Patent Application
20220354949
The present invention relates to novel compounds and their use as therapeutic agents in human and veterinary medicine. The compounds of the present invention can be used in the treatment of pathological conditions including cancer, skin disorders, muscle disorders, disorders of the lung, disorders of the haematopoietic system including the haematologic system and immune system-related disorders.
The present invention covers novel molecules that show remarkable biological activity on human and animal derived cells. According compounds were found to influence the growth and survival of cancer cells and primary non-cancer cells. In particular, molecules were identified that are able to completely or partially inhibit cell growth or result in cell death. Moreover, some of the compounds were found to impact cellular signaling pathways, in particular the Notch signaling pathway. According molecules were found to enhance the Notch signaling pathway.
Thus, the present invention relates to compounds as defined herein that feature antiproliferative activity, which can be used in the treatment of benign and malignant hyperproliferative disorders in human and veterinary medicine. In particular, the present invention relates to compounds as defined herein for the treatment of disorders of the haematopoietic system including the haematologic system and immune system-related disorders, concerning malignancies of both the myeloid lineage and the lymphoid lineage, malignant and non-malignant disorders of the skin and mucosa, e.g. cornification disorders, malignant and non-malignant disorders of the muscle, including hyperproliferative disorders of the muscle, such as muscle hyperplasia and muscle hypertrophy, disorders of the neuroendocrine system, hyperproliferative disorders, cancer and pre-cancerous lesions of the skin and mucosa, such as non-melanoma skin cancer including squamous and basal cell carcinoma, actinic keratosis, hyperproliferative disorders and cancer of the oral cavity and tongue, hyperproliferative disorders and cancer of the neuroendocrine system such as medullary thyroid cancer, hyperproliferative disorders and cancer of the haematopoietic system including the haematologic system such as leukemia and lymphoma, hyperproliferative disorders and cancer of the lung, breast, stomach, genitourinary tract, e.g. cervical cancer and including cancer of the ovaries, in human and veterinary medicine.
The biological activity, e.g. the antiproliferative activity of the claimed compounds can be attributed to but may not be limited to Notch signaling enhancing activity. Thus, the present invention also relates to compounds as defined herein that feature Notch enhancing activity, which can be used in the treatment of pathological conditions that are responsive for Notch-regulation, such as cancer, skin diseases, muscle disorders, disorders of the haematopoietic system including the haematologic system and immune system-related disorders, in human and veterinary medicine.
The compounds of the present invention relate to bisarylether structures composed of two six-membered aromatic cycles, wherein one of the aromatic cycles is an unsubstituted or substituted benzyl ring and the other aromatic cycle is an unsubstituted or substituted aryl ring, which optionally contains N-atoms, thus optionally being a six-membered heteroaromatic cycle.
All such bisarylether structures share the common feature of containing a substituent in both para-positions relative to the ether bond, wherein such substituent on the benzyl ring, which cannot be a heteroaromatic cycle, is preferably selected from apolar residues and/or from sterically demanding residues; and wherein such substituent on the aryl ring which can optionally be a heteroaromatic cycle, is selected from structural units preferably containing a high amount of heteroatoms.
A first aspect of the present invention relates to compounds of general formula (I) and salts and solvates thereof:
R1=C1-C12 preferably C4-C12 alkyl, C2-C12 preferably C4-C12 alkenyl, C2-C12 preferably C4-C12 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, —OC1-C12 preferably —OC3-C12 alkyl, —OC2-C12 preferably —OC3-C12 alkenyl, —OC2-C12 preferably —OC3-C12 alkynyl, —OC3-C8 cycloalkyl, —OC5-C8 cycloalkenyl, —OC5-C12 bicycloalkyl, —OC7-C12 bicycloalkenyl, —OC5-C14 tricycloalkyl, —SC1-C12 preferably —SC3-C12 alkyl, —SC2-C12 preferably —SC3-C12 alkenyl, —SC2-C12 preferably —SC3-C12 alkynyl, —SC3-C8 cycloalkyl, —SC5-C8 cycloalkenyl, —SC5-C12 bicycloalkyl, —SC7-C12 bicycloalkenyl, —SC5-C14 tricycloalkyl, —NHR7 or —NR7R8 wherein R7 and R8 are independently from each other selected from: C1-C12 preferably C3-C12 alkyl, C2-C12 preferably C3-C12 alkenyl, C2-C12 preferably C3-C12 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, or wherein R7 can form a ring structure together with Re wherein the said ring structure including the N-atom is selected from three to eight membered cyclic structures or five to twelve membered bicyclic structures and wherein all said ring structures can additionally contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom contained in the ring structure, and particularly wherein such a replacement results in residues that contain at least twice the number of C atoms than heteroatoms independently selected from O, S and N;
wherein all alkyl, alkenyl and alkynyl residues contained in the definitions of R1, R7 and R8 are linear or branched, and are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH2, —NO2, ═O, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, linear or branched —OC1-C5 alkyl such as —OCH3, —OC3-C5 cycloalkyl such as —O (cyclopropyl), linear or branched —NH(C1-C5 alkyl), linear or branched —N(C1-C5 alkyl)(C1-C5 alkyl), —NH(C3-C5 cycloalkyl) such as —NH(cyclopropyl), —N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), linear or branched —N(C1-C5 alkyl)(C3-C5 cycloalkyl);
wherein all alkyl, alkenyl and alkynyl residues contained in the definitions of R1, R7 and R8 can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, and wherein such a replacement results in residues that contain at least twice the number of C atoms than heteroatoms independently selected from O, S and N, and wherein such replacement additionally cannot result in one of the groups selected from C═O, S═O and N═O directly bound to an aromatic ring;
wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R1, R7 and R8 can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, and wherein such a replacement results in residues that contain at least the same number of C atoms than heteroatoms independently selected from O, S and N;
wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R1, R7 and R8 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;
wherein bicyclic and tricyclic residues include fused, bridged and spiro systems;
and wherein R1 is preferably selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, sec-butyl, tert-butyl, tert-pentyl, tert-octyl, 3-pentyl, —CF3, —CF2CF3, —(CF2)2CF3, —CH(CF3)2, —CH2SCH3, —CH2CH2SCH3, —CH2SCH2CH3, —CH2CH2SCH2CH3, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxymethyl, dimethyl-aminomethyl, dimethyl-aminoethyl, diethyl-aminomethyl, ethyl-methyl-aminomethyl, cyclopropyl, methyl-cyclopropyl, ethyl-cyclopropyl, trifluoromethyl-cyclopropyl, perfluoroethyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl preferably norbornyl, bicyclooctyl, bicyclooctenyl, bicyclononyl, methylbicyclononyl, adamantyl, tricyclodecyl, oxiranyl, oxetanyl, tetrahydrofuranyl, methyltetrahydrofuranyl, trimethyltetrahydrofuranyl, tetrahydropyranyl, aziridinyl, N-methylaziridinyl, azetidinyl, N-methylazetidinyl, difluoroazetidinyl, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, difluoropiperidinyl, thiiranyl, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, dimethylpiperazinyl, dithianly, morpholinyl, N-methylmorpholinyl, thiomorpholinyl, N-methylthiomorpholinyl, oxa-azaspiroheptyl, N-methyloxa-azaspiroheptyl, azaspiroheptyl, N-methylazaspiroheptyl, thia-azaspiroheptyl, N-methylthia-azaspiroheptyl, difluorothia-azaspiroheptyl, azaspirooctyl, N-methylazaspirooctyl, oxa-azaspirooctyl, N-methyloxa-azaspirooctyl, oxa-azaspirononyl, N-methyloxa-azaspirononyl, azaspirononyl, N-methylazaspirononyl, oxa-azaspirodecyl, N-methyloxa-azaspirodecyl, azaspirodecyl, N-methylazaspirodecyl, dihydro-oxazinyl, N-methyldihydro-oxazinyl, oxazolidinyl, N-methyloxazolidinyl, dioxolanyl, imidazolidinyl, N-methylimidazolidinyl, N,N-dimethylimidazolidinyl, azepanyl, N-methylazepanyl, azaspirohexyl, N-methylazaspirohexyl, oxa-azadispirodecyl, N-methyloxa-azadispirodecyl, azadispirodecyl, N-methylazadispirodecyl, oxa-azabicyclooctyl, N-methyloxa-azabicyclooctyl, azabicyclooctyl, N-methylazabicyclooctyl, azabicycloheptyl, N-methylazabicycloheptyl, azabicyclononyl, N-methylazabicyclononyl, azaadamantyl, —O(adamantyl), oxa-azabicyclononyl, N-methyloxa-azabicyclononyl, oxa-azabicycloheptyl, N-methyloxa-azabicycloheptyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, N,N-dimethyldiazabicyclooctyl, diazabicycloheptyl, N-methyldiazabicycloheptyl, N,N-dimethyldiazabicycloheptyl; 4-oxocyclohexyl; 3-oxocyclopentyl; 2-oxocyclobutyl, 4-oxobicyclo[4.1.0]heptan-1-yl;
and wherein R1 is even more preferably selected from C4-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, cyclic, bicyclic and tricyclic residues, wherein the alkyl, alkenyl and alkynyl residues are preferably branched, including:
R2-R5 are independently from each other selected from —H, —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH2, —NO2, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, linear or branched C2-C4 alkynyl, C3-C6 cycloalkyl, —CH2(C3-C6 cycloalkyl), linear or branched —OC1-C3 alkyl, —O(cyclopropyl), linear or branched —NH(C1-C3 alkyl), linear or branched —N(C1-C3 alkyl)(C1-C3 alkyl), —NH(cyclopropyl), —N(cyclopropyl)2, linear or branched —N(C1-C3 alkyl)(cyclopropyl); wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R2-R5 are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH3, —CF3, —OH and —OCH3, —OCF3, —NH2, —NHCH3, —N(CH3)2; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R2-R5 can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, and wherein such a replacement cannot result in one of the groups selected from C═O and S═O directly bound to an aromatic ring;
