, alkylation of the general formula X-CR ⁶ R ⁷ -R ² (8) is reacted with where X is comprised of an leaving group such as Cl
Br, I or OSO2CH3, which lead to 6A, where W is comprised of
-CR ⁶ R ⁷ -. This reaction is carried out in a solvent such as tetrahydrofuran or N, N-dimethylformamide, in the presence of a base, for example, triethylamine or potassium carbonate at temperatures between 0 ° C and 100 ° C.
Alternatively for compounds of formula 6A, where W is comprised of
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CR ⁶ R ⁷ -, R ⁶ is comprised of hydrogen, alkyl or cycloalkyl, and R ⁷ is comprised of H, amine 7 is reacted with aldehydes or ketones of the general formula R ⁶ -C (0) -R ² ( 9) in a reductive amination reaction, which leads to 6A. This reaction is carried out in the presence of a suitable reducing agent, for example, sodium borohydride or sodium triacetoxyy-borohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane or mixtures thereof , under temperatures between 0 ° C and 50 ° C.
[0090] In an form alternative, the amine 7 is taken to react with one acid carboxylic suitable gives formula R ² -COOH (10), what leads to compounds of the formula 6A, in that W is comprised of -C (0) -. The reaction is
carried out in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, Ν, Ν'-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, 0- (benzotriazol-l-yl) -N, N, Ν ', Ν'-tetramethyluronium hexafluoro-phosphate, 0- (7-azabenzotriazol-l-yl) -N, N, Ν', Ν 'tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidine-hexafluorophosphate phosphonium, in aprotic solvents, such as dichloromethane, tetrahydrofuran, N, Ndimethylformamide, N-methylpyrrolidinone and their mixtures at temperatures between -40 ° C and 80 ° C in the presence or absence of a base, such as triethylamine, diisopropylethylamine, 4 -methylmorpholine and / or 4 (dimethylamino) pyridine.
[0091] Alternatively, amine 7 is reacted with a suitable sulfonyl chloride of formula R2-SO2C1 (11), which leads to a compound of formula
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6A, where W is comprised of -S (02) -. A reaction is carried out in a suitable solvent, such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, for example, triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0 ° C and the boiling point of the solvent or mixture of solvents.
[0092] Alternatively, amine 7 is reacted with a suitable N- (chlorocarbonyl) amine of formula R2-N (RIO) -C (0) -Cl (12) which leads to a compound of formula 6A , where W is comprised of -C (0) -NR10-, or with an isocyanate of formula R2-NCO (13), which leads to a compound of formula 6A, where W is comprised of -C (0) NR ¹⁰ - and R ¹⁰ is comprised of H.
[0093] Alternatively, amine 7 is reacted with phosgene or phosgene equivalent (diphosgene, triphosgene) in the presence of a base (eg, pyridine, triethylamine) in a solvent such as dichloromethane or tetrahydrofuran, to the corresponding N- (chlorocarbonyl) amine of formula 14 is provided, which is then reacted with the amine of formula HN (RIO) R2 (15), in the presence of a base, such as triethylamine or diisopropylethylamine, in a solvent such as such as dichloromethane, tetrahydrofuran, or N, N-dimethylformamide, which lead to compounds of the formula 6A, where W is comprised of -C (0) -NR ¹⁰ .
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PG — Ν
R ⁹
Ο
Cl
In
[0094] according to an alternative form, the amine is reacted with phosgene or phosgene equivalent (diphosgene, triphosgene) in the presence of a base (for example, pyridine, triethylamine), in a solvent such as dichloromethane or tetrahydrofuran, to the corresponding N- (chlorocarbonyl) amine of formula 14, which is then reacted with amines of formula H-0 or H-AO, in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent, such as dichloromethane, tetra hydrofuran, or N, N-dimethylformamide, which leads to compounds of formula 6A, where W is comprised of -C (O) - and R and comprised of O or AO.
[0095] In a way the amine 7 with a chloroform
C (O) -Cl (16) or with an alternative ester, the appropriate _z 2 of formula R-0 of imidazole-1-carboxylate (17) is reacted, which leads to the compounds of formula 6A, where W is comprised of -C (0) -0-. The reaction is carried out in a suitable solvent, for example, acetonitrile or N, Ndimethylformamide, optionally in the presence of a base, for example, diisopropylethylamine or triethylamine, at temperatures between 0 ° C and 100 ° C.
[0096] Chloroformates 16 are found commercially available or can be prepared
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Z z 2 from the corresponding alcohols of formula R -OH, by reaction with phosgene or a phosgene equivalent (eg diphosgene, triphosgene) as described in this context or in the literature.
[0097] Imidazole-1-carboxylate esters 17 can be prepared from the corresponding alcohols of formula R -OH, by reaction with 1,1'carbonyldiimidazole as described in this context or in the literature.
[0098] The N- (chlorocarbonyl) amines 12 are synthesized from the corresponding amines 15 by means of reaction with phosgene or a phosgene equivalent (diphosgene, triphosgene, 1,1'-carbonyldiimidazole) as described in the literature.
[0099] Isocyanates 13 are found commercially available or can be prepared from the corresponding amines of the formula R -NH ₂ , by means of reaction with phosgene or a phosgene equivalent (for example, diphosgene, triphosgene, 1,1'carbonildiimidazole ) as described in the literature.
[00100] Amines 7, alkylating agents 8, aldehydes / ketones 9, carboxylic acids 10, sulfonyl chlorides 11, and amines 15 are found commercially available or can be synthesized as described in this context or in the literature.
[00101] The carbamates 6 in which A is understood by CH, and W is understood by -C (O) -N (R ¹⁰ ), are represented by the general formula 6B, in which R ¹⁴ is understood by N (R) R . Carbamates 6 where A is comprised of CH, W
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33/81 .9
PG-N
001021 The amine amine of formula
PG-N
[00103] A ✓ 2 ✓ and comprised by -C (0) - and R and comprised by O or AO are also represented by the general formula 6B, where R ¹⁴ is comprised by O or AO.
O <6B
R ¹⁴
6B is produced from carboxylic acid 18 by means of a coupling reaction with an HN (R ¹⁰ ) R ² (15), H-0 or H-AO.
^r 7)
O) - 18 oh q
reaction is carried out in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N, Ν'-dicyclohexyl carbodiimide, l— (3— dimethylaminopropyl) -3-ethyl-carbodiimide, hexafluoro-phosphate 0- ( benzotriazol-1-yl) -N, N, Ν ', Ν' tetramethyluronium, hexafluoro phosphate 0- (7azabenzotriazol-l-yl) -N, N, Ν ', Ν'-tetramethyluronium or bromo-tris- hexafluorophosphate pyrrolidine-phosphonium, in aprotic solvents such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, Nmethylpyrrolidinone and mixtures under temperatures between -40 ° C and 80 ° C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4methylmorpholine and / or 4- (dimethylamino) pyridine.
[00104] Carboxylic acids 18 are found commercially available or can be produced as described in the literature.
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[00105] The compounds of formula (I), where A is comprised of N can be produced from the amine precursors of general formula 19 by reaction with appropriate reagents, using methods such as are known in the art.
Y — N / Η ₁₉
R v7q ~; _n
[00106] For example, an amine of formula 19 is reacted with alkylating agents of the general formula XCR ⁶ R ⁷ -R ² (8) where X is comprised of a leaving group, such as Cl, Br, I, or OSO2CH3, which leads to compounds of formula (I), where A is comprised of N and W is comprised of -CR ⁶ R ⁷ -. This reaction is carried out in a solvent such as tetrahydrofuran or N, Ndimethylformamide, in the presence of a base, for example, triethylamine or potassium carbonate, at temperatures between 0 ° C and 100 ° C.
[00107] Alternatively, an amine of formula 19 is reacted with aldehydes or ketones of the general formula R ⁶ -C (O) -R ² (9) in a reductive amination reaction, which leads to the compounds of formula (I) where A is comprised of N, W is comprised of -CR ⁶ R ⁷ -, R ⁶ is comprised of hydrogen, alkyl or cycloalkyl, and R ⁷ is comprised of H. This reaction is carried out in the presence of an agent suitable reducing agent, for example, sodium borohydride or sodium triacetoxy borohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane or mixtures thereof, at temperatures between 0 ° C and 50 ° C ° C.
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[00108] Alternatively, amine 19 is reacted with a suitable carboxylic acid of formula R COOH (10), which leads to compounds of formula (I) in which A is comprised of N and W is comprised of - C (O) -. The reaction is carried out in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, Ν, Ν'-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) 3-ethyl-carbodiimide hydrochloride, O- (hexafluoro-phosphate) benzotriazol1-yl) -N, N, Ν ', Ν'-tetramethyluronium, 0 (7-azabenzotriazol-l-yl) hexafluoro-phosphate -N, N, Ν', Ν'-tetramethyluronium or bromo-tris hexafluoro phosphate -pyrrolidine-phosphonium, in aprotic solvents such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, Nmethylpyrrolidinone and mixtures under temperatures between -40 ° C and 80 ° C in the presence or absence of a base such as triethylamine, diisopropiethylamine , 4methylmorpholine and / or 4- (dimethylamino) pyridine.
[00109] Alternatively, amine 19 is reacted with a suitable sulfonyl chloride of formula R SO2CI (11), which leads to (I) where A is comprised of N and W is comprised of -S ( O2) -. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, for example, triethylamine, diisopropylethylamine, pyridine, potassium hydrogen carbonate, potassium carbonate, at temperatures between 0 ° C and the boiling point of the solvent or mixture of solvents.