wherein R2-R3 each are preferably —H, R4 is preferably —H or —F, and R5 is preferably —H, —F, —Cl, —Br, —CH3, —CF3, —CH═CH2, —C≡CH, —CH2OH, —CH2NHCH3, —OH, —OCH3, —OCF3, cyclopropyl, oxiranyl, —CH2—N-morpholinyl, —C(CH3)3, —CH2OCH3, —NO2, —CN, —NH2, —N(CH3)2, —OCH(CH3)2, —CH2NH2, —CH2N(CH3)2;
wherein the six-membered aromatic ring, to which substituents R1 to R5 are bound as defined in general formula (I), is preferably selected from:
X1-X4 are independently from each other selected from N, CR9, CR10, CR11, CR12; R9-R12 are independently from each other selected from —H, —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH2, —NO2, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, linear or branched C2-C4 alkynyl, C3-C6 cycloalkyl, —CH2(C3-C6 cycloalkyl), linear or branched —OC1-C3 alkyl, —O(cyclopropyl), linear or branched —NH(C1-C3 alkyl), linear or branched —N(C1-C3 alkyl)(C1-C3 alkyl), —NH(cyclopropyl), —N(cyclopropyl)2, linear or branched —N(C1-C3 alkyl)(cyclopropyl);
wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R9-R12 are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH3, —CF3, —OH and —OCH3, —OCF3, —NH2, —NHCH3, —N(CH3)2;
wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R9-R12 can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, and wherein such a replacement cannot result in one of the groups selected from C═O and S═O directly bound to an aromatic ring;
wherein R9-R12 are preferably selected from —H, —F, —Cl, —Br, —CH3, —CF3, —OH, —OCH3, —OCF3, cyclopropyl, oxiranyl, —C(CH3)3, —N(CH3)2, —NH2, —CN, —CH2OCH3, —OCH(CH3)2, —CH2NH2, —CH2N(CH3)2, —CH2OH, —NO2, —CH2—N-morpholinyl;
and wherein the six-membered aromatic ring containing X1-X4 as defined in general formula (I) is preferably selected from:
R6=—H, C1-C8 preferably C1-C4 alkyl, C2-C8 preferably C2-C4 alkenyl, C2-C8 preferably C2-C4 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, C5-C12 bicycloalkyl, C7-C12 bicycloalkenyl, C8-C14 tricycloalkyl, and aromatic and heteroaromatic residues preferably six-membered aromatic cycles and five to six membered heteroaromatic cycles;
and wherein bicyclic and tricyclic residues include fused, bridged and spiro systems;
wherein said cycloalkyl, cycloalkenyl bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues contained in the definition of R6 can optionally be linked through a C1 alkylene or a C2 alkylene or a C3 alkylene linker to the N to which R6 is bound;
wherein all aromatic and heteroaromatic residues contained in the definition of R6 are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH2, —NO2, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched —OC1-C3 alkyl such as —OCH3, —O(cyclopropyl), linear or branched —NH(C1-C3 alkyl), linear or branched —N(C1-C3 alkyl)(C1-C3 alkyl), —NH(cyclopropyl), —N(cyclopropyl)2, linear or branched —N(C1-C3 alkyl)(cyclopropyl);
wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues, and alkylene linkers contained in the definition of R6 are linear or branched, and are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH2, ═O, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched —OC1-C3 alkyl such as —OCH3, —O(cyclopropyl), linear or branched —NH(C1-C3 alkyl), linear or branched —N(C1-C3 alkyl)(C1-C3 alkyl), —NH(cyclopropyl), —N(cyclopropyl)2, linear or branched —N(C1-C3 alkyl)(cyclopropyl);
wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and heteroaromatic residues, and alkylene linkers contained in the definition of R6 can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
wherein R6 is preferably —H, —CH3, —CH2CH3, n-propyl, isopropyl, cyclopropyl, —CF3 and —CF2CF3, benzyl, tert-butyl, phenyl, cyclohexyl, 1-phenylethyl, 2,2-dimethyl-1-phenylpropyl, (1-naphtyl)-methyl, 4-methoxybenzyl, 4-trifluoromethylbenzyl, tetrahydropyranyl;
wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues contained in the definitions of R2-R6 and R9-R12 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;
Y=—H, linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, —OH, linear or branched —OC1-C6 alkyl, linear or branched —OC2-C6 alkenyl, linear or branched —OC2-C6 alkynyl, —OC3-C6 cycloalkyl, —OC5-C6 cycloalkenyl, —CN, aromatic and heteroaromatic residues preferably six-membered aromatic cycles and five- to six-membered heteroaromatic cycles, —S(O)R13 and —S(O)2R13 wherein R13 is selected from linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, —CF3, and —C6H4CH3;
wherein all cycloalkyl, cycloalkenyl, aromatic and heteroaromatic residues contained in the definition of Y can optionally be linked through a C1 alkylene, or a C2 alkylene, or a C3 alkylene, or an —O—, or an —O—CH2—, or an —O—CH2—CH2— linker to the N to which Y is bound;
wherein all aromatic and heteroaromatic residues contained in the definition of Y are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH2, —NO2, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched —OC1-C3 alkyl such as —OCH3, —O(cyclopropyl), linear or branched —NH(C1-C3 alkyl), linear or branched —N(C1-C3 alkyl)(C1-C3 alkyl), —NH(cyclopropyl), —N(cyclopropyl)2, linear or branched —N(C1-C3 alkyl)(cyclopropyl);
wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues, and alkylene linkers contained in the definition of Y are linear or branched, and are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH2, ═O, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched —OC1-C3 alkyl such as —OCH3, —O(cyclopropyl), linear or branched —NH(C1-C3 alkyl), linear or branched —N(C1-C3 alkyl)(C1-C3 alkyl), —NH(cyclopropyl), —N(cyclopropyl)2, linear or branched —N(C1-C3 alkyl)(cyclopropyl);
wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and heteroaromatic residues, and alkylene linkers contained in the definition of Y can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic and heteroaromatic residues and alkylene linkers contained in the definition of Y can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;
wherein Y is preferably —H, —CH3, —CH2CH3, n-propyl, isopropyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, —CF3, —CF2CF3, —OH, —OCH3, —OCH2CH3, —OCH2(cyclopropyl), —CN, —S(O)C(CH3)3, —S(O)2CH3, —S(O)2CF3, —S(O)2C6H4CH3, —OCH2C6H5 and —OC6Hs; and for R6=—H or —CH3 or benzyl, then Y is preferably —OH, —OCH3, —OCH2CH3, —OCH2(cyclopropyl);
wherein Y can form a ring structure together with R6, wherein the said ring structure including the N-atom of formula I is selected from three-membered rings, four-membered rings, five-membered rings, six-membered rings, from five- to twelve-membered bicyclic residues, from eight- to fourteen-membered tricyclic residues, and from heteroaromatic residues, wherein all rings, bicyclic, tricyclic and heteroaromatic residues can additionally contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom contained in the ring structure, and wherein all rings, bicyclic, tricyclic and heteroaromatic residues are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, ═O, —CH3, —CF3, morpholinyl;
and wherein bicyclic and tricyclic residues include fused, bridged and spiro systems;
wherein the ring structure of Y together with R6 including the N-atom of formula I is preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, difluoropiperidinyl, morpholinyl, morpholinylazetidinyl, hydroxyazetidinyl, azetidinonyl, azetidinyl, difluoroazetidinyl, azaspirohexyl, azaspiroheptyl, difluoroazaspiroheptyl, hydroxyazaspiroheptyl, methylhydroxyazaspiroheptyl, trifluoromethylhydroxyazaspiroheptyl, azaspirooctyl, azaspirononyl, oxa-azaspiroheptyl, oxa-azaspirooctyl, oxa-azaspirononyl, thia-azaspiroheptyl, oxazolidinyl, tetrahydro-oxazinyl, isoxazolidinyl, oxazinane, isoxazolidine, piperazine;
and wherein the ring structure of Y together with R6 including the N-atom of formula I is even more preferably selected from:
Z1 and Z2 are selected from the following groups:
wherein Z1 is selected from linear or branched C1-C3 alkyl preferably —CH3, cyclopropyl, oxiranyl, N-methyl-aziridinyl, thiiranyl, —CN, —N3, —CF3, —CF2CF3, and wherein Z2 is independently selected from —H and linear or branched C1-C3 alkyl preferably —CH3, —CF3, —CF2CF3 (general formula Ia);
wherein Z1 is preferably —CH3, —CF3, —CN, cyclopropyl; and/or wherein Z2 is preferably —H, —CH3 and —CF3; e.g.:
or wherein Z1 and Z2 are together ═O, ═S, ═NR14 (general formula Ib); wherein R14 is selected from —H, —OH, —OCH3, —CN, —S(O)C(CH3)3, —S(O)2CH3, —S(O)2CF3, linear or branched C1-C3 alkyl preferably —CH3, cyclopropyl, —CF3, —CF2CF3, —CH2CF3, —C6Hs, —CH2C6Hs;
wherein Z1 and Z2 are together preferably ═O, ═NR14; wherein R14 is preferably selected from —H, —CH3, cyclopropyl, —OH, —OCH3, —CN:
or wherein Z1 and Z2 form together a cyclic residue including the carbon atom to which they are bound (general formula Ic); wherein the cyclic residue is selected from three-membered rings, four-membered rings five-membered rings and six-membered rings, wherein all rings optionally can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom contained in the ring structure; wherein all rings are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, ═O, —CH3 and —CF3;
wherein Z1 and Z2 form together preferably a three membered or four membered cyclic residue including the carbon atom to which they are bound; wherein this cyclic residue is preferably selected from cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl and thietanyl; and
wherein this cyclic residue is optionally substituted preferably with —F, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, ═O, —CH3 and —CF3;
and wherein this cyclic residue is even more preferably selected from:
wherein all alkyl and cyclic residues contained in the definitions of Z1 and Z2 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated.
Following preferred definitions of R1-R14, X1-X4, Z1, Z2 and Y may be optionally independently and/or in combination applied on all aspects including preferred and certain aspects, on all embodiments including preferred and certain embodiments, and on all subgenera as defined in the present invention:
A preferred aspect of the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═O and wherein at least one of R6 and Y is different from H,
and R1-R5, R7-R13 and X1-X4 are defined as in general formula (I) including their substitutions and preferred definitions.
A further preferred aspect of the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein Y is selected from residues as contained in the general definition of Y, which are bound with an oxygen atom to the N to which Y is bound,
and wherein Y is even more preferably —OH, —OCH3, —OCH2CH3, —OCH2(cyclopropyl), —OC6H5 and —OCH2C6H5,
and R1-R12, R14, X1-X4, Z1 and Z2 are defined as in general formula (I) including the substitutions and preferred definitions.
A further preferred aspect of the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R1 is selected from residues as contained in the general definition of R1, which contain four or more preferably six or more and even more preferably seven or more carbon atoms,
and wherein R1 contains no heteroatom,
and wherein R1 is even more preferably selected from cyclic, bicyclic and tricyclic structures,
and wherein R1 is even more preferably selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecyl and adamantyl,
and wherein R1 is most preferably adamantyl,
and R2-R6, R9-R14, X1-X4, Z1, Z2 and Y are defined as in general formula (I) including the substitutions and preferred definitions.
A further preferred aspect of the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R1 is selected from residues as contained in the general definition of R1, which contain four or more, preferably six or more and even more preferably seven or more carbon atoms,
and wherein R1 contains one or more preferably one to two heteroatoms independently selected from O, S and N in replacement of a carbon atom contained in R1,
and wherein R1 is even more preferably selected from cyclic, bicyclic and tricyclic structures, or wherein R1 is selected from residues containing cyclic, bicyclic and tricyclic structures,
and wherein R1 is even more preferably selected from tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxa-azabicycloheptyl, N-methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, aza-adamantyl and —O(adamantyl),
and wherein R1 is most preferably tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicyclooctyl, aza-adamantyl and —O(adamantyl),
and R2-R14, X1-X4, Z1, Z2 and Y are defined as in general formula (I) including the substitutions and preferred definitions.
A further preferred aspect of the present invention relates to compounds of general formula (I) and salts and solvates thereof, which fall under the scope of the herein defined subgenera:
wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions R7 and R8 can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definition of R1 can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, with the optional proviso that the combination of the said heteroatoms in a terminal position is different from the residues —CN, —NCO, —NCS and —N3 if not explicitly contained in the definition of R1;
wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R1, R7 and R8 can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;
In a certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R1 is adamantyl,
and wherein Z1 and Z2 are defined as in general formula (I), including general formula (Ia), general formula (Ib) and general formula (Ic), including the substitutions and preferred definitions, optionally with the proviso that in the case of general formula (Ib) Z1 and Z2 are together different from ═O,
and wherein R14 is defined as in general formula (Ib) including the substitutions and preferred definitions,
and wherein Y, R2-R6, R9-R13 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (I-1):
and wherein the compounds of structure (I-1) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0014, XPW-0028, XPW-0042, XPW-0182, XPW-0924, XPW-3038, XPW-3052, XPW-4633, XPW-4642 and XPW-4643.
In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein Y and R6 are defined as in general formula (I) including the substitutions and preferred definitions, wherein Y forms a ring structure together with R6, and wherein such ring structure contains an O-atom in replacement of one of the ring-C-atoms that is directly linked to the N-atom to which Y and R6 are bound,
and wherein Z1 and Z2 are defined as in general formula (I), including general formula (Ia), general formula (Ib) and general formula (Ic), including the substitutions and preferred definitions,
and wherein R14 is defined as in general formula (Ib) including the substitutions and preferred definitions,
and wherein R1-R5, R7-R12 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (I-2):
and wherein the compounds of structure (I-2) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, stomach, breast, and cancer of the neuroendocrine system.
Examples are compounds XPW-4637 and XPW-4638.
In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein Y is selected from —S(O)R13 and —S(O)2R13,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 contains four or more, preferably six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I),
and wherein Z1 and Z2 are defined as in general formula (I), including general formula (Ia), general formula (Ib) and general formula (Ic), including the substitutions and preferred definitions,
and wherein R14 is defined as in general formula (Ib) including the substitutions and preferred definitions,
and wherein R2-R13 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (I-3):
and wherein the compounds of structure (1-3) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0547, XPW-0548, XPW-0552, XPW-0560, XPW-0566, XPW-0574, XPW-0575, XPW-0576, XPW-0580, XPW-0588, XPW-0603, XPW-0604, XPW-0608, XPW-0616, XPW-2675, XPW-2676, XPW-2688, XPW-2703, XPW-2704, XPW-2708, XPW-2716, XPW-2732, XPW-2744, XPW-4633 and XPW-4642.
In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein Y is —OH,
and wherein R6 is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R6 is different from —H,
and wherein Z1 and Z2 are defined as in general formula (I), including general formula (Ia), general formula (Ib) and general formula (Ic), including the substitutions and preferred definitions,
and wherein R14 is defined as in general formula (Ib) including the substitutions and preferred definitions,
and wherein R1-R5, R7-R12 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (I-4):
and wherein the compounds of structure (I-4) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0182, XPW-0674, XPW-0675, XPW-0678, XPW-0679, XPW-0686, XPW-0700, XPW-0734, XPW-0742, XPW-1750, XPW-2805, XPW-2806, XPW-4612, XPW-4614, XPW-4616, XPW-4617, XPW-4618, XPW-4619, XPW-4620, XPW-4621, XPW-4622, XPW-4626, XPW-4631, XPW-4632, XPW-4640, XPW-4644, XPW-4646 and XPW-4647.
In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein Y is —OCH3,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 including any substituent contains no heteroatom selected from O, S, N, optionally with the proviso that R1 contains two or more carbon atoms,
and wherein Z1 and Z2 are defined as in general formula (I), including general formula (Ia), general formula (Ib) and general formula (Ic), including the substitutions and preferred definitions,
and wherein R14 is defined as in general formula (Ib) including the substitutions and preferred definitions,
and wherein R2-R6, R9-R12 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (I-5):
and wherein the compounds of structure (I-5) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast.
Examples are compounds XPW-0702, XPW-0706, XPW-0714, XPW-0716, XPW-0720, XPW-0728, XPW-2833, XPW-2834, XPW-2847, XPW-2848 and XPW-4605.
In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R6 is —H and Y is —OCH3,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R1 is selected from cyclic, bicyclic and tricyclic structures,
and wherein Z1 and Z2 are defined as in general formula (I), including general formula (Ia), general formula (Ib) and general formula (Ic), including the substitutions and preferred definitions,
and wherein R14 is defined as in general formula (Ib) including the substitutions and preferred definitions,
and wherein R2-R5, R7-R12 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (I-6):
and wherein the compounds of structure (I-6) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast.
Examples are compounds XPW-0706, XPW-0714, XPW-2833 and XPW-2834.
In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein Y and R6 are defined as in general formula (I) including the substitutions and preferred definitions, wherein Y forms a ring structure together with R6,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 is selected from cyclic, bicyclic and tricyclic structures, optionally with the proviso that R1 including any substituent contains no or one heteroatom selected from O, S, N,
and wherein Z1, Z2 and R14 are defined as in general formula (Ib), including the substitutions and preferred definitions,
and wherein R2-R5, R7-R12, and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (I-7):
and wherein the compounds of structure (I-7) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0762, XPW-0770, XPW-0776, XPW-0784, XPW-0790, XPW-0798, XPW-0818, XPW-2890, XPW-2898, XPW-2904, XPW-2912, XPW-2918, XPW-2926, XPW-4576, XPW-4577, XPW-4578, XPW-4579, XPW-4580, XPW-4581, XPW-4583, XPW-4586, XPW-4589, XPW-4592 and XPW-4594.
In a further certain embodiment, the present invention relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Z1 is —CF3,
and wherein Y is defined as in general formula (I) including the substitutions and preferred definitions, optionally with the proviso that Y is different from —H,
and wherein Z2 is defined as in general formula (Ia) including the substitutions and preferred definitions,
and wherein R1-R13 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ia-1):
and wherein the compounds of structure (Ia-1) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0014, XPW-0020, XPW-0028, XPW-0042, XPW-0182, XPW-4633, XPW-4642 and XPW-4643.
In a further certain embodiment, the present invention relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Z1 is —CF3,
and wherein R6 is defined as in general formula (I) including the substitutions and preferred definitions, optionally with the proviso that R6 is different from —H,
and wherein Z2 is defined as in general formula (Ia) including the substitutions and preferred definitions,
and wherein R1-R5, R7-R13, X1-X4 and Y are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ia-2):
and wherein the compounds of structure (Ia-2) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0014, XPW-0020, XPW-0028, XPW-0042, XPW-0182, XPW-4633, XPW-4642 and XPW-4643.