[00110] Alternatively, amine 19 is reacted with the appropriate N- (chlorocarbonyl) amine of the formula
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10
R -N (R) -C (0) -Cl (12) which leads to compounds of formula (I), where W is comprised of -C (0) -NR ¹⁰ -, or with an isocyanate of formula R - NCO (13), which leads to compounds of formula (I), where W is comprised of -C (O) -NR ¹⁰ - and R ¹⁰ is comprised of Η. The reaction is carried out in a suitable solvent, for example, acetonitrile or N, Ndimethylformamide, optionally in the presence of a base, for example, diisopropyl ethylamine or triethylamine, at temperatures between 0 ° C and 100 ° C.
[00111] Alternatively, amine 19 is reacted with a suitable chloroformate of formula R-0-C (0) Cl (16) or with an imidazole-1-carboxylate ester (17), which leads to compounds of formula (I), where W is comprised of -C (0) -0-. The reaction is carried out in a suitable solvent, for example, acetonitrile or N, Ndimethylformamide, optionally in the presence of a base, for example, diisopropyl ethylamine or triethylamine, at temperatures between 0 ° C and 100 ° C.
[00112] Alternatively, amine 19 is reacted with phosgene or phosgene equivalent (diphosgene, triphosgene) in the presence of a base (eg, pyridine, triethylamine) in a solvent, such as dichloromethane or tetrahydrofuran, to providing the corresponding N- (chlorocarbonyl) amine of formula 20, which is then reacted with amine of formula HN (R) R (15), in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane, tetrahydrofuran, or N, N-dimethylformamide, which leads to compounds of formula (I), where W is comprised of -C (O) -NR ¹⁰ -.
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[00113] Alternatively, amine 19 is reacted with phosgene or a phosgene equivalent (diphosgene, triphosgene) in the presence of a base (eg, pyridine, triethylamine), in a solvent such as dichloromethane or tetrahydrofuran , for the corresponding N- (chlorocarbonyl) amine of formula 20, which is then reacted with amines of formula H-0 or H-AO, in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane, tetrahydrofuran, or N, N-dimethylformamide, which leads to the compounds of formula (I), where W is comprised of -C (O) - and R is comprised of O or AO.
[00114] Amines 19 can be synthesized from their tert-butyl carbamate derivatives of formula 21 by means of carbamate deprotection. Deprotection can be carried out in the presence of a suitable acid, for example, hydrochloric acid or trifluoroacetic acid, in a solvent such as water, 2-propanol, dichloromethane, or 1,4dioxane, at temperatures between 0 ° C and 30 ° C .
[00115] The tert-butyl carbamates 21 can be synthesized from amine precursors of formula 22 and appropriate reagents, using methods that are widely known in the art.
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[00116] For example, amine 22 is reacted with a suitable carboxylic acid of formula R ¹ -COOH (2) which leads to compounds of formula 21, where Y is comprised of -C (O) -. The reaction is carried out in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N, N'dicyclohexylcarbodiimide, 1— (3— dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, O- (hexafluoro-phosphate) benzotriazol-l-yl) -N, N, Ν ', Ν'-tetramethyluronium, O- (7-azabenzotriazol-l-yl) hexafluoro-phosphate -N, N, Ν', Ν'tetramethyluronium or bromine hexafluoro phosphate -trispirrolidine-phosphonium, in aprotic solvents such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, Nmethylpyrrolidinone and mixtures under temperatures between -40 ° C and 80 ° C in the presence or absence of a base such as triethylamine, diisopropylethylamine , 4methylmorpholine and / or 4- (dimethylamino) pyridine.
[00117] Amine 22 can also be reacted with suitable acylating reagents, such as acyl chlorides of formula R ¹ -COC1 (3) to provide compounds of formula 21, where Y is comprised of -C (O ) The reaction is carried out in a solvent, such as dichloromethane, tetrahydrofuran, or N, N-dimethylformamide, in the presence of a base, such as triethylamine or 4methylmorpholine, at temperatures between 0 ° C and 80 ° C.
[00118] Alternatively, amine 22 is reacted with a suitable chloroformate ester of formula R ¹ -OC (O) -Cl (4), or with an imidazole-1-carboxylate ester
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39/81 of formula 5, which leads to a compound of formula 21, where Y is comprised of -0C (0) -. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, for example, triethylamine, diisopropyl ethylamine, pyridine, potassium hydrogencarbonate , potassium carbonate, at temperatures between 0 ° C and the boiling point of the solvent or mixtures of solvents.
[00119] Alternatively, amine 22 can be caused to react with a phosgene or a phosgene equivalent (for example, triphosgene) for the corresponding N-chlorocarbonylamine 22A, in the presence of a base (for example, pyridine) in a suitable solvent, for example, dichloromethane, at temperatures between -78 ° C and +20 ° C. N-chlorocarbonylamine 22A is then reacted with alcohol of formula R ¹ -OH, which leads to a compound of formula 21, where Y is comprised of -OC (O) -. This reaction is carried out in a suitable solvent (for example, acetonitrile or dichloromethane) in the presence of a suitable base (for example, sodium hydride, pyridine or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3, 2 polystyrene-binding diazaphosphorin), at temperatures between 20 ° C and the boiling point of the solvent.
[00120] Amines of commercially available or
22The formula 22 are found can be produced as
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[00121] Amines of formula 22 are found commercially available or can be produced as described in this context or in the literature.
[00122] The compounds of formula (I), where A is comprised of CH and W is comprised of -C (O) -NR ¹⁰ - can be produced from carboxylic acid precursors of general formula 23 by means of reaction with appropriate amine reagents of the general formula HN (R) R (15). Similarly, the compounds of formula (I), where A is comprised of CH, W is comprised of C (O), and R and comprised of O or AO, can be produced from carboxylic acid precursors of the formula general 19 by reaction with appropriate amine reagents from
general formula H-0 or H-AO, using methods that are known in technical. R ⁹ Jm O Y -N231/ή OH R vTq V / n [00123] For example, this reaction is performed in presence of an agent of coupling such as 1,1'-
carbonyldiimidazole, Ν, Ν'-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, O- (benzotriazol-l-yl) -Ν, Ν, Ν ', Ν'- Methyluronium tetra, O- (7-azabenzotriazol-lil) -Ν, Ν, Ν ', Ν'-tetramethyluronium or hexafluoro phosphate, bromo-tris-pyrrolidine-phosphonium phosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran , Ndimethylformamide, N-methylpyrrolidinone and their mixtures
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41/81 at temperatures between -40 ° C and 80 ° C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and / or 4 (dimethylamino) pyridine.
[00124] The compounds of formula (I), where A is comprised of CH and W is comprised of -C (O) -O- can be produced from carboxylic acid precursors of general formula 23 by reaction with appropriate alcohols of the general formula R -OH, using methods as are known in the art.
[00125] For example, this reaction is carried out in the presence of a coupling agent such as 1,1'carbonyldiimidazole, N, Ν'-dicyclohexyl carbodiimide, 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, hexafluoro -O- (benzotriazol-l-yl) -N, N, Ν ', Ν'tetramethyluronium, hexafluoro 0- (7azabenzotriazol-l-yl) -N, N, Ν', Ν'-tetramethyluronium or hexafluoro bromo-tris-pyrrolidine-phosphonium phosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, Nmethylpyrrolidinone and their mixtures under temperatures between -40 ° C and 80 ° C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4methylmorpholine and / or 4- (dimethylamino) pyridine.
[00126] Alternatively, the reaction is carried out in two stages in which carboxylic acid 19 is first converted to acid chloride 24, using methods and reagents that are known in the art, for example, thionyl chloride or chloride oxalyl. The acid chloride 24 is then reacted with alcohol R -OH in a
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42/81 suitable solvent, for example, dichloromethane or acetonitrile, optionally in the presence of a catalyst, for example, pyridine or 4- (dimethylamino) pyridine, at temperatures between -40 ° C and + 100 ° C.
F 07p-Y — N 24 1/ Cl R ' 7q v Jn [00127] Theacids carboxylic 23 can to be
produced from the corresponding ester precursors 25, wherein R ^a is comprised of lower alkyl, for example, methyl or ethyl, using methods and reagents as are known in the art. For example, the reaction is carried out in the presence of a base, for example, potassium hydroxide, sodium hydroxide, or lithium hydroxide, in solvents such as water, methanol, ethanol, tetrahydrofuran, or mixtures thereof, at temperatures between 20 ° C and 100 ° C.
of the formula can be synthesized from amine precursors of formula 26 and appropriate reagents, using methods that are widely known .9
HN
What
O — R ^a
[00129] For example, the amine is reacted with a suitable carboxylic acid of the formula
R ^ COOH (2) that
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43/81 leads to compounds of formula 25, where Y is comprised of -C (0) -. The reaction is carried out in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N, N'dicyclohexylcarbodiimide, 1— (3— dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, 0- (benzotriazol hexafluoro phosphate -l-yl) -N, N, Ν ', Ν'-tetramethyluronium, 0- (7-azabenzotriazol-l-yl) -N, N, Ν', Ν'tetramethyluronium or brominated hexafluoro phosphate- trispirrolidine-phosphonium, in aprotic solvents such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, Nmethylpyrrolidinone and mixtures under temperatures between -40 ° C and 80 ° C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4methylmorpholine and / or 4- (dimethylamino) pyridine.