In a further certain embodiment, the present invention relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Z1 is —CF3, and wherein Y and R6 are each —H,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, optionally with the proviso that R1 contains five or more, preferably six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from 0, S and N as defined in general formula (I),
and wherein Z2 is defined as in general formula (Ia) including the substitutions and preferred definitions,
and wherein R2-R5, R7-R12 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ia-3):
and wherein the compounds of structure (Ia-3) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, ovaries, and cancer of the neuroendocrine system.
An example is compound XPW-0014.
In a further certain embodiment, the present invention relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Z1 is —CN,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, and wherein R1 contains three or more, preferably six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I), optionally with the proviso that R1 including any substituent contains no heteroatom selected from O, S and N,
and wherein Z2 is defined as in general formula (Ia) including the substitutions and preferred definitions,
and wherein R2-R13, X1-X4 and Y are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ia-4):
and wherein the compounds of structure (Ia-4) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias, and cancer of the skin.
An example is compound XPW-0314.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I), and wherein R1 is selected from cyclic, bicyclic and tricyclic structures,
and wherein R5 is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R5 is different from —H,
and wherein Z1, Z2 and R14 are defined as in general formula (Ib), including the substitutions and preferred definitions,
and wherein R2-R4, R6-R13 and X1-X4 and Y are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-1):
and wherein the compounds of structure (Ib-1) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-4575, XPW-4577, XPW-4578, XPW-4579, XPW-4580, XPW-4581, XPW-4583, XPW-4584, XPW-4585, XPW-4586, XPW-4587, XPW-4588, XPW-4589, XPW-4590, XPW-4591, XPW-4592, XPW-4593, XPW-4594 and XPW-4595.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein X4 is N,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I), and wherein R1 is selected from cyclic, bicyclic and tricyclic structures,
and wherein Z1, Z2 and R14 are defined as in general formula (Ib), including the substitutions and preferred definitions,
and wherein R2-R13, X1-X3 and Y are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-2):
and wherein the compounds of structure (Ib-2) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-4623, XPW-4624, XPW-4628, XPW-4629, XPW-4630, XPW-4631, XPW-4632, XPW-4634, XPW-4635, XPW-4636 and XPW-4644.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═O, and wherein Y is —OCH3,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 including any substituent contains no heteroatom selected from O, S, N, optionally with the proviso that R1 contains two or more carbon atoms,
and wherein R2-R6, R9-R12 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-3):
and wherein the compounds of structure (Ib-3) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast.
Examples are compounds XPW-0702, XPW-0706, XPW-0714, XPW-0716, XPW-0720, XPW-0728, XPW-2833, XPW-2834, XPW-2847, XPW-2848 and XPW-4605.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Y and R6 are defined as in general formula (I) including the substitutions and preferred definitions, wherein Y forms a ring structure together with R6,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 is selected from cyclic, bicyclic and tricyclic structures, optionally with the proviso that R1 including any substituent contains no or one heteroatom selected from O, S, N,
and wherein Z1, Z2 and R14 are defined as in general formula (Ib), including the substitutions and preferred definitions,
and wherein R2-R5, R7-R12, and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-4):
and wherein the compounds of structure (Ib-4) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0762, XPW-0770, XPW-0776, XPW-0784, XPW-0790, XPW-0798, XPW-0818, XPW-2890, XPW-2898, XPW-2904, XPW-2912, XPW-2918, XPW-2926, XPW-4576, XPW-4577, XPW-4578, XPW-4579, XPW-4580, XPW-4581, XPW-4583, XPW-4586, XPW-4589, XPW-4592 and XPW-4594.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═O, and wherein R1 is adamantyl,
and wherein R5 is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R5 is different from —H,
and wherein Y, R2-R4, R6, R9-R13 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-5):
and wherein the compounds of structure (Ib-5) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-4585, XPW-4586, XPW-4587, XPW-4591, XPW-4592 and XPW-4593.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═O, and wherein R1 is adamantyl, and wherein X4 is N,
and wherein R2-R6, R9-R13, X1-X3 and Y are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-6):
and wherein the compounds of structure (Ib-6) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-4623, XPW-4624, XPW-4628, XPW-4629, XPW-4630, XPW-4631, XPW-4632, XPW-4634, XPW-4635, XPW-4636 and XPW-4644.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═O, and wherein Y is —OH, and wherein R6 is —H,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I),
and wherein R5 is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R5 is different from —H,
and wherein R2-R4, R7-R12 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-7):
and wherein the compounds of structure (Ib-7) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-4584, XPW-4587, XPW-4590 and XPW-4593.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═O, and wherein Y is —OH, and wherein R6 is —H, and wherein X4 is N,
and wherein R1-R5, R7-R12 and X1-X3 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-8):
and wherein the compounds of structure (Ib-8) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-4623, XPW-4628, XPW-4630 and XPW-4636.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═O, and wherein Y is —OH, and wherein R6 is —H, and wherein X1 and X2 are each N,
and wherein R1-R5, R7-R12, X3 and X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-9):
and wherein the compounds of structure (Ib-9) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
An example is compound XPW-4625.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═O, and wherein Y is —OH, and wherein R6 is —H, and wherein X1 is N, and wherein X4 is CR10, and wherein R10 is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R10 is different from —H,
and wherein R1-R5, R7-R9, R11, R12, X2 and X3 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-10):
and wherein the compounds of structure (Ib-10) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
An example is compound XPW-4639.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═O, and wherein Y is —CH3, and wherein R6 is —CH3,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I),
and wherein R5 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R5 is different from —H, optionally with the additional proviso that R5 is different from —OCH3,
and wherein R2-R4, R7-R12 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-11):
and wherein the compounds of structure (Ib-11) are—particularly without the additional proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, and cancer of the neuroendocrine system.
Examples are compounds XPW-4575, XPW-4585, XPW-4588, XPW-4591 and XPW-4595.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 is selected from unsubstituted and substituted cycloalkyl and cycloalkenyl, wherein such cycle contains four or more, preferably six or more ring carbon atoms that cannot be replaced by a heteroatom selected from O, S and N,
and wherein R5 is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R5 is different from —H,
and wherein Z1, Z2 and R14 are defined as in general formula (Ib), including the substitutions and preferred definitions,
and wherein R2-R4, R6-R13, X1-X4 and Y are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-12):
and wherein the compounds of structure (Ib-12) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-4575, XPW-4577, XPW-4578, XPW-4579, XPW-4580, XPW-4581, XPW-4583, XPW-4584, XPW-4588, XPW-4589, XPW-4590, XPW-4594 and XPW-4595.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═NR14,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 is selected from cyclic, bicyclic and tricyclic structures, optionally with the proviso that R1 including any substituent contains no or one heteroatom selected from O, S, N,
and wherein R14 is defined as in general formula (Ib) including the substitutions and preferred definitions,
and wherein R2-R13, X1-X4 and Y are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-13):
and wherein the compounds of structure (Ib-13) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue and breast.
Examples are compounds XPW-0832 and XPW-4574.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═O, and wherein Y is —OH, and wherein R6 is —H, and wherein X1 is CR11, X2 is CR8, X3 is CR9 and X4 is CR10,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 contains four or more, preferably six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I), with the proviso that R1 including any substituent contains one or two heteroatoms selected from O, S, N,
and wherein R2-R5 and R7-R12 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-14):
and wherein the compounds of structure (Ib-14) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0661, XPW-0665, XPW-0667 and XPW-4613.
In a further certain embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z1 and Z2 are together ═O, and wherein R6 is —CH3,
and wherein X1 is CR11, X2 is CR8, X3 is CR9 and X4 is CR10,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, wherein R1 is selected from cyclic, bicyclic and tricyclic structures, with the proviso that R1 including any substituent contains one or two heteroatoms selected from O, S, N,
and wherein R2-R5, R7-R13 and Y are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ib-15):
and wherein the compounds of structure (Ib-15) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, breast, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0539, XPW-0541 and XPW-0679.
In a further certain embodiment, the present invention relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z1 and Z2 form together a cyclic residue including the carbon atom to which they are bound, and wherein Z1 and Z2 are defined as in general formula (Ic) including the substitutions and preferred definitions,
and wherein R6 is defined as in general formula (I) including the substitutions and preferred definitions, optionally with the proviso that R6 is different from H,
and wherein R1-R5, R7-R13, X1-X4 and Y are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ic-1):
and wherein the compounds of structure (Ic-1) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0902, XPW-0916, XPW-0924, XPW-0930, XPW-3038 and XPW-3052.
In a further certain embodiment, the present invention relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z1 and Z2 form together a cyclic residue including the carbon atom to which they are bound, and wherein Z1 and Z2 are defined as in general formula (Ic) including the substitutions and preferred definitions, optionally with the proviso that the said cyclic residue contains one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom contained in the ring structure, and/or that the said cyclic residue is substituted with one or more substituents as defined in general formula (Ic),
and wherein R1-R13, X1-X4 and Y are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ic-2):
and wherein the compounds of structure (Ic-2) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0902, XPW-0916, XPW-0924, XPW-0930, XPW-3038 and XPW-3052.
In a further certain embodiment, the present invention relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z1 and Z2 form together a cyclic residue including the carbon atom to which they are bound, and wherein Z1 and Z2 are defined as in general formula (Ic) including the substitutions and preferred definitions, optionally with the proviso that the said cyclic residue is a four-membered ring,
and wherein R1-R13, X1-X4 and Y are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ic-3):
and wherein the compounds of structure (Ic-3) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0902, XPW-0916, XPW-0924, XPW-0930, XPW-3038 and XPW-3052.
In a further certain embodiment, the present invention relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z1 and Z2 form together a cyclic residue including the carbon atom to which they are bound, and wherein Z1 and Z2 are defined as in general formula (Ic) including the substitutions and preferred definitions,
and wherein Y and R6 are each —H,
and wherein R1 is defined as in general formula (I) including the substitutions and preferred definitions, optionally with the proviso that R1 contains five or more, preferably six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from 0, S and N as defined in general formula (I),
and wherein R2-R5, R7-R12 and X1-X4 are defined as in general formula (I) including the substitutions and preferred definitions,
and wherein the compounds share the following structure (Ic-4):
and wherein the compounds of structure (Ic-4) are—particularly without the proviso—preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.
Examples are compounds XPW-0916, XPW-0924 and XPW-3052.
In some embodiments, the following compounds shown in Table 1 to Table 3 are explicitly excluded from the scope of the invention:
The compounds of Table 1 specifically indicated by CAS registry numbers have been identified by the inventors as state of the art. In embodiments where these compounds are encompassed by general formula (I) or any subgeneric formula as defined herein, they are explicitly excluded from the 5 scope of the invention with regard to compound protection. To the best of the inventors' knowledge, these compounds are not known for any medical use. Thus, the invention encompasses any medical use for compounds of Table 1.
The compounds of Table 2 specifically indicated by CAS registry numbers have been identified by the inventors as state of the art. In embodiments, where these compounds are encompassed by general formula (I) or any subgeneric formula as defined herein, they are explicitly excluded from the scope of the invention with regard to compound protection. To the best of the inventors' knowledge, these compounds are not known for any medical use as defined in the invention. Thus, the compounds of Table 2 are explicitly included into the scope of the invention with regard to medical use as defined herein, particularly in the treatment of non-malignant or malignant hyperproliferative diseases.
The compounds of Table 3 specifically indicated by CAS registry numbers have been identified by the inventors as state of the art. In embodiments, where these compounds are encompassed by general formula (I) or any subgeneric formula as defined herein, they are explicitly excluded from the scope of the invention with regard to compound protection. Further, these compounds are, to the best of the inventors' knowledge, known for a medical use, which in some embodiments may be encompassed by a medical use as defined herein. Thus, the compounds of Table 3 may be explicitly excluded from the scope of the invention with regard to compound protection and with regard to certain medical use in some embodiments as defined herein.
Specific examples of compounds falling under the scope of compounds contained in pending application PCT/EP2018/054686 have been identified in the present application to have novel medical use, in particular to have growth inhibitory properties on muscle cells, keratinocytes, and cells and malignant cells selected from cervical cancer, cutaneous T-cell lymphoma, acute promyelocytic leukemia, acute myeloid leukemia, oral and tongue squamous cell carcinoma, epidermoid squamous cell carcinoma and lung squamous cell carcinoma cells.
Thus, these compounds as well as salts and solvates thereof are particularly suitable for the treatment of hyperproliferative muscle diseases, hyperproliferative skin diseases as defined herein as well as for the treatment of cervical cancer, cutaneous T-cell lymphoma, acute promyelocytic leukemia, acute myeloid leukemia, epidermoid skin cancer such as non-melanoma skin cancer, cancer of the oral cavity, cancer of the tongue and lung cancer as defined herein.
Specific examples of compounds falling under the scope of compounds contained in pending application PCT/EP2018/054686 have been identified in the present application to have further novel medical use, in particular to have growth inhibitory properties on cells and malignant cells selected from T-cell leukemia, B-cell leukemia, gastric cancer, breast cancer, ovarian cancer and medullary thyroid cancer.
Thus, these compounds as well as salts and solvates thereof are particularly suitable for the treatment of diseases of the haematopoietic system including the haematologic system such as T-cell leukemia, B-cell leukemia, as well as for the treatment of gastric cancer, breast cancer, ovarian cancer and cancer of the neuroendocrine system as defined herein.
The herein identified novel medical use for specific compounds falling under the scope of compounds contained in pending application PCT/EP2018/054686 are shown in Table 4 and Table 5, wherein the medical applications are selected from the treatments of hyperproliferative muscle diseases (A), hyperproliferative skin diseases as defined herein (B), cervical cancer (C), cutaneous T-cell lymphoma (D), acute promyelocytic leukemia (E), acute myeloid leukemia (F), epidermoid skin cancer (G), cancer of the oral cavity (H), cancer of the tongue (I), lung cancer (J), T-cell leukemia (K), B-cell leukemia (L), gastric cancer (M), breast cancer (N), ovarian cancer (0) and cancer of the neuroendocrine system (P).
The following compounds described in PCT/EP2018/054686 are specifically claimed for the indicated medical use.
The following compounds described in PCT/EP2018/054686 are specifically claimed for the indicated medical use.
Specific examples of compounds falling under the scope of formula (I) are shown in Table 6 to Table 54. Intermediates are denoted as “XPW-I”.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated intermediates used for the synthesis of XPW-0001 to XPW-5062 as well as their salts and solvates. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.
The above table constitutes an individualized description of each of the specifically indicated intermediates used for the synthesis of XPW-0001 to XPW-5062 as well as their salts and solvates. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.
The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.
Also included are isomers, e.g. enantiomers or diastereomers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above.
The term “C1-C12 alkyl” comprises all isomers of the corresponding saturated aliphatic hydrocarbon groups containing one to twelve carbon atoms; this includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methylbutyl, iso-pentyl, 2-methylbut-2-yl, 3-methylbut-2-yl, all hexyl-isomers, all heptyl-isomers, all octyl-isomers, all nonyl-isomers, all decyl-isomers, all undecyl-isomers and all dodecyl-isomers.
The term “C2-C12 alkenyl” comprises all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing two to twelve carbon atoms linked by (i.e. comprising) one or more double bonds; this includes vinyl, all propenyl-isomers, all butenyl-isomers, all pentenyl-isomers, all hexenyl-isomers, all heptenyl-isomers, all octenyl-isomers, all nonenyl-isomers, all decenyl-isomers, all undecenyl-isomers and all dodecenyl-isomers.
The term “C2-C12 alkynyl” comprises all isomers of the corresponding unsaturated acetylenic hydrocarbon groups containing two to twelve carbon atoms linked by (i.e. comprising) one or more triple bonds; this includes ethynyl, all propynyl-isomers, all butynyl-isomers, all pentynyl-isomers, all hexynyl-isomers, all heptynyl-isomers, all octynyl-isomers, all nonynyl-isomers, all decynyl-isomers, all undecynyl-isomers and all dodecynyl-isomers. The term “alkynyl” also includes compounds having one or more triple bonds and one or more double bonds.
The term “C3-C8 cycloalkyl” comprises the corresponding saturated hydrocarbon groups containing three to eight carbon atoms arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
The term “C5-C8 cycloalkenyl” comprises the corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups containing five to eight carbon atoms, of which at least one is sp3-hybridized, and which are arranged in a monocyclic ring structure and linked by (i.e. comprising) one or more double bonds; this includes all cyclopentenyl-isomers, all cyclohexenyl-isomers, all cycloheptenyl-isomers, all cyclooctenyl-isomers.
The term “C5-C12 bicycloalkyl” comprises the corresponding saturated hydrocarbon groups containing five to twelve carbon atoms arranged in a bicyclic ring structure; wherein these bicyclic ring structures include fused, bridged and spiro systems;
The term “C7-C12 bicycloalkenyl” comprises the corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups containing seven to twelve carbon atoms arranged in a bicyclic ring structure and linked by (i.e. comprising) one or more double bonds; wherein these bicyclic ring structures include fused, bridged and spiro systems;
The term “C8-C14 tricycloalkyl” comprises the corresponding saturated hydrocarbon groups containing eight to fourteen carbon atoms arranged in a tricyclic ring structure; wherein these tricyclic ring structures include fused, bridged and spiro systems;
The terms “cyclic”, “bicyclic”, “tricyclic”, “cycloalkyl”, “cycloalkenyl”, “bicycloalkyl”, “bicycloalkenyl” and “tricycloalkyl” for R1 mean that such cyclic, bicyclic or tricyclic residue is directly linked by a chemical bond to the aromatic ring to which R1 is bound, and wherein the terms “cyclic”, “bicyclic”, “tricyclic”, “cycloalkyl”, “cycloalkenyl”, “bicycloalkyl”, “bicycloalkenyl” and “tricycloalkyl” for a substituent of R1 mean that such cyclic, bicyclic or tricyclic residue is directly linked by a chemical bond to one of the C-atoms or N-atoms or O-atoms or S-atoms contained in R1; e.g. “R1 is cyclohexyl” means that the cyclohexyl residue is linked to the aromatic ring to which R1 is bound; and “R1 is methyl and R1 is substituted with cyclohexyl” means that the resulting —CH2(cyclohexyl) residue is linked to the aromatic ring to which R1 is bound.
In case a carbon atom is replaced by a heteroatom selected from O, N, or S, the number of substituents on the respective heteroatom is adapted according to its valency, e.g. a —CR2— group may be replaced by a —NR—, —NR2′—, —O— or —S— group.
The term “perhalogenated” relates to the exhaustive halogenation of the carbon scaffold; according residues comprise the corresponding perfluorinated, perchlorinated, perbrominated and periodinated groups. Preferably, the term “perhalogenated” relates to perfluorinated or perchlorinated groups, more preferably to perfluorinated groups.