[00130] Amine 25 can also be caused to react with suitable acylating reagents, such as acyl chlorides of the formula R ¹ -COC1 (3) to lead to the compounds of formula 26, where Y is comprised of -C (0 ) -. The reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran, or N, N-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0 ° C and 80 ° C.
[00131] Alternatively, amine 26 is reacted with a suitable chloroformate ester of formula R ¹ -OC (0) -Cl (4), or with an imidazole-1-carboxylate ester of formula 5, leading to a compound of formula 25, where Y is comprised of -0C (0) -. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a
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44/81 base, for example, triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0 ° C and the boiling point of the solvent or mixture of solvents.
[00132] Alternatively, amine 26 can be reacted with phosgene or a phosgene equivalent (eg, triphosgene) to the corresponding N-chlorocarbonylamine 26A, in the presence of a base (eg, pyridine) in a suitable solvent, for example, dichloromethane, at temperatures between -78 ° C and + 20 ° C. Then, N-chlorocarbonylamine 26A is reacted with alcohol of formula R ¹ -OH, which leads to a compound of formula 25, where Y is comprised of -OC (O) -. This reaction is carried out in a suitable solvent (for example, acetonitrile or dichloromethane) in the presence of a suitable base (for example, sodium hydride, pyridine or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3, 2 polystyrene-binding diazaphosphorin), at temperatures between 20 ° C and the boiling point of the solvent.
26From
general formula 26, adequately protected precursors 27 are synthesized.
.9
PG-N
THE
O — R ^a
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[00134] Suitable protecting groups (PG) are comprised of tert-butoxycarbonyl or benzyloxycarbonyl. Deprotection of intermediates 27 can be carried out using methods and reagents that are known in the art.
[00135] For example, in case PG is comprised of benzyloxycarbonyl, deprotection can be carried out by hydrogenation under pressures between 1 bar and 100 bar, in the presence of a suitable catalyst, such as palladium on activated carbon, at temperatures situated between 20 ° C and 150 ° C, in solvents such as methanol or ethanol.
[00136] Alternatively, if PG is comprised of tert-butoxycarbonyl, deprotection can be carried out in the presence of a suitable acid, for example, hydrochloric acid or trifluoro acetic acid, in a solvent such as water, 2- propanol, dichloromethane or 1,4dioxane, at temperatures between 0 ° C and 30 ° C.
[00137] Esters 27, in which R ^a is comprised of methyl or ethyl, are produced from carboxylic acids 18, using methods and reagents that are known in the art. For example, 18 alkylated with methyl iodide or ethyl bromide, in the presence of a base, for example, potassium carbonate, in a solvent such as N, N-dimethylformamide, under -20 ° C and +30 ° C, which leads to a methyl or ethyl ester 27, respectively.
[00138] Also an embodiment of the present invention is comprised of a process for preparing a compound of formula (I) as defined above which comprises reacting a compound of formula (II) in the presence of a compound of formula (III);
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(Η) (I) where R, R, R, m, n, p and p are as defined above and W is comprised of -C (0) -.
[00138] In particular, in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N, N'dicyclohexylcarbodiimide, 1— (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride, O-hexafluoro-phosphate (benzotriazol-l-yl) -N, N, Ν ', Ν'-tetramethyluronium, hexafluoro-phosphate O- (7-azabenzotriazol-l-yl) -N, N, Ν', Ν 'tetramethyluronium or hexafluoro phosphate bromo-trispirrolidino-phosphonium, in particular O- (7-azabenzotriazol-l-yl) -N, N, Ν ', Ν'-tetramethyluronium hexafluorophosphate, in an aprotic solvent, such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide , Nmethylpyrrolidinone and mixtures thereof, with particularity N, N-dimethylformamide, in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4methylmorpholine and / or 4- (dimethylamino) pyridine, particularly in the presence of 4-methylmorpholine and under a temperature comprised between -78 ° C and reflux, in particular between -10 ° C and room temperature.
[00139] Also an object of the present invention is comprised of a compound according to formula (I) as described in this context for use as a therapeutically active substance.
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[00140] Similarly, an objective of the present invention is comprised of a pharmaceutical composition comprising a compound according to formula (I) as described in this context and a therapeutically inert carrier.
[00141] A particular embodiment of the present invention is comprised of a compound according to formula (I) as described in this context for the treatment or prophylaxis of ocular conditions, with particular glaucoma.
[00142] The present invention also relates to the use of a compound according to formula (I) as described in this context for the preparation of a medicament for the treatment or prophylaxis of ocular conditions, with particular glaucoma.
[00143] Also an object of the invention consists of a method for the treatment or prophylaxis of ocular conditions, with particular glaucoma, which method comprises administering an effective amount of a compound according to formula (I) as described in this context.
[00144] Renal conditions include, but are not limited to, acute kidney injury and chronic kidney disease with and without proteinuria, including end-stage renal disease (ESRD). In more detail, this includes decreased creatinine clearance and decreased glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of the reticulated mesangial matrix with or without significant hypercellularity (with particular nephropiated amyloidosis
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48/81 diabetic), focal thrombosis of glomerular capillaries (with particular thrombotic microangiopathies), global fibrinotic necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary (endothelial) cells and mesangial) and / or extracapillary (crescents) such as in nephritis of glomerular entities, focal segmental glomerular sclerosis, IgA nephropathy, systemic vasculitis / diseases, as well as acute and chronic kidney transplant rejection.
[00145] Liver conditions include, but are not limited to, liver cirrhosis, liver congestion, cholestatic liver disease, including pruritus, non-alcoholic hepatitis and chronic acute liver transplant rejection.
[00146] Inflammatory conditions include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, abnormal and similar evacuation disorders, as well as inflammatory diseases of the respiratory tract such as fibrosis idiopathic pulmonary disease (IPF), chronic obstructive pulmonary disease (EPOC) or chronic bronchial asthma.
[00147] Other conditions of the respiratory system include, but are not limited to, other diffuse parenchymal lung diseases of different etiologies include iatrogenic drug-induced fibrosis, work-induced and / or environmental fibrosis,
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49/81 systemic diseases and vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans' cell granulomatosis, lymphangioleiomyomatosis, hereditary diseases (Hermansqui-Pudlak syndrome, tuberous sclerosis, neurofibrosis of tuberics, neurofibrosis, neurofibrosis , familial interstitial lung disease), radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis or acute respiratory distress syndrome (ARDS).
[00148] The conditions of the nervous system include, but are not limited to, neuropathic pain, schizophrenia, neuroinflammation (for example, astrogliosis), peripheral and / or autonomic (diabetic) and similar neuropathies.
[00149] Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular disease, as well as thrombotic microangiopathies, proliferating arteriopathy (such as swollen myointimate cells surrounded by nodular thickening of the mucinous extracellular matrix), atherosclerosis, decreased vascular adherence (such as stiffness, reduced ventricular compliance and reduced vascular adherence), endothelial dysfunction and the like.
[00150] Cardiovascular conditions include, but are not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia, such as atrial fibrillation, stroke and other vascular damage .
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[00151] Fibrotic diseases include, but are not limited to, myocardial vascular fibrosis and renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and encapsulation epidemic.
[00152] Cancer and cancer metastases include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver carcinoma, gastrointestinal cancer and metastatic progression and aggressiveness of the same.
[00153] Eye conditions include, but are not limited to, proliferating and non-proliferating (diabetic) retinopathy, age-related dry and wet macular degeneration (AMD), macular edema, central / venous arterial occlusion, traumatic injury , glaucoma and the like. In particular, the eye condition is comprised of glaucoma.
[00154] Metabolic conditions include, but are not limited to, obesity and diabetes.
[00155] Also an embodiment of the present invention is comprised of the compounds of formula (I) as described in this context, when manufactured according to any of the described processes.
Test procedures
PRODUCTION OF FULL-LENGTH HUMAN ATX, WITH AND WITHOUT ITS MARKER
[00156] Autotaxin Cloning (ATX - ENPP2): The cDNA was prepared from total RNA from commercial human hematopoietic cells and used as a template