The following contains definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
The compounds of the present invention may form salts, which are also within the scope of this invention. Reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterions (internal or inner salts) are included within the term “salt(s)” as used herein (and may be formed, for example, where the substituents comprise an acid moiety such as a carboxyl group and an amino group). Also included herein are quaternary ammonium salts such as alkylammonium salts. Salts of the compounds may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary salts resulting from the addition of an acid include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, chlorates, bromates, iodates, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
Exemplary salts resulting from the addition of a base (formed, for example, where the substituents comprise an acidic moiety such as a carboxyl group) include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, tert-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science 1977, 66 (2), each of which is incorporated herein by reference in its entirety.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Furthermore, in the case of the compounds of the invention which contain an asymmetric carbon atom or an atropoisomeric bond, the invention relates to the D form, the L form and D,L mixtures and also, where more than one asymmetric carbon atom or atropoisomeric bond is present, to the diastereomeric forms. Those compounds of the invention which contain asymmetric carbon atoms or atropoisomeric bonds, and which as a rule accrue as racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use an optically active starting substance from the outset, with a corresponding optically active or diastereomeric compound then being obtained as the end product.
Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
Also included are solvates and hydrates of the compounds of the invention and solvates and hydrates of their pharmaceutically acceptable salts.
The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, rotamers, and isotopes of the structures depicted, unless otherwise indicated.
In some embodiments, the compound can be provided as a prodrug. The term “prodrug”, as employed herein, denotes a compound, which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the invention, or a salt and/or solvate thereof.
In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof.
Pharmaceutical Methods
The compounds according to the invention have been found to have pharmacologically important properties, which can be used therapeutically. The compounds of the invention can be used alone, in combination with each other or in combination with other active compounds.
In certain embodiments, compounds of the present invention may exhibit growth inhibiting properties in hyperproliferative processes.
The antiproliferative activities of compounds falling under formula (Ia), (Ib) and (Ic), respectively, were investigated on cells or cell lines originating from a disorder of the haematopoietic system, including the myeloid cell compartment and the lymphoid cell compartment (T-cells and B-cells), the neuroendocrine system, the cervix, the breast, the ovaries, the lung, the gastrointestinal tract, and the mucosal epithelium, as well as from the skin epithelium and from the muscle. To this end, HL-60 cells, NB-4 cells, HH cells, RPMI-8402 cells, TANOUE cells, TT cells, HeLa cells, MDA-MB-231 cells, FU-OV-1 cells, LOU-NH91 cells, 23132/87 cells, CAL-27 cells, BHY cells, SCC-25 cells, A-431 cells, human primary epidermal keratinocytes (HPEK), and C2C12 cells were seeded into 96-well plates suitable for fluorescence assays (CORNING #3598) at following initial cell numbers: 1000 cells per well for HL-60; 1000 cells per well for NB-4; 5000 cells per well for HH; 5000 cells per well for RPMI-8402; 1500 cells per well for TANOUE; 9000 cells per well for TT; 2000 cells per well for HeLa; 3000 cells per well for MDA-MB-231; 3000 cells per well for FU-OV-1; 4000 cells per well for LOU-NH91; 2000 cells per well for 23132/87; 2000 cells per well for CAL-27; 1500 cells per well for BHY; 1500 cells per well for SCC-25; 700 cells per well for A-431; 1000 cells per well for HPEK; 500 cells per well for C2C12. The cells were treated with compounds at indicated final concentrations (diluted from the 1000× stock-solutions in DMSO to a final DMSO concentration of 0.1% v/v in H2O (Water For Injection, WFI, Fisherscientific #10378939)) or with the empty carrier DMSO at 0.1% v/v as control for 5 days. At day 5 after starting the treatments the cells were subjected to the alamarBlue® Proliferation Assay (Bio-Rad Serotec GmbH, BUF012B) according to the protocol of the manufacturer. The readout was taken with a multi-well plate-reader in the fluorescence mode with applying a filter for excitation at 560 nm (band width 10 nm) and for emission at 590 nm (band width 10 nm). Control treatments for growth inhibition with commercial compounds such as Methotrexate (MTREX) and Resveratrol (RES) were included on every plate. Some of the test compounds of the present invention were obtained and applied as their salts. According cases are indicated in the column “Specification” in Table 55 to Table 92 and by their sum formula in Table 93.
The assays were performed in duplicate or more replicates of independent single experiments each containing a six-fold replicate for every condition. For every individual plate, the measured fluorescence intensity values of the conditions with compound treatment were normalized against the corresponding equally weighted arithmetic mean of the fluorescence intensity values of the six DMSO treated control wells in order to obtain the relative values to a baseline level of 1.0.
Two independent outlier analyses were performed according to the methods by Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12). Outliers confirmed by at least one of the methods were excluded from the calculations but not more than one value out of six per compound within a single experiment. The weighted arithmetic mean (here abbreviated as AVEw) for each compound was calculated from the normalized values over all independent replicates of the single experiments comprising the six replicates each. The corresponding standard deviation for the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Müihlig, Taschenbuch der Mathematik, 5th edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and was combined with the Gauß' error propagation associated with the performed calculation for the normalization. The resulting standard deviation is herein referred to as “combined standard deviation”.
In cases with considerable variation in the normalized equally weighted arithmetic means derived from two independent replicates, the number of independent replicates was increased to three or more. In the cases of four or more independent replicates, a second-line outlier analysis was applied on all normalized equally weighted arithmetic means according to the methods by Peirce and Chauvenet as described above.
In certain embodiments, the compounds of the present invention may be growth inhibitors in hyperproliferative processes, including malignant and non-malignant hyperproliferative processes.
In one embodiment, several compounds of the invention were found to inhibit the growth of HL-60 cells (human acute myeloid leukemia cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 3. HL-60 cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of HL-60 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of HL-60 cells. The so far identified HL-60 growth inhibitors relate to the compounds listed in Table 55 and Table 56. The entries of Table 55 and Table 56 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 55 relate to novel compounds, wherein the data in Table 56 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of NB-4 cells (human acute promyelocytic leukemia cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 207. NB-4 cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of NB-4 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of NB-4 cells. The so far identified NB-4 growth inhibitors relate to the compounds listed in Table 57 and Table 58. The entries of Table 57 and Table 58 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 57 relate to novel compounds, wherein the data in Table 58 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of HH cells (human cutaneous T-cell lymphoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 707. HH cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of HH cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of HH cells. The so far identified HH growth inhibitors relate to the compounds listed in Table 59 and Table 60. The entries of Table 59 and Table 60 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 59 relate to novel compounds, wherein the data in Table 60 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of RPMI-8402 cells (human T cell acute lymphoblastic leukemia cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 290. RPMI-8402 cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of RPMI-8402 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds.
The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of RPMI-8402 cells. The so far identified RPMI-8402 growth inhibitors relate to the compounds listed in Table 61 and Table 62. The entries of Table 61 and Table 62 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 61 relate to novel compounds, wherein the data in Table 62 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of TANOUE cells (human B cell leukemia cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 399. TANOUE cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of TANOUE cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of TANOUE cells. The so far identified TANOUE growth inhibitors relate to the compounds listed in Table 63 and Table 64. The entries of Table 63 and Table 64 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 63 relate to novel compounds, wherein the data in Table 64 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of TT cells (human medullary thyroid carcinoma cells) obtainable from the American Type Culture Collection (ATCC) under the accession number ATCC-CRL-1803. TT cells were cultivated in F-12K medium (Fisherscientific, #11580556, or ATCC, #ATCC-30-2004) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of TT cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of TT cells. The so far identified TT growth inhibitors relate to the compounds listed in Table 65 and Table 66. The entries of Table 65 and Table 66 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 65 relate to novel compounds, wherein the data in Table 66 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of HeLa cells (human cervical adenocarcinoma cells) obtainable from the American Type Culture Collection (ATCC) under the accession number ATCC-CCL-2. HeLa cells were cultivated in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of HeLa cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of HeLa cells. The so far identified HeLa growth inhibitors relate to the compounds listed in Table 67 and Table 68. The entries of Table 67 and Table 68 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 67 relate to novel compounds, wherein the data in Table 68 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of MDA-MB-231 cells (human breast carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 732. MDA-MB-231 cells were cultivated in Leibovitz's L-15 (no phenol red) medium (Fisherscientific, #11540556) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 0% CO2.
A compound is considered as a growth inhibitor of MDA-MB-231 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of MDA-MB-231 cells. The so far identified MDA-MB-231 growth inhibitors relate to the compounds listed in Table 69 and Table 70. The entries of Table 69 and Table 70 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 69 relate to novel compounds, wherein the data in Table 70 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of FU-OV-1 cells (human ovarian carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 444. FU-OV-1 cells were cultivated in Ham's F-12/DMEM (1:1) medium (Fisherscientific, #11514436) containing 10% fetal bovine serum (Fisherscientific, #15517589) and 1 mM sodium pyruvate (Fisherscientific, #11501871) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of FU-OV-1 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ib) have been identified as growth inhibitors of FU-OV-1 cells. The so far identified FU-OV-1 growth inhibitors relate to the compounds listed in Table 71 and Table 72. The entries of Table 71 and Table 72 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 71 relate to novel compounds, wherein the data in Table 72 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of LOU-NH91 cells (human lung squamous cell carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 393. LOU-NH91 cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of LOU-NH91 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of LOU-NH91 cells. The so far identified LOU-NH91 growth inhibitors relate to the compounds listed in Table 73 and Table 74. The entries of Table 73 and Table 74 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 73 relate to novel compounds, wherein the data in Table 74 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of 23132/87 cells (human gastric adenocarcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 201. 23132/87 cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of 23132/87 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of 23132/87 cells. The so far identified 23132/87 growth inhibitors relate to the compounds listed in Table 75 and Table 76. The entries of Table 75 and Table 76 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 75 relate to novel compounds, wherein the data in Table 76 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of CAL-27 cells (human tongue squamous cell carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 446. CAL-27 cells were cultivated in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of CAL-27 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of CAL-27 cells. The so far identified CAL-27 growth inhibitors relate to the compounds listed in Table 77 and Table 78. The entries of Table 77 and Table 78 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 77 relate to novel compounds, wherein the data in Table 78 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of BHY cells (human oral squamous cell carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 404. BHY cells were cultivated in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of BHY cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of BHY cells. The so far identified BHY growth inhibitors relate to the compounds listed in Table 79, Table 80 and Table 81. The entries of Table 79, Table 80 and Table 81 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 79 relate to novel compounds, wherein the data in Table 80 and Table 81 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of SCC-25 cells (human tongue squamous cell carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 617. SCC-25 cells were cultivated in Ham's F-12/DMEM (1:1) medium (Fisherscientific, #11514436) containing 10% fetal bovine serum (Fisherscientific, #15517589) and 1 mM sodium pyruvate (Fisherscientific, #11501871) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of SCC-25 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of SCC-25 cells. The so far identified SCC-25 growth inhibitors relate to the compounds listed in Table 82 and Table 83. The entries of Table 82 and Table 83 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 82 relate to novel compounds, wherein the data in Table 83 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of A-431 cells (human epidermoid squamous cell carcinoma cells) obtainable from the Cell Lines Service GmbH (CLS) under the accession number 300112. A-431 cells were cultivated in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of A-431 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of A-431 cells. The so far identified A-431 growth inhibitors relate to the compounds listed in Table 84 and Table 85. The entries of Table 84 and Table 85 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 84 relate to novel compounds, wherein the data in Table 85 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of human epidermal keratinocyte progenitors, (HPEKp, pooled), obtainable from CELLnTEC Advanced Cell Systems AG under the accession number HPEKp. HPEKp cells were cultivated in CnT-Prime epithelial culture medium (CELLnTEC, #CnT-PR, a fully defined, low calcium formulation, completely free of animal or human-derived components) without addition of further components at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of HPEKp cells, if—at a reference concentration of 10 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of HPEKp cells. The so far identified HPEKp growth inhibitors relate to the compounds listed in Table 86, Table 87 and Table 88. The entries of Table 86, Table 87 and Table 88 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 86 relate to novel compounds, wherein the data in Table 87 and Table 88 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In one embodiment, several compounds of the invention were found to inhibit the growth of C2C12 cells (murine myoblast cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 565. C2C12 cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37° C. and 5% CO2.
A compound is considered as a growth inhibitor of C2C12 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ia), (Ib) and (Ic), respectively, have been identified as growth inhibitors of C2C12 cells. The so far identified C2C12 growth inhibitors relate to the compounds listed in Table 89, Table 90 and Table 91. The entries of Table 89, Table 90 and Table 91 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
The data in Table 89 relate to novel compounds, wherein the data in Table 90 and Table 91 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.
In certain embodiments, compounds of the present invention may be modulators, in particular enhancers of Notch signalling.
The communication between cells via Notch signaling (reviewed in Kopan et al., Cell 2009, 137, 216-233; Bray, Nat. Rev. Mol. Cell Biol. 2016, 17, 722-735) is in the first step mediated by two types of transmembrane proteins: The Notch receptors being distributed across the cell membrane of the signal-receiving cell and the Notch ligands covering the membrane of the signal-sending cell. Mechanistically, Notch signaling is activated by receptor-ligand interaction, which leads to the proteolytic release of the intracellular domain (NICD) of the membrane bound Notch receptor into the inside of the signal-receiving cell. Subsequent translocation of NICD into the nucleus in turn leads to the transcriptional activation of certain and cell type specific genes. The Notch-mediated alteration of the previous gene-expression program of a cell is manifested in according cellular changes, which represent the response of the cell to a Notch signal.
The activation level of Notch signaling can be quantified in vitro reliably by measuring the expression levels of Notch specific target genes. This can be accomplished by the quantification of corresponding mRNA or protein of a particular Notch target gene. Alternatively, cells can be genetically modified to carry a luciferase gene as an artificial Notch target gene, which is expressed in dependence of Notch activity. In this setting, Notch signaling levels can be quantified by measuring the luciferase-derived bioluminescence values.
An according Notch-reporter assay, i.e. a luciferase-based luminescence readout, was used here to quantify the ability of the claimed compounds to augment Notch signaling in a cellular system. For this purpose, HeLa cells, obtainable from the American Type Culture Collection (ATCC) under the accession number ATCC-CCL-2, were transiently transfected for 24 hours using FuGENE® HD (Promega, #E2311) as transfection reagent with expression vectors of a membrane-tethered form of the constitutively active intracellular domain of the human Notch1 receptor (hNotch1ΔE) to activate the Notch signaling cascade (BPS Bioscience, customized human analogue to Notch Pathway Reporter Kit #60509 component C), a Firefly luciferase being expressed under the control of a Notch-responsive promoter to monitor Notch signaling (BPS Bioscience, Notch Pathway Reporter Kit #60509, CSL luciferase reporter vector from component A not premixed with Renilla luciferase vector), and a Renilla luciferase being constitutively expressed in a Notch signaling independent manner to include a measure for the cell number per sample (Promega, pRL-SV40, #E2231). HeLa cells were cultivated in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589). The transfection was carried out in a 100 mm-culture dish (StarLab, #CC7682-3394) with cells being properly attached to the plate at a cell confluency of 80-90% in a total volume of 7 mL culture medium. Per dish to be transfected, a transfection mix was prepared by adding to 238 μL Opti-MEM (Fisherscientific, #10149832) 40 μL of the hNotch1ΔE expression vector (100 ng/μL), 80 μL of the CSL luciferase reporter vector (40 ng/μL), 4 μL of the pRL-SV40-Renilla luciferase vector (10 ng/μL), and in the last step 18.1 μL of FuGENE® HD. After addition of FuGENE® HD the transfection mix was let stand for 15 min at room temperature and hereafter equally distributed into the culture dish. After 24 hours of transfection, the transfected cells were carefully detached from the dish using 0.5 mM EDTA in PBS and seeded into 96-well plates suitable for luminescence readouts (CORNING, #3610) at 10′000 cells per well. The cells were then incubated with the test-compounds at a final concentration of 10 μM (diluted from 10 mM stock-solutions in DMSO to a final DMSO concentration of 0.1% v/v in H2O (Water For Injection, WFI, Fisherscientific #10378939)) or with the empty carrier DMSO at 0.1% v/v as control for 20 hours. Hereafter, the cells were washed once with PBS and then lysed with 30 μL per well of Passive Lysis Buffer (Promega, #E194A, component of Dual-Luciferase® Reporter Assay System, #E1910) by gently shaking the plates for 20 min at room temperature with an orbital plate shaker. Directly after the lysis, first the Firefly and then the Renilla luciferase values were measured consecutively from the same well with a luminescence reader immediately after applying 15 μL per well each of the corresponding enzyme substrates needed to create the luminescence signals (Promega, Dual-Luciferase® Reporter Assay System, #E1910).
The suitability of the assays for monitoring Notch signaling was controlled by additionally including a generally accepted commercial Notch inhibitor, i.e. DAPT, as negative control, as well as the reported Notch enhancer resveratrol (RES) as positive control (Pinchot et al., Cancer 2011, 117, 1386-1398; Truong et al., Ann. Surg. Oncol. 2011, 18, 1506-1511; Yu et al., Mol. Cancer Ther. 2013, 12, 1276-1287). Both control compounds were likewise tested at 10 μM.
Per single experiment the measurement was performed in six replicates per compound. For every compound, this experiment was repeated in three or more independent replicates. The values of the Notch-reporter luciferase were normalized by division through the corresponding individual Notch-independent Renilla values in order to eliminate the impact of variation in the absolute cell numbers in between the samples. For every individual plate, a second normalization was performed against the equally weighted arithmetic mean (here abbreviated as AVE) of the six associated Renilla-normalized DMSO-control values within a single experiment in order to obtain the relative values to a baseline level of 1.0. The statistical calculations were performed in analogy to the proliferation assay as described above. To this end, two independent outlier analyses were performed according to the methods by Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12). Outliers confirmed by at least one of the methods were excluded from the calculations but not more than one value out of six per compound within a single experiment. The weighted arithmetic mean AVEw for each compound was calculated from the double-normalized values over all independent replicates of the single experiments comprising the six replicates each. The corresponding standard deviation for the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Mühlig, Taschenbuch der Mathematik, 5th edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and was combined with the Gauß' error propagation associated with the performed calculation for the normalization. The resulting standard deviation is herein referred to as “combined standard deviation”.
In cases with considerable variation in the double-normalized equally weighted arithmetic means derived from three independent replicates, the number of independent replicates was increased to four or more. In the cases of four or more independent replicates, a second-line outlier analysis was applied on all double-normalized equally weighted arithmetic means according to the methods by Peirce and Chauvenet as described above.
A compound is considered as a Notch signaling augmenting molecule, i.e. an enhancer of Notch signaling, if the weighted arithmetic mean of the luminescence values after subtraction of the corresponding combined standard deviation amounts to 1.1 or higher, in particular to 1.2 or higher, 1.3 or higher, 1.4 or higher, 1.5 or higher, 1.7 or higher, and 2.0 or higher relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all double-normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1·10−2.
According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (Ib) and (Ic), respectively, have been identified as enhancers of Notch signaling. The so far identified Notch enhancers relate to the compounds listed in Table 92. The entries of Table 92 are categorized by the corresponding weighted arithmetic mean of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.
Several other molecules have not been identified as enhancers of Notch signaling according to the above method.