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51/81 in the superimposed PCR to generate a full-length human ORF ENPP2 with or without a 3'-6xHis marker. These flat length inserts were cloned into the vector pcDNA3.lV5-His TOPO (Invitrogen). The DNA sequences of several unique clones were verified. The DNA of a correct full-length clone was used to transfect Hek293 cells for verification of protein expression. The encoded ENPP2 sequence conforms to Swissprot entry Q13822, with or without the additional 6xHis Cterminal marker.
[00157] ATX fermentation: The recombinant protein was produced by means of transient large-scale transfection in tank bioreactors subjected to 20 L controlled stirring (Sartorius). During cell growth and transfection, temperature, agitator speed, pH and dissolved oxygen concentration were maintained under 37 ° C, 120 rpm, 7.1 and 30% DO, respectively. Freestyle 293-F cells (Invitrogen) were cultured in suspension in Freestyle 293 medium (Invitrogen) and transfected in approx. 1-1.5 x 10E6 cells / mL with the above plasmid DNA using X-tremeGENE Ro-1539 (commercial product, Roche Diagnostics) as a complexing agent. The cells were fed with a concentrated nutrient solution (J Immunol Methods 194 (1996), 19, 1199 (page 193)) and induced by sodium butyrate (2 mM) in 72 h after transfection and harvested in 96 h after transfection . Expression was analyzed using Western Blot, enzymatic assay and / or IMAC analytical chromatography. After cooling the cell suspension to 4 ° C in a direct flow heat exchanger,
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52/81 cells and sterile filtration of the supernatant was performed by means of filtration through Zeta Plus 60M02 E16 (Cuno) and Sartopore 2 XLG (Sartorius) filtration units. The supernatant was stored at 4 ° C before purification.
[00158] Purification of ATX: 20 liters of culture supernatant were conditioned for ultra filtration by adding Brij 35 under a final concentration of 0.02% and adjusting the pH to 7.0 using 1 M HCl. the supernatant was first microfiltered through a 0.2 pm PES filter Ultran-Pilot Open Channel (Whatman) and then concentrated to 1 liter via a PES filter from Ultran-Pilot Screen Channel with MWCO 30 kDa (Whatman) . Before IMAC chromatography, NiSO4 was added at a final concentration of 1 mM. The clean supernatant was then applied to a HisTrap column (GE Healthcare) previously equilibrated in 50 mM Na2HPO4, pH 7.0, 0.5 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN3 . The column was washed in a decent way with the same buffer containing 20 mM, 50 mM and 50 mM imidazole, respectively. The protein was subsequently eluted using a linear gradient to 0.5 m imidazole in 15 column volumes. Fractions containing ATX were pooled and concentrated using an Amicon cell equipped with a 30 kDa PES filter membrane. The protein was further purified by means of size exclusion chromatography in preparation class Superdex S-200 (XK 26/100) (GE Healthcare) in 20 mM BICINE, pH 8.5; 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaNg. The final protein yield after purification was 5-10 mg ATX per liter of culture supernatant. The protein was
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ATX HUMAN ENZYME INHIBITION TEST
[00159] ATX inhibition was measured by means of a fluorescence extinction assay using a specifically labeled substrate analog (substrate MR121). To obtain this substrate MR121, BOC and TBS protected the propyl ester from 2-hydroxy-6-amino- (R) 3- ({2- [3- (2 --- {2 --- [2- ( 2-amino-ethoxy) -ethoxy] -ethoxy} -ethoxy) propionylamino] -ethoxy} -hydroxy-phosphoryloxy) -hexanoic (Ferguson et al., Org Lett 2006, 8 (10), 2023) was marked with fluorophore MR121 ( CAS 185308-24- 1, 1- (3carboxypropyl) -11-ethyl-1,2,3,4,8,9,10,11-octahidrodipyride [3,2-b: 2 ', 3'-i] phenoxazin - 13-ium) in the free amine on the ethanolamine side and then, after deprotection, later with tryptophan on the aminohexanoic acid side.
[00160] Test work solutions were prepared as follows: Test buffer (50 mM TrisHC1, 140 mM NaCl, 5 mM KC1, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 0.01% Triton-X-100 , pH 8.0; ATX solution: ATX stock solution (labeled human His) (1.08 mg / mL in 20 mM bicine, pH 8.5; 0.15 M NaCl, 10% glycerol, 0.3% CHAPS , 0.02% NaN ₃ ), diluted to 1.4 - 2.5x final concentration in assay buffer; MR121 substrate solution: MR121 substrate stock solution (800 μΜ MR121 substrate in DMSO), diluted to 2 - 5x final concentration in assay buffer.
[00161] The test compounds (10 mM stock in DMSO, 8 pL) were obtained in 384-well sample plates (Corning Costar # 3655) and diluted with 8 pL of DMSO. Serial dilutions in line were performed by transferring 8
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54/81 pL of cpd solution for the next row to row 0. Compound control solutions were mixed five times and 2 pL was transferred to the 384-well assay plates (Corning Costar # 3702). Then, 15 µl of 41.7 nM ATX solution (final concentration of 30 nM) was added, mixed five times and then incubated for 15 minutes at 30 ° C. 10 µl of MR121 substrate solution (final concentration of 1 µM) was added, mixed 30 times and then incubated for 15 minutes at 30 ° C. Fluorescence was then measured every 2 minutes for 1 hour (Perkin Elmer plate: reader with multimode vision); light intensity: 2.5%; exp. time: 1.4 sec, Filter: Fluo_630 / 690 nm) and the IC ₅ q values were calculated from the readings.
[00162]
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Examples ATXIC50 (μΜ) 1.00 0.005 1.01 0.012 1.02 0.01 1.03 0.013 1.04 0.013 1.05 0.018 1.06 0.002 2.00 0.012
Examples ATXIC50 (μΜ) 2.01 0.03 2.02 0.12 2.03 0.018 3.00 0.006 3.01 0.02 3.02 0.012 3.03 0.019 4.00 0.01
Examples ATXIC50 (μΜ) 4.01 008 4.02 006 4.03 007
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[00163] The compounds of formula (I) and their pharmaceutically acceptable salts or esters as described in this context are provided with IC50 values between 0.00001 μΜ and 1000 μΜ, particular compounds have IC50 values between 0 , 0005 μΜ and 500 μΜ, even more particular compounds have IC50 values between 0.0005 μΜ and 50 μΜ, even more particular compounds have IC50 values between_ 0.0005 μΜ and 5 μΜ. These results were obtained by using the enzymatic assay previously described in this context.
[00164] The compounds of formula (I) and their pharmaceutically acceptable salts can be used in the form of medicaments (for example, in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered internally, such as orally (for example, in the form of tablets, coated tablets, pills, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example, in the form of nasal spray), rectally (for example, in the form of suppositories) or topically ocular (for example, in the form of solutions, ointments, gels or polymeric water-soluble inserts). However, administration can also be carried out parenterally, such as intramuscularly, intravenously or intraocularly (for example, in the form of sterile injectable solutions).
[00165] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert organic inorganic adjuvants
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57/81 for the production of tablets, coated tablets, pills, hard gelatin capsules, injection solutions or topical formulations. Lactose, its derivatives of corn starch, talc, stearic acid or its salts and the like, can be used, for example, in the form of adjuvants for tablets, pills and hard gelatin capsules.
[00166] Adjuvants which are suitable for soft gelatin capsules are comprised, for example, of vegetable oils, waxes, fats, semi-solid substances and liquid polyols, and the like.
[00167] Adjuvants suitable for the production of solutions and syrups are comprised, for example, of water, polyols, sucrose, inverted sugar, glucose, and the like.
[00168] Adjuvants suitable for injectable solutions are comprised, for example, of water, alcohols, polyols, glycerol, vegetable oils, and the like.
[00169] Suitable adjuvants for suppositories are understood, per example, per natural oils or hardened, waxes, fats, polyols semi-solids or
liquids, and the like.
[00170] Adjuvants suitable for topical ocular formulations are comprised, for example, of cyclodextrins, mannitol or many other carriers and excipients that are known in the art.
[00171] In addition, pharmaceutical preparations may contain preservatives, solubilizing agents, viscosity-increasing substances,
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58/81 stabilization, wetting agents, emulsifiers, sweeteners, dyes, flavors, salts for osmotic pressure variation, buffers, concealers or antioxidants. They may also contain other therapeutically valuable substances.
[00172] The dosage can vary in wide limits and, of course, will be adjusted according to the individual requirements in each particular case. In general, in the case of oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (for example, about 300 mg per person), preferably divided into 1-3 individual doses, which may consist, for example, of the same amounts, if appropriate. In the case of topical administration, the formulation can contain 0.001% to 15%, by weight, of the drug and the required dose, which can be between 0.1 and 25 mg, can be administered by a single daily dose or per week, by multiple doses (2 to 4) per day, per multiple doses per week. Nevertheless, it will be evident that the indicated upper or lower limit can be exceeded when this is
indicated as[00173] appropriate. THE invention is illustrated The follow through in Examples, which no have a limitative character. [00174] At the case of examples in preparation are obtained in form; The. of a mixture in enantiomers, the enantiomers pure s can be obtained through methods
described in this context or by methods known to persons skilled in the art, such as, for example, chiral chromatography or crystallization.
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Examples
[00175] All examples and intermediates were prepared under a nitrogen atmosphere, if not specified otherwise.
[00176] Abbreviations: aq. = aqueous; CAS-RN = Chemical Abstracts Service record number; HPLC = high performance liquid chromatography; MS = mass spectrum; PS-BEMP = 2 -tert-butylimino -2 -diethylamino -1,3 dimethylperhydro -1,3,2-diazaphosphorin bound to polystyrene; sat. = saturated.
Example 1
Trans -5 - (1H-benzotriazole -5-carbonyl) -3a -fluoro hexahydro-pyrrole [3,4 -c] pyrrole -2-carboxylic acid 4-trifluoromethoxy-benzyl ester
THE
[00177] To a suspension of trans-3a-fluorohexahydro-pyrrolo [3,4-c] pyrrole-2-carboxylic acid 4trifluoromethoxy-benzyl ester (intermediate 4.01; 139 mg, 361 pmol), 4-methylmorpholine (183 mg, 1.81 mmol) and lH-benzo [d] [1,2,3] triazole-5carboxylic acid (CAS-RN 23814-12-2; 58.9 mg, 361 pmol) in N, Ndimethylformamide (3 mL) O- (7-azabenzotriazol-l-yl) -Ν, Ν, Ν ', Ν'-tetramethyluronium (137 mg, 361 pmol) hexafluoro phosphate was added at room temperature, then after 16 h the reaction mixture was divided between sodium hydrogen carbonate solution sat. aq. and 4: 1 ethyl acetate / 2 methyltetrahydrofuran. The organic layer was washed with
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60/81 aqueous saturated ammonium chloride solution and saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution, 90: 10: 0.25) provided the title compound (158 mg 89%). Light yellow foam, MS: 494.2 (M + H) ⁺ .
[00178] The examples set out below were produced in analogy to example 1, replacing trans-3a-fluorohexahydro-pyrrolo [3,4-c] pyrrole-2carboxylic acid 4-trifluoromethoxy-benzyl acid hydrochloride and 1H-benzo [d] [1,2,3] triazole-5-carboxylic acid by the appropriate carboxylic acid.
[00179]
Ex. Systematic name Amine / Acidcarboxylic MS, m / e 1.01 4-trifluoromethoxy ester Ester hydrochloride 4 - 506.2-benzyl acid trifluoromethoxy - (M + H) ⁺ trans -5 - (1H - benzyl trans acid benzotriazole -5 - -3a -fluoro -hexahidro - carbonyl) -3a -methoxy - pyrrole [3,4 -c] pyrrole hexahydro-pyrrole [3,4 - -2-carboxylic c] pyrrole -2 - (intermediate 4.01) / carboxylic 1H -benzoic acid 0 [d] [1,2,3] triazole -5 - carboxylic acid (CAS -RN^f V XJ QS n 23814 -12 -2) 0
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1.02 trans -1 - [5 - (1Hbenzotriazole -5 -carbonyl) -3a-methoxy 3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] -3 - [4(trifluoromethoxy) phenyl] -propan -1 -onaTHE0 Trans -1 dihydrochloride - (3amethoxyhexahydropyrrole[3.4 -c] pyrrole -2 (1H) 11) -3 - (4(trifluoromethoxy)phenyl) propan -1 -one(intermediate 6.01) /1H -benzoic acid[d] [1,2,3] triazole-5 carboxylic (CAS -RN23814 -12 -2) 502.3(M-H) 1.03 trans - [5 - [2cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4 carbonyl] -3a-methoxy 3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -11] - (1Hbenzotriazole -5 -yl) methanonevAr ^^ · Trans dihydrochloride - (2 -cyclopropyl -6 -((tetrahydro-2H-pyran 4-yl) methoxy) pyridin -4 -11) 3a-methoxyhexahydropyrrolo [3,4 -c] pyrrole -2 (1H) -yl)methanone (intermediate6) / acid 1Hbenzo [d] [1,2,3] triazole -5-carboxylic acid (CAS -RN23814 -12 -2) 547.3 (M + H) ⁺ 1.04 Ester 4-trifluoromethoxy-benzylic acidtrans -5 - (1H -benzotriazole -5 -carbonyl) -3a-methyl hexahydro-pyrrole [3,4 —c] pyrrole -2 -carboxylic0H N = t0 Ester 4 trifluoromethoxy hydrochloride -benzylic acid -3a -methyl -hexahydro pyrrole [3,4 -c] pyrrole -2-carboxylic acid(intermediate 4) / 1H benzo [d] [1,2,3] triazole -5-carboxylic acid (CAS -RN23814 -12 -2) 490.2 (M + H) ⁺
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1.05 trans -5 - [3a-methoxy -2 - [3 - [4(trifluoromethoxy) phenyl] propanoyl] -3,4,6,6a tetrahydro -1H -pyrrole [3,4 —c] pyrrole -5 carbonyl] -3 -methyl -1H -benzimidazole -2 -onaThe Trans -1 - (3a-methoxy hexahydropyrrolo [3,4 cjpirrol -2 (1H) -yl) -3 (4(trifluoromethoxy) phenyl) propan -1 -one (intermediate 6.01) / 3-methyl -2-oxo 2,3-dihydro -1H benzo [d] imidazole -5 carboxylic acid (CAS -RN 863564 -77 -6) 533.2 (M + H) ⁺ 1.06 trans -5 - [5 - [2 cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4 carbonyl] -3a-methoxy 3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -carbonyl] -3 -methyl -1H -benzimidazole -2one 9 ^z 0 trans dihydrochloride - (2 -cyclopropyl -6 -((tetrahydro -2H -pyran 4 -yl) methoxy) pyridin -4 yl) 3a methoxyhexahydropyrrole[3.4 —c] pyrrole -2 (1H) yl) methanone(intermediate 6) / 3-methyl -2-oxo -2,3 dihydro -1H-benzo [d] imidazole -5-carboxylic acid (CAS -RN 863564 -77 -6) 576.3 (M + H) ⁺
Example 2 trans - [3a -Methoxy -5 - (1,4,6,7 tetrahydrotriazolo [4,5-cpyridine -5-carbonyl) -3,4,6,6a -tetrahydro -1H -pyrrole [3,4 - cjpirrol -2 -yl] - [2 cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4 -yl] methanone
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[00180] Step 1: trans chloride -2 - [2 Cyclopropyl -6 - (oxan -4-ylmethoxy) pyridine -4-carbonyl] 3a-methoxy -3,4,6,6a -tetrahydro -1H -pyrrole [3 , 4 -c] pyrrole -5 -carbonyl
[00181] To a solution of (2cyclopropyl-6 - ((tetrahydro-2H-pyran-4-yl) methoxy) pyridinyl dihydrochloride)
4-yl) (trans-3a-methoxy hexahydropyrrolo [3,4-c] pyrrol2 (1H) -yl) methanone (intermediate 6; 288 mg, 577 pmol) and N, N-diisopropyl ethylamine (186 mg, 1.44 mmol) in dichloromethane (10 mL) a solution of triphosgene (85.6 mg, 288 pmol) in dichloromethane (10 mL) was added under 0 ° C. After 1½ h the ice bath was removed, then after another 2½ h the reaction mixture was partitioned between 1 M aqueous hydrochloric acid solution and dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated to provide the title compound (230 mg, 86%), which was used directly in the next step. White solid.
[00182] Step_____2: _____ trans- [3a-Methoxy-5- (1,4, 6, 7tetrahydrotriazolo [4,5-c] pyridine-5-carbonyl) -3, 4, 6, 6atetrahydro-1H-pyrrole [3, 4-c] pyrrol-2-yl] - [2-cyclopropyl6- (oxan-4-ylmethoxy) pyridin-4-yl] methanone
[00183] To a clear colorless solution of chloride
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64/81 trans-2- [2-cyclopropyl-6- (oxan-4-ylmethoxy) pyridine-4carbonyl] -3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrole [3,4-c] pyrrole-5-carbonyl (140 mg, 302 pmol) in dichloromethane (10 ml) was added a solution of N, N-diisopropylethylamine (117 mg, 905 pmol) and 4,5,6,7-tetrahydro-ΙΗ- [1 , 2,3] triazolo [4,5-c] pyridine (CAS-RN 706757-05-3; 37.5 mg, 302 pmol) in N, N-dimethylformamide (10 mL) at room temperature, then after 15 ha reaction mixture was divided between water and dichloromethane. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution, 90: 10: 0.25) provided the title compound (85 mg, 51%). White solid. MS: 550.3 (M-H).
[00184] The following examples were produced in analogy to example 2, replacing (2-cyclopropyl-6 - ((tetrahydro-2H-pyran-4-yl) methoxy) pyridin-4-yl) dihydrochloride (trans- 3a-methoxy hexa hydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) methanone by the appropriate amine 1 and 4,5,6,7-tetrahydro-ΙΗ- [1,2,3] triazole [4, 5-c] pyridine by the appropriate amine 2.
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[00185]
Ex. Systematic name Amine 1 / Amine 2 MS, m / e 2.01 trans-1- [3a-methoxy-5 (1,4, 6, 7-tetrahydrotriazolo [4,5-c] pyridine-5-carbonyl) -3,4,6,6atetrahydro-1H-pyrrolo [3,4- c] pyrrol-2-yl] 3- [4- (trifluoromethyl oxy) phenyl] propan-1-0 / ^N: ΛΙ. ^F HY 0 Dihydrochloridetrans-1- (3a-methoxy hexa hydropyrrole[3,4-c] pyrrole-2 (1H) yl) -3- (4-(trifluoromethoxy) phenyl) propan-l-one(intermediate 6.01) / 4,5,6,7-tetrahydro-1H [1,2,3] triazolo [4,5c] pyridine (CAS-RN706757-05-3) 507.3 (Μ-Η) 2.02 trans-1- [5- (3hydroxy-5,7-dihydro4H- [1,2] oxazolo [5,4-c] pyridine-6-carbonyl) -3a-methoxy3,4,6,6a-tetrahydrolH-pyrrole [ 3,4-c] pyrrol-2-yl] -3- [4- (trifluoromethoxy) phenyl] -propan-1ona - o-M rq jCTl / s ϋ 7 ^ 0 ^^ Jsl NJ ^FH γ - 0 dihydrochloridetrans-1- (Sa-met oxyhexahidr opirrolo[3,4-c] pyrrole-2 (1H) yl) -3- (4-(trifluoromethoxy) phenyl) propan-l-one(intermediate 6.01) / 4,5,6,7-tetrahydroisoxazole [5.4-c]pyridin-3 (2H) -one(CAS-RN 64603-91-4) 525, 2 (M + H)+
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2.03 trans- [5- (3-hydroxy-
5,7-dihydro-4H- [1,2] oxazolo [5,4-c] pyridine-6-carbonyl) 3a-methoxy-3,4,6,6atetrahydro-1H-pyrrolo [3,4-c] pyrrole -2-yl] [2-cyclopropyl-6 (oxan-4-ylmethoxy) pyridin-4-yl] methanone
trans- (2-cyclopropyl6 - ((tetrahydro-2Hpiran-4il) methoxy) pyridin-4il) 3a-methoxy hexa hydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methanone (intermediate 6) / dihydrochloride
4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3 (2H) -one (CAS-RN 64603-91-4)
566, 3 (ΜΗ)
Examples 3 and 4 trans - [3a-methoxy -5 - (1,4,6,7 -tetrahydrotriazolo [4,5 -c] pyridine -5 -carbonyl) -3,4,6,6a tetrahydro -1H - pyrrole [3,4 -c] pyrrole -2-yl] - [2 cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4-yl] methanone, enantiomer 1 and enantiomer 2
[00186] trans - [3a -Methoxy -5 - (1,4,6,7 tetrahydrotriazolo [4,5 -c] pyridine -5 -carbonyl) 3,4,6,6a -tetrahydro -1H -pyrrole [3, 4 -c] pyrrole -2 -yl] [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4yl] methanone racemic (example 2; 85 mg, 154 μιηοΐ) was separated by means of preparation HPLC using if Chiralpak AD in the form of stationary phase and heptane / ethanol / ammonium acetate 60: 40: 0.004 in the form of the eluent. This produced the fastest eluting enantiomers 1 (example 3; 22 mg, 26%; yellow foam)
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67/81 clear, MS: 552.4 (M + H) ⁺ ) and the slowest eluting enantiomer 2 (example 4; 16 mg, 19%; white foam).
552.4 (M + H) ⁺ ).
[00187] The examples set out below were produced in analogy to examples 3 and 4 by separating chiral HPLC from its racemates, using a stationary and eluent phase as shown below.
[00188]