In some cases, the growth inhibiting properties correlate with Notch enhancing properties, in other cases the growth inhibiting properties do not correlate with Notch enhancing properties.
The biological activity of the claimed compounds can be attributed to but may not be limited to Notch signaling enhancing activity. The Notch regulating properties of the claimed compounds can be used alternatively or in combination with the mechanisms leading to antiproliferative effects in medicinal treatments, preferably in the treatment of hyperproliferative disorders including cancer and non-malignant hyperproliferative disorders.
In one aspect, the present invention relates to the treatment of skin, skin appendages, mucosa, mucosal appendages, cornea, and all kinds of epithelial tissue. The term “skin” relates to tissue including epidermis and dermis. The term “mucosa” relates to mucous and submucous tissues including oral mucosa, nasal mucosa, ocular mucosa, mucosa of the ear, respiratory mucosa, genital mucosa, urothelial mucosa, anal mucosa and rectal mucosa. The term “appendages” relates to tissue including hair follicles, hair, fingernails, toenails and glands including sebaceous glands, sweat glands, e.g. apocrine or eccrine sweat glands and mammary glands.
In one embodiment, the present invention relates to treatment of non-melanoma skin cancer and pre-cancerous lesions, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), sebaceous gland carcinoma, Merkel cell carcinoma, angiosarcoma, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, dermatofibrosarcoma, actinic keratosis (AK) or Bowen's disease (BD), and cancer and pre-cancerous lesions of other squamous epithelia e.g. cutaneous SCC, lung SCC, head and neck SCC, oral SCC, tongue SCC, esophageal SCC, cervical SCC, periocular SCC, SCC of the thyroid, SCC of the penis, SCC of the vagina, SCC of the prostate and SCC of the bladder.
In a further embodiment, the present invention relates to the treatment of skin and mucosal disorders with cornification defects (keratoses) and/or abnormal keratinocyte proliferation, such as Psoriasis, Darier's disease, Lichen planus, Lupus erythematosus, Ichthyosis or Verruca vulgaris (senilis).
In a further embodiment, the invention relates to the treatment of skin and mucosal diseases, and skin and mucosal cancer each related to and/or caused by viral infections, such as warts, and warts related to HPV (human papilloma virus), papillomas, HPV-related papillomas, papillomatoses and HPV-related papillomatoses, e.g. Verruca (plantar warts), Verruca plana (flat warts/plane warts), Verruca filiformis (filiform warts), mosaic warts, periungual warts, subungual warts, oral warts, genital warts, fibroepithelial papilloma, intracanalicular papilloma, intraductal papilloma, inverted papilloma, basal cell papilloma, squamous papilloma, cutaneous papilloma, fibrovasular papilloma, plexus papilloma, nasal papilloma, pharyngeal papilloma, Papillomatosis cutis carcinoides, Papillomatosis cutis lymphostatica, Papillomatosis confluens et reticularis or laryngeal papillomatosis (respiratory papillomatosis), Herpes-related diseases, e.g. Herpes labialis, Herpes genitalis, Herpes zoster, Herpes corneae or Kaposi's sarcoma and HPV-related cancer of the cervix, vulva, penis, vagina, anus, oropharynx, tongue and oral cavity.
In a further embodiment, the invention relates to the treatment of atopic dermatitis.
In a further embodiment, the invention relates to the treatment of acne.
In a further embodiment, the invention relates to the treatment of wounds of the skin, wherein the process of wound healing is accelerated.
In a further embodiment, the invention relates to the treatment of cancer related to and/or caused by viral infections, i.e. oncoviral infections, e.g. cancer related to HBV- and HCV (hepatitis virus B and C) such as liver cancer, cancer related to EBV (Epstein-Barr virus) such as Burkitt lymphoma, Hodgkin's and non-Hodgkin's lymphoma and stomach cancer, cancer related to HPV (human papilloma virus) such as cervical cancer, cancer related to HHV (human herpes virus) such as Kaposi's sarcoma, and cancer related to HTLV (human T-lymphotrophic virus) such as T-cell leukemia and T-cell lymphoma.
A further aspect of the present invention relates to the treatment of immune system-related disorders. The term “immune system-related disorders” as used herein applies to a pathological condition of the haematopoietic system including the haematologic system, in particular a pathological condition of immune cells belonging to the innate or adaptive immune system.
A further aspect of the present invention relates to the therapeutic use in immune system-related applications. The term “immune system-related application” as used herein applies to the intervention into proliferation, differentiation and/or activation of cell lineages of the haematopoietic system including the haematologic system in order to modulate an immune response (immune modulation). The term “immune system-related application” as used herein also applies to the intervention into the cellular and non-cellular microenvironment of sites of action of immune cells in order to support and/or enable immune cells in their performance. In particular, the interventions as here defined with the term “immune system-related application” relate to immune cells belonging to the innate or adaptive immune system.
Thus, the compounds of the invention may be used in immunotherapy, alone or together with other immunotherapeutic methods or compounds, as immunologic adjuvant, e.g. as vaccine adjuvant, or as adjuvant for immunotherapy. The term “immunotherapy” as used herein applies to activation-immunotherapy in patients without immune deficiency or with acquired or congenital immune deficiency, and as immune recovery to enhance the functionality of the immune system in the response against pathogens or pathologically transformed endogenous cells, such as cancer cells.
The term “other immunotherapy methods” as used herein applies to vaccinations, antibody treatment, cytokine therapy, the use of immune checkpoint inhibitors and immune response-stimulating drugs, as well as to autologous transplantations of genetically modified or non-modified immune cells, which may be stimulated with intercellular signals, or signaling molecules, or antigens, or antibodies, i.e. adoptive immune-cell transfer.
The method of use of the present invention in immune system-related applications and other immunotherapy methods relates to the use in vivo, in vitro, and ex vivo, respectively.
Specific examples are activation and/or enhancement of activation of peripheral T-lymphocytes, including T-helper cells and cytotoxic T-cells, in order to amplify an immune response, particularly the stimulation of proliferation and/or production and/or secretion of cytokines and/or cytotoxic agents upon antigen recognition in order to amplify an immune response, such as the activation and/or enhancement of activation of B-lymphocytes in order to amplify an immune response, particularly the stimulation of proliferation and/or antibody production and/or secretion, such as the enhancement of an immune response through augmentation of the number of specific immune-cell subtypes, by regulation of differentiation and/or cell fate decision during immune-cell development, as for example to regulate, particularly to augment the number of immune cells belonging to the T- and B-cell lineage, including marginal zone B-cells, cytotoxic T-cells or T-helper (Th) subsets in particular Th1, Th2, Th17 and regulatory T-cells; or the use as immunologic adjuvant such as vaccine adjuvant.
A still further aspect of the invention relates to the treatment of muscular diseases including diseases of skeletal muscle, cardiac muscle and smooth muscle.
In one embodiment, the invention relates to the treatment of muscular dystrophies (MD).
Specific examples are Duchenne MD, Becker MD, congenital MD, Limb-Girdle MD, facioscapulohumeral MD, Emery-Dreifuss MD, distal MD, myotonic MD or oculopharyngeal MD.
In a further embodiment, the invention relates to the treatment of hyperproliferative disorders of the muscle, including myoblastoma, rhabdomyoma, and rhabdomyosarcoma, as well as muscle hyperplasia and muscle hypertrophy.
In a further embodiment, the compounds of the invention may be used for muscle regeneration after pathologic muscle degeneration or atrophy, e.g. caused by traumata, caused by muscle ischemia or caused by inflammation, in aging-related muscle-atrophy or in disease-related muscle atrophy such as myositis and fibromyositis or poliomyelitis.
A still further aspect relates to the treatment of disorders of the neuroendocrine system such as cancer of the neuroendocrine system, comprising neuroendocrine small cell carcinomas, neuroendocrine large cell carcinomas and carcinoid tumors, e.g. of the brain, thyroid, pancreas, gastrointestinal tract, liver, esophagus, and lung, such as neuroendocrine tumor of the pituitary gland, neuroendocrine tumor of the adrenal gland, medullary thyroid cancer (MTC), C-cell hyperplasia, anaplastic thyroid cancer (ATC), parathyroid adenoma, intrathyroidal nodules, insular carcinoma, hyalinizing trabecular neoplasm, paraganglioma, lung carcinoid tumors, neuroblastoma, gastrointestinal carcinoid, Goblet-cell carcinoid, pancreatic carcinoid, gastrinoma, glucagenoma, somatostatinoma, VIPoma, insulinoma, non-functional islet cell tumor, multiple endocrine neoplasia type-1, or pulmonary carcinoid.
A still further aspect relates to the treatment of disorders of the lung such as cancer of the lung, comprising small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), including lung squamous cell carcinoma, lung adenocarcinoma and lung large cell carcinoma.
A still further aspect relates to the treatment of cancers or precancerous lesions of the brain, pancreas, breast, ovaries, liver, thyroid, genitourinary tract, gastrointestinal tract, and endothelial tissue, including glioma, mixed glioma, glioblastoma multiforme, astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, ependymoma, anaplastic ependymoma, myxopapillary ependymoma, subependymoma, brain stem glioma, optic nerve glioma, and forebrain tumors, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma, pancreatic pseudopapillary neoplasm, pancreatic intraductal papillary-mucinous neoplasm, pancreatic mucinous cystadenocarcinoma, pancreatoblastoma and pancreatic intraepithelial neoplesia, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, papillary thyroid cancer and follicular thyroid cancer, cervical cancer, hormone receptor-positive breast cancer and hormone receptor-negative breast cancer, ovarian cancer, gastric cancer and angiosarcoma.
As used herein, the term “treating” or “treatment” refers