Ex. Starting material(racemic) Sign ofoptical rotation Stationary phase; eluent MS, m / e 3.01 trans- [5- (3-hydroxy-5,7dihydro-4H- [1,2] oxazolo [5,4-c] pyridine-6-carbonyl) -3a-methoxy3,4,6,6a-tetrahydro-1Hpyrrolo [3,4-c] pyrrol2-yl] - [2-cyclopropyl-6 (oxan-4-ylmethoxy) pyridin-4-yl] methanone(example 2.03) n. The.(enantiome offaster elution) ChiralpakAD;heptane / ol ethan / ammonium acetate60: 40: 0.004 568.3 (M + H) ⁺ 4.01 n. The.(enantiome ofslower elution) 568.3 (M + H) ⁺ 3.02 benzyl ester 4-trans-5- acid trifluoromethoxy (1Hbenzotriazole-5-carbonyl) -3a-methylhexahydro-pyrrolo [3,4-c] pyrrole-2-carboxylic (example 1.04) (+) ChiralpakAD;heptane / ol ethan / ammonium acetate60: 40: 0.004 490.3 (M + H) ⁺ 4.02 (-) 490.2 (M + H) ⁺ 3.03 benzyl ester 4-trifluoromethoxy-detrans-5- (1H-benzotriazol-5carbonyl) -3a-methoxy- (-) ChiralpakAD;heptane / ol ethan / ammonium acetate 506, 2 (M + H) ⁺
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4.03 hexahydro-pyrrole [3,4c] pyrrole-2carboxylic (example 1.01) (+) 60: 40: 0.004 506, 2 (M + H) ⁺
Intermediaries
Intermediate 1 trans-tert-butyl 3a-methyl hexa hydropyrrolo [3,4-
c] pyrrole-2 (1H) -carboxylate
[00189] Step _____ 1: _____ t rans-Dimet il _____ l-benzyl-3methylpyrrolidine-3,4-dicarboxylate
[00190] A ____ solution ____ of ____ N-benzyl-1-methoxy-N ((trimethylsilyl) methyl) methanamine (CAS-RN 93102-05-7; 1.74 g, 17.0 mmol) in dichloromethane (5 mL) was added to a mixture cooled with ice of dimethyl 2-methylfumarate (CASRN 617-53-8; 1.00 g, 6.32 mmol) and trifluoroacetic acid (79.3 mg, 696 pmol) in dichloromethane (10 ml) under 0-5 ° C. The resulting yellow solution was allowed to reach room temperature for 20 h, then it was partitioned between aq. sat. and dichloromethane. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution, 95: 5: 0.25) provided the title compound (1.61 g, 87%). Light yellow oil, MS: 292.2 (M + H) ⁺ .
[00191] Step 2: trans-1-tert-butyl 3,4-dimethyl 3-methylpyrrolidine-1,3,4-tricarboxylate
[00192] A solution of trans-dimethyl l-benzyl-3
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69/81 methylpyrrolidine-3,4-dicarboxylate (1.56 g, 5.35 mmol) and di-tert-butyl dicarbonate (1.29 g, 5.89 mmol) in methanol (20 mL) was subjected to stirring under at room temperature under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on activated charcoal, 165 mg, 1.55 mmol). After 3 hours, insoluble material was removed by filtration through diatomaceous earth and the filtrate was concentrated. Chromatography (silica gel; 1: 1 heptane to ethyl acetate / heptane gradient) provided the title compound (1.47 g, 91%). Colorless oil, MS: 202.1 (M + HMe ₃ COCO) ⁺ .
[00193] Step______3: ______ trans-tert-butyl ______ 3, 4bis (hydroxymethyl) -3-methyl pyrrolidine-1-carboxylate
[00194] A solution of trans-1-tert-butyl 3,4-dimethyl 3-methylpyrrolidine-1,3,4-tricarboxylate (1.47 g, 4.87 mmol) in tetrahydrofuran (12 mL) was cooled to 0 ° C and treated with lithium borohydride solution (2 M in tetrahydrofuran, 5.47 ml, 10.9 mmol), then after 30 min. the ice bath was removed and the reaction mixture was stirred at room temperature. After 18 h the excess reagent was destroyed by slowly adding aq. 1 M under 0 ° C to pH 1. The resulting clear solution was extracted with dichloromethane, the organic layer was washed with water and saline, dried over magnesium sulfate, filtered and evaporated. chromatography (silica gel, heptane-ethyl acetate gradient) provided the title compound (1.05 g, 88%). Colorless viscous oil, MS: 190.1 (M + H-isobutene) ⁺ .
[00195] Step 4: trans -tert -butyl 3 -methyl -3.4 Petition 870180024184, of 26/03/2018, p. 75/103
70/81 bis ____ ((((methylsulfonyl) ___ oxy) methyl) pyrrolidine -1 carboxylate
[00196] Methanesulfonyl chloride (1.41 g, 12.4 mmol) was added dropwise under 0 ° C to a clear colorless solution of trans -tert-butyl 3.4 bis (hydroxymethyl) -3-methylpyrrolidine -1 -carboxylate (1.01 g, 4.12 mmol) and N, N-diisopropyl ethylamine (3.19 g,
24.7 mmol) in dichloromethane (10 mL) was cooled to 0 ° C. After 30 min., The reaction mixture was partitioned between a solution of saturated aqueous ammonium chloride and dichloromethane. The organic layer was washed with sat. Sodium hydrogencarbonate solution. aq. and saline solution, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, heptane-ethyl acetate gradient) provided the title compound (1.53 g, 92%). Yellow viscous oil, MS: 346, 1 (M + H-isobutene) ⁺ .
[00197] Step 5: trans-tert-butyl 5-benzyl-3a-methyl hexa hydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate
[00198] To a solution of trans-tert-butyl 3-methyl-
3,4-bis (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate (1.52 g, 3.79 mmol) in toluene (20 mL) triethylamine (1.15 g, 11.4 mmol) was added and benzylamine (811 mg, 7.57 mmol). The reaction mixture was heated to reflux, then after 20 h another portion of triethylamine (1.15 g, 11.4 mmol) and benzylamine (811 mg, 7.57 mmol) was added, then after another 20 h under reflux the reaction mixture was washed with 1 M aq. and saline solution, dried over magnesium sulfate, filtered and evaporated. Chromatography
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71/81 (silica gel, heptane gradient - ethyl acetate) provided the title compound (875 mg, 73%). Light yellow colored solid, MS: 317.2 (M + H) ⁺ .
[00199] Step 6: trans-tert-butyl 3a-methyl hexa hydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate
[00200] A solution of (3aR, 6aR) -tert -butyl 5 benzyl -3a -methyl hexa hydropyrrolo [3,4 -c] pyrrole -2 (1H) -carboxylate (870 mg, 2.75 mmol) in methanol ( 10 mL) was subjected to stirring at room temperature under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on activated charcoal, 146 mg, 1.37 mmol), then after 5 h insoluble material was removed through filtration through diatomaceous earth. The filtrate was evaporated to provide the title compound (640 mg, 93%) which contained about 10% methanol. Colorless viscous oil, MS: 227.2 (M + H) ⁺ .
Intermediate 2
[00201] trans -tert -butyl 3a -fluoro hexa hydropyrrolo [3,4 -c] pyrrole -2 (1H) -carboxylate
[00202] The title compound was produced in analogy to intermediate 1, replacing dimethyl 2methylfumarate with diethyl 2-fluoro fumarate (CAS-RN 4495-776). Colorless viscous oil, MS: 231.2 (M + H) ⁺ .
Intermediate 3
[00203] trans -tert -butyl 3a-methoxy hexa hydropyrrolo [3,4 -c] pyrrole -2 (1H) -carboxylate
[00204] The title compound was produced in analogy to intermediate 1, replacing dimethyl 2methyl fumarate with dimethyl 2-methoxy fumarate (CAS-RN 221505-6). Colorless viscous oil, MS: 243.2 (M + H) ⁺ .
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Intermediate 4
[00205] Trans -3a -methyl -hexahydro pyrrole [3,4 -c] pyrrole -2-carboxylic acid benzyl ester 4 hydrochloride
[00206] Step 1: trans -2 -tert -butyl 5 - (4 (trifluoromethoxy) benzyl) 3a -methyltetrahydro pyrrolo [3,4 —c] pyrrole -2,5 (1H, 3H) -dicarboxylate
[00207] To a solution of (4- (trifluoromethoxy) phenyl) methanol (474 mg, 2.47 mmol) in acetonitrile (20 mL) was added 1,1'-carbonyldiimidazole (413 mg, 2.47 mmol) and the reaction mixture was heated to 50 ° C, then after 3 h triethylamine (1.25 g, 12.3 mmol) and trans -tert-butyl 3a-methyl hexa hydropyrrolo [3,4 -c] pyrrole -2 (1H ) carboxylate (intermediate 1; 621 mg, 2.47 mmol) were added and the reaction mixture was heated to reflux. After 15 h the reaction mixture was partitioned between ethyl acetate sat. aq. and sodium hydrogen carbonate solution. The organic layer was washed with saturated aqueous ammonium chloride solution and saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient from dichloromethane to dichloromethane / methanol / 25% aqueous ammonium solution, 95: 5: 0.25) provided the title compound (821 mg, 75%). Light yellow oil, MS: 389.2 (M + H-isobutene) ⁺ .
[00208] Step 2: Trans -3a -methyl-hexahydro pyrrolo [3,4 -ç] pyrrole -2-carboxylic acid benzyl ester 4 hydrochloride
[00209] A solution of trans-2-tert-butyl 5— (4 - (trifluoromethoxy) benzyl) 3a-methyltetra hydropyrrolo [3,4 Petition 870180024184, 26/03/2018, p. 78/103
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c] pyrrole-2.5 (1H, 3H) -dicarboxylate (812 mg, 1.83 mmol) and hydrochloric acid solution (5-6 M in 2-propanol, 10.2 mL, 51.2 mmol) in 2-propanol (5 ml) was stirred for 15 h at room temperature, then concentrated to dryness. The residue was triturated in tert-butyl methyl ether and the precipitate was collected by filtration to produce the title compound (662 mg, 95%). White solid, MS: 345.1 (M + H) ⁺ .
Intermediate 4.01
[00210] This trans-3a-fluoro-hexahydro-pyrrolo [3,4-c] pyrrole-2-carboxylic acid benzyl 4-trifluoromethoxy
[00211] The title compound was produced in analogy to intermediate 4, replacing the trans-tertbutyl-3-methyl hexa hydropyrrolo [3,4-c] pyrrole-2 (1H) carboxylate with trans-tert-butyl 3a-fluoro hexa hydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate (intermediate 2). White solid, MS: 349.1 (M + H) ⁺ .
Intermediate 5
[00212] trans-3a-methoxy-hexahydro-pyrrole [3,4-c] pyrrole-2-carboxylic acid ester dihydrochloride 3- (2,2-dimethylpropionylamino) -5-trifluoromethyl-pyridin-2-ylmethyl
[00213] Step 1: trans-tert-butyl 5- (chlorocarbonyl) 3a ~ methoxy hexa hydropyrrole ____ [3, 4-c] ____ pyrrole-2 (1H) carboxylate
[00214] To a solution of trans -tert-butyl 3a methoxy hexa hydropyrrolo [3,4 -c] pyrrole -2 (1H) carboxylate (intermediate 3; 440 mg, 1.82 mmol) and pyridine (646 mg, 8, 17 mmol) in dichloromethane (5 mL) was added
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74/81 dropwise a solution of triphosgene (242 mg, 817 pmol) in dichloromethane (4 ml) under 0 ° C. After 30 min. the bath was removed, then after 4 h the reaction mixture was partitioned between dichloromethane and aq. 1 Μ. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to provide the title compound (372 mg, 67%) as a light yellow foam.
[00215] Step 2: trans -2 -tert -butyl 5 - ((3 pivalamido -5 - (trifluoro methyl) pyridin -2 -yl) methyl) 3a-methoxytetrahydropyrrolo [3,4 -c] pyrrole -2,5 (1H, 3H) dicarboxylate
[00216] To a solution of trans -tert-butyl 5 (chlorocarbonyl) -3a-methoxy hexa hydropyrrolo [3,4 -c] pyrrole -2 (1H) -carboxylate (370 mg, 1.21 mmol) in acetonitrile (25 mL) N - (2 - (hydroxymethyl) 5 - (trifluoromethyl) pyridin-3-yl) pivalamide (intermediate 8; 335 mg, 1.21 mmol) and PS-BEMP (CAS-RN 144 6424-8 6-) were added 7; 1.5 g, 1.21 mmol). The orange suspension was heated under reflux for 21 h, then the insoluble material was removed by filtration. To the filtrate was added PS-Trisamine (CAS-RN 1226492-10-9;
315 mg, 1.21 mmol) and the reaction mixture was stirred at room temperature for 18 h, then the insoluble material was removed by means of filtration and the filtrate was evaporated. Chromatography (silica gel; by flash chromatography on silica, eluting with a gradient of dichloromethane to dichloromethane / methanol / 25% aqueous ammonia 95: 5: 0.25) produced the compound
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75/81 titer (333 mg, 50%). White foam, MS: 545.3 (M + H) ⁺ .
[00217] Step 3: 3 - (2,2-Dimethyl propionylamino) -5-trifluoromethyl-pyridin -2-ylmethyl ester of trans -3a -methoxy -hexahydro-pyrrole dihydrochloride [3,4 -
c] pyrrole -2-carboxylic
[00218] A solution of trans -2 -tert -butyl 5 - ((3-pivalamido -5 - (trifluoromethyl) pyridin -2 -yl) methyl) 3rd methoxytetrahydropyrrolo [3,4 -c] pyrrole -2,5 ( 1H, 3H) dicarboxylate (325 mg, 597 pmol) and hydrochloric acid solution (5-6 M in 2-propanol, 3.34 ml, 16.7 mmol) in 2propanol (2 ml) was subjected to stirring under temperature 18 h, then the reaction mixture was concentrated to dryness. The residue was triturated in methyl tert-butyl ether and the precipitate was collected by filtration to provide the title compound (291 mg, 94%). White solid, MS: 445.2 (M + H) ⁺ .
Intermediate 6
[00219] Trans - (2-cyclopropyl-6 - ((tetrahydro-2H-pyran-4-yl) methoxy) pyridin-4-yl) 3a-methoxy hexa hydropyrrolo [3,4 -c] pyrrole -2 ( 1H) -yl) methanone
[00220] Step 1: trans -tert -butyl 5 - (2 cyclopropyl -6 - ((tetrahydro-2H-pyran-4-yl) methoxy) isonicotinoyl) -3a-methoxy hexa hydropyrrole [3,4 -c] pyrrole - 2 (1H) -carboxylate
[00221] To a solution of trans-tert-butyl 3a-methoxy hexa hydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate (500 mg, 2.06 mmol) in N, N-dimethylformamide (40 mL) 2-cyclopropyl-6 - ((tetrahydro-2H-pyran-4Petition 870180024184, dated 26/03/2018, p. 81/103
76/81 il) methoxy) isonicotinic (intermediate 7; 572 mg, 2.06 mmol) and 4-methylmorpholine (1.04 g, 10.3 mmol). The solution was cooled to 0 ° C, then O- (7-azabenzotriazol-1-yl) -N, N, Ν ', N'tetramethyluronium hexafluorophosphate (824 mg, 2.17 mmol). The ice bath was removed, then, after 96 h, the reaction mixture was partitioned between the sodium hydrogen carbonate solution and ethyl acetate / methyl 4-tetrahydrofuran 4: 1. The organic layer was washed with sodium chloride solution. aqueous saturated ammonium and saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient from dichloromethane to dichloromethane / methanol / 25% aqueous ammonia solution, 90: 10: 0.25 gave the title compound (977 mg; 94%). Yellow viscous oil, MS: 502.3 (M + H) ⁺ .
[00222] Step 2: Trans dihydrochloride - (2 Cyclopropyl -6 - ((tetrahydro-2H-pyran-4-yl) methoxy) pyridin-4-yl) 3a-methoxy hexa hydropyrrole [3,4 -c] pyrrole - 2 (1H) -yl) methanone
[00223] A solution of trans -tert-butyl 5 - (2 - cyclopropyl -6 - ((tetrahydro -2H -pyran -4 -yl) methoxy) isonicotinoyl) -3a-methoxy hexa hydropyrrole [3,4 -c] pyrrole -2 (1H) -carboxylate (977 mg, 1.95 mmol) and a solution of hydrochloric acid (5-6 M in 2 -propanol, 8.57 mL, 42.8 mmol) in 2-propanol (8 mL) was subjected to stirring at room temperature for 16 h, then the mixture of
reaction was concentrated up to drying • 0 residue was crushed in third -butyl methyl ether and The precipitate was collected through in filtration for if provide the compound of the title (858 mg, 88%) . Solid in White color, MS:
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402.3 (M + H) ⁺ .
Intermediate 6.01
[00224] trans -1 - (3a-methoxy hexa hydropyrrolo [3,4 -c] pyrrole -2 (1H) -yl) -3 - (4 (trifluoromethoxy) phenyl) propan -1 -one dihydrochloride
[00225] The title compound was produced in analogy to example 6, replacing 2-cyclopropyl-6 - ((tetrahydro-2H-pyran-4-yl) methoxy) isonicotinic acid with 3- (4- (trifluoromethoxy) phenyl acid) ) propanoic. Brown viscous oil, MS: 359.2 (M + H) ⁺ .
Intermediate 7
[00226] 2-Cyclopropyl -6 - ((tetrahydro-2H pyran -4-yl) methoxy) isonicotinic acid
[00227] Step 1: Methyl 6 -cyclopropyl -2 -oxo -1,2 dihydropyridine -4-carboxylate
[00228] A suspension of 6-cyclopropyl -2 oxo -1,2-dihydropyridine -4-carboxylic acid (CAS-RN 15019028-6; 400 mg, 2.23 mmol) in methanol (4 mL) and sulfuric acid (12 pL) was heated under 70 ° C for 48 h, then concentrated in vacuo. The residue was suspended in dichloromethane (10 ml), then the insoluble material was removed by filtration and the filtrate evaporated to produce the title compound (427 mg, 99%). Light brown semi-solid, MS: 194.1 (M + H) ⁺ .
[00229] Step 2: Methyl 2-cyclopropyl-6 - ((tetrahydro2H-pyran-4-yl) methoxy) isonicotinate
[00230] To a stirred suspension of methyl 6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (212 mg, 1.1 mmol) in acetonitrile (5 mL) was added
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78/81 potassium carbonate (455 mg, 3.29 mmol) and 4- (iodomethyl) tetrahydro-2H-pyran (CAS-RN 101691-94-5; 744 mg, 3.29 mmol). The reaction mixture was heated under 80 ° C for 16 h and then evaporated in vacuo. The residue was purified by means of chromatography (silica gel; heptane gradient ethyl acetate) to produce the title compound (188 mg, 59%). Colorless oil, MS: 292.2 (M + H) ⁺ .
[00231] Step 3: 2-Cyclopropyl-6 - ((tetrahydro2H-pyran ~ 4-yl) methoxy) isonicotinic acid
[00232] To a solution of methyl 2-cyclopropyl-6 ((tetrahydro-2H-pyran-4-yl) methoxy) isonicotinate (184 mg, 632 pmol) in tetrahydrofuran (2 ml) and water (2 ml) lithium monohydrate (53.0 mg, 1.26 mmol) and the resulting mixture was stirred at room temperature for 16 h. The mixture was partially evaporated in order to remove the tetrahydrofuran. The aqueous phase was divided between 1 M aqueous hydrochloric acid solution and ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, filtered and evaporated to provide the title compound (218 mg, quant.). Colorless oil, MS: 276.1 (M-H).
Intermediate 8
[00233] N - (2 - (Hydroxymethyl) -5 - (trifluoromethyl) pyridin -3 -yl) pivalamide
[00234] Step ____ 1: ____ Methyl ____ 3-pivalamide ____- 5____y (trifluoromethyl) picolinate
[00235] To a brown colored solution of methyl 3 amino-5- (trifluoromethyl) picolinate (CAS-RN 866775-17-9; 2.00 g, 8.63 mmol) in pyridine (25 mL) was added
Petition 870180024184, of 03/26/2018, p. 84/103
79/81 pivaloyl chloride (2.08 g, 17.3 mmol) under 0 ° C. After 20 min. the ice bath was removed, then after 5 h the reaction mixture was partitioned between 1 M aqueous hydrochloric acid solution and ethyl acetate. The organic layer was washed with water and saline, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; heptane-ethyl acetate gradient) provided the title compound (2.46 g, 92%). Light yellow solid, MS: 305.1 (M + H) ⁺ .
[00236] Step_________2: _________ N- (2- (Hydroxymethyl) -5 (trifluoromethyl) pyridin-3-yl) pivalamide
[00237] To a clear, pale yellow solution of methyl 3-pivalamido-5- (trifluoromethyl) picolinate (2.45 g, 8.05 mmol) in tetrahydrofuran (60 mL) was added a solution of calcium chloride (1.79 g, 16.1 mmol) in ethanol (60 mL), then sodium boron hydride (914 mg, 24.2 mmol) was added in three parts over a period of 30 min. The white suspension was subjected to stirring for 90 min. at room temperature, then divided between water and saturated aqueous ammonium chloride solution. The organic layer was washed with saline, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane - ethyl acetate gradient) provided the title compound (1.97 g; 89%). Light yellow viscous oil, MS: 277.1 (M + H) ⁺ .
Intermediate 9
[00238] 3-Fluoro -4 - (trans -3a fluoro octahidropyrrolo [3,4 -c] pyrrole -2-carbonyl) hydrochloride benzene sulfonamide
[00239] Stage 1: trans -tert -butil 3a -fluoro -5 Petition 870180024184, of 03/26/2018, p. 85/103
80/81 (2-fluoro -4-sulfamoyl benzoyl) hexa hydropyrrolo [3,4 -
c] pyrrole -2 (1H) -carboxylate
[00240] The title compound was produced in analogy to intermediate 6, step 1, by substituting trans-tert-butyl 3a-methoxy hexa hydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate tert-butyl 3a-fluoro hexa hydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate and 2-cyclopropyl-6 - ((tetrahydro-2H-pyran-4-yl) methoxy) isonicotinic acid 2- fluoro-4-sulfamoyl benzoic (CASRN 714968-42-0). Light yellow foam, MS: 432.2 (M + H) ⁺ .
[00241] Step 2: 3-fluoro-4- (trans-3afluoro octa hydropyrrolo [3,4-c] pyrrole-2-carbonyl) benzene sulfonamide hydrochloride
[00242] The title compound was produced in analogy to intermediate 6, step 2 from transtert-butyl 3a-fluoro-5- (2-fluoro-4-sulfamoyl benzoyl) hexahydropyrrolo [3,4-c] pyrrole-2 ( 1H) -carboxylate. White solid, MS: 332.0 (M + H) ⁺ .
Example A
[00243] A compound of formula (I) can be used in a manner known to you in the form of the active ingredient for the production of tablets of the following composition:
Per pill
Active ingredient 200 mg
Micro crystalline cellulose 155 mg
Corn starch 25 mg
Petition 870180024184, of 03/26/2018, p. 86/103
81/81
Baby powder
5 mg
Hydroxypropylmethylcellulose 20 mg
5 mg
Example B
[00244] A compound of formula (I) can be used in a manner known to you in the form of the active ingredient for the production of capsules of the following composition:
Per capsule
Active ingredient 100.0 mg Starch corn 20.0 mg Lactose95, 0 mg Baby powder4.5 mg Stearate magnesium 0.5 mg 220.0 mg
Petition 870180024184, of 03/26/2018, p. 87/103

权利要求:
Claims (11)
[1]
1. Compounds of formula (I)

[2]
11/11

[3]
3/11

[4]
4 5
R and R are independently selected from
Petition 870180024184, of 03/26/2018, p. 90/103
4/11
H, halogen, hydroxy, cyano, C1-g-alkyl, C1-galoxy, C1-6-alkoxy-C1-6-alkyl, halo-C1-alkoxy, halo-C1-alkyl, hydroxy-C1- g-alkyl, C3-8cycloalkyl, C3 ^ -cycloalkyl -Ci-g-alkyl, C3-8cycloalkyl -Ci-g-alkoxy, Cs-s-cycloalkoxy, C3-8cycloalkoxy -Ci-g-alkyl, Ci-g- alkyl alkylcarbonylamino, Cs-s-cycloalkyl carbonylamino, C1-g-alkyl tetrazolyl, C1-6 alkyl tetrazolyl-C1-6 alkyl or hetero cycloalkyl-C1-6 alkoxy;
R ⁶ is comprised of H or C 1 -alkyl;
R ⁷ is comprised of H, C 1 -alkyl, halogen, haloC 6 -alkyl or C 1 -alkoxy;
R ⁹ is comprised of halogen, C1-g-alkyl or C1-galcoxy;
m, n, p and q are selected independently from 1 or 2;
r is comprised of 1, 2 or 3;
or pharmaceutically acceptable salts.
2. A compound according to claim 1, wherein
R ¹ is comprised of substituted phenyl-C 1 -alkyl or substituted pyridinyl, wherein substituted f-enyl-C 1 -alkyl and substituted pyridinyl-C 1 -alkyl are replaced by R, R and R;
Y is comprised of -0C (0) - or -C (0) -;
W is comprised of -C (0) -;
2 Z z
R is selected from the 0, AJ, AN and AO ring systems;
the _z
R is comprised of halo-C1-e-alkoxy or
Petition 870180024184, of 03/26/2018, p. 91/103
[5]
5/11 tet rhydropyranyl-C1-6-alkoxy;
R ⁴ is comprised of H or C3 - g-cycloalkyl;
R is comprised of H;
R ⁶ is comprised of C 1 -g-alkyl;
R ⁹ is comprised of halogen, C1-g-alkyl or C1-galcoxy;
m, n, p and q are comprised of 1;
or the pharmaceutically acceptable salts.
A compound according to claim 1 or
2, where R ¹ is substituted phenyl-C 1 -alkyl or substituted pyridinyl, where phenyl-C 1 -alkyl substituted and pyridinyl-C 1 -alkyl substituted _z 3 4 5 are replaced by R , R and R.
Compound according to any of the claims that
Y is comprised of -C (0) -.
Compound according to any one of the claims
2 'that R is selected from the 0, AJ, AN and AO ring systems.
[6]
A compound according to any one of claims 1 to 6, wherein
2 '
R e selected from the AJ and AO ring systems.
[7]
A compound according to any one of claims 1 to 7, wherein the _z
R and understood by _{halo-Ci-6-alkoxy} or tetrahydropyranyl Ci-g-alkoxy.
Compound according to any one of the claims
1 to 9, where
R ⁴ is understood by
H or
C ₃ g-cycloalkyl.
9.
Compound according to any one of the claims
1 to 11 in
5 'that R is understood by
H.
Petition 870180024184, of 03/26/2018, p. 92/103
6/11
10. Compound, according with any an of claims 1 to 12, where R ⁶ is understood per Cl-6- alkyl.11. Compound, according with any an of claims 1 to 13, where R ⁷ is comprised of H. 12. Compound, according with any an of claims 1 to 13, where R ⁹ is understood per Cl-6- alkoxy.13. Compound, according with any an of claims 1 to 15, where m, n, p and q are understood by 1.14. Compound, according with any an of
claims 1 to 17, wherein
R ¹ is comprised of substituted phenyl-C 1 -alkyl or substituted pyridinyl, wherein substituted f-enyl-C 1 -alkyl and substituted pyridinyl-C 1 -alkyl are replaced by R, R and R;
Y is comprised of -C (0) -;
W is comprised of -C (0) -;
R is selected from the AJ and AO ring systems;
the _z
R is comprised of halo-C1-g-alkoxy or tetra
hydropyranyl-C1-6-alkoxy; R ⁴ is comprised of H or C3 -Cycloalkyl; R is comprised of H; R ⁶ is comprised of C 1 -g-alkyl; R ⁷ is comprised of H; R ⁹ is comprised of Ci-g-alkoxy;
m, n, p and q are comprised of 1
Petition 870180024184, of 03/26/2018, p. 93/103
7/11 or pharmaceutically acceptable salts.
15. A compound according to any one of claims 1 to 20, selected from
4-trifluoromethoxy-benzyl ester of trans acid 5 - (1H-benzotriazole-5-carbonyl) -3a-fluoro-hexahydro pyrrolo [3,4-c] pyrrole -2-carboxylic;
4-trifluoromethoxy-benzyl ester of trans acid 5 - (1H-benzotriazole-5-carbonyl) -3a-methoxy-hexahydro pyrrolo [3,4-c] pyrrole -2-carboxylic;
trans -1 - [5 - (1H -benzotriazole -5 -carbonyl) -3a -methoxy -3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] -3 - [4 - (trifluoromethoxy) phenyl] propan -1 -one;
trans - [5 - [2 -cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] -3a-methoxy -3,4,6,6a tetrahydro -1H -pyrrole [3,4 -c] pyrrole - 2-yl] - (1H benzotriazole -5-yl) methanone;
4-trifluoromethoxy-benzyl ester of trans acid 5 - (1H-benzotriazole-5-carbonyl) -3a-methyl-hexahydro pyrrolo [3,4-c] pyrrole -2-carboxylic;
trans -5 - [3a-methoxy -2 - [3 - [4 (trifluoromethoxy) phenyl] propanoyl] -3,4,6,6a -tetrahydro 1H -pyrrole [3,4 -c] pyrrole -5 -carbonyl] - 3-methyl -1H benzimidazole -2-one;
trans -5 - [5 - [2 -cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] -3a-methoxy -3,4,6,6a tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2-carbonyl] -3 methyl -1H-benzimidazole -2 -one;
trans - [3a-methoxy -5 - (1,4,6,7 tetrahydrotriazolo [4,5 -c] pyridine -5-carbonyl)
Petition 870180024184, of 03/26/2018, p. 94/103
[8]
11/11
3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] [2 -cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4 -yl] methanone;
trans -1 - [3a-methoxy -5 - (1,4,6,7 tetrahydrotriazolo [4,5 -c] pyridine -5 -carbonyl) -3,4,6,6a -tetrahydro -1H -pyrrole [3, 4 -c] pyrrole -2 -yl] -3 - [4 (trifluoromethoxy) phenyl] propan -1 -one;
trans -1 - [5 - (3-hydroxy -5,7-dihydro -4H [1,2] oxazolo [5,4 -c] pyridine -6 -carbonyl) -3a-methoxy 3,4,6,6a - tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] 3 - [4 - (trifluoromethoxy) phenyl] propan -1 -one;
trans - [5 - (3-hydroxy -5,7-dihydro -4H - [1,2] oxazolo [5,4 -c] pyridine -6-carbonyl) -3a-methoxy 3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4 -yl] methanone;
trans - [3a-methoxy -5 - (1,4,6,7 -tetrahydrotriazolo [4,5 -c] pyridine -5 -carbonyl) -3,4,6,6a tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] - [2 cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4 -yl] methanone;
trans - [5 - (3-hydroxy -5,7-dihydro -4H - [1,2] oxazolo [5,4 -c] pyridine -6-carbonyl) -3a-methoxy 3,4,6,6a -tetrahydro -1H -pyrrole [3,4 -c] pyrrole -2 -yl] [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4 -yl] methanone;
4-trifluoromethoxy-benzyl (+) trans -5 - (1H-benzotriazole -5-carbonyl) -3a-methyl hexahydro-pyrrole [3,4-c] pyrrole -2-carboxylic acid ester;
4 -trifluoromethoxy-benzyl acid ester (-)
Petition 870180024184, of 03/26/2018, p. 95/103
[9]
9/11 trans -5 - (1H -benzotriazole -5 -carbonyl) -3a-methoxy hexahydro-pyrrole [3,4 -c] pyrrole -2-carboxylic;
trans - [5 - (3-hydroxy -5,7-dihydro -4H [1,2] oxazolo [5,4 -c] pyridine -6 -carbonyl) -3a-methoxy 3,4,6,6a -tetrahydro- 1H -pyrrole [3,4 -c] pyrrole-2-yl] - [2-cyclopropyl-6 - (oxan-4-ylmethoxy) pyridin-4-yl] methanone;
4 -trifluoromethoxy-benzyl (-) trans -5 - (1H-benzotriazole -5-carbonyl) -3a-methylhexahydro-pyrrole [3,4 -c] pyrrole -2-carboxylic acid ester;
4-trifluoromethoxy-benzyl (+) trans -5 - (1H-benzotriazole -5-carbonyl) -3a-methoxyhexahydro-pyrrole [3,4 -c] pyrrole -2-carboxylic acid ester;
and their pharmaceutically acceptable salts.
A compound according to any one of claims 1 to 21, selected from trans -1 - [5 - (1H-benzotriazole -5-carbonyl) -3a-methoxy -3,4,6,6a -tetrahydro- 1H -pyrrole [3,4 -c] pyrrole -2 -yl] -3 - [4 - (trifluoromethoxy) phenyl] propan -1 -one;
trans - [5 - [2 -cyclopropyl -6 - (oxan -4 ylmethoxy) pyridine -4-carbonyl] -3a-methoxy -3,4,6,6a tetrahydro -1H -pyrrole [3,4 -c] pyrrole - 2-yl] - (1H benzotriazole -5-yl) methanone;
trans - [5 - (3-hydroxy -5,7-dihydro -4H [1,2] oxazolo [5,4 -c] pyridine -6 -carbonyl) -3a-methoxy 3,4,6,6a -tetrahydro - 1H -pyrrole [3,4 -c] pyrrole -2-yl] - [2-cyclopropyl -6 - (oxan -4-ylmethoxy) pyridin -4 yl] methanone;
and their pharmaceutically acceptable salts.
Petition 870180024184, of 03/26/2018, p. 96/103
[10]
11/10
A process for preparing a compound according to any one of claims 1 to 22, which comprises reacting a compound of formula (II) in the presence of a compound of formula (III), wherein R, R, R, m , n, p and p are as defined in any one of claims 1 to 22 and W is comprised of -C (O) -.

[11]
Ocular conditions, a method which comprises administering an effective amount of a compound according to any one of claims 1 to 22.
A compound according to any one of claims 1 to 22, when manufactured according to the process of claim 26.
25. The invention as described in this context.

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同族专利:

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公开号 | 公开日

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JP2018528243A|2018-09-27|

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KR20180054830A|2018-05-24|

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HK1246787A1|2018-09-14|

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CO2017011151A2|2018-03-28|

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US20180208602A1|2018-07-26|

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US20200079779A1|2020-03-12|

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US10787459B2|2020-09-29|

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JP6846414B2|2021-03-24|

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TW201720824A|2017-06-16|

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PH12018500408A1|2018-08-29|

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PE20180461A1|2018-03-06|

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EP3353180B1|2022-03-16|

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WO2017050732A1|2017-03-30|

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CL2018000596A1|2018-08-03|

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IL255570D0|2018-01-31|

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AU2016328535A1|2017-11-09|

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RU2018114289A|2019-10-24|

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AR106101A1|2017-12-13|

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MA42918A|2018-08-01|

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EP3353180A1|2018-08-01|

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MX2018002217A|2018-03-23|

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CN107635995A|2018-01-26|

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CA2983782A1|2017-03-30|

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法律状态:
2020-05-19| B11A| Dismissal acc. art.33 of ipl - examination not requested within 36 months of filing|

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2020-08-11| B11Y| Definitive dismissal - extension of time limit for request of examination expired [chapter 11.1.1 patent gazette]|

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2021-10-19| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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EP15186645|2015-09-24|

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EP15186645.6|2015-09-24|

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PCT/EP2016/072243|WO2017050732A1|2015-09-24|2016-09-20|Bicyclic compounds as atx inhibitors|

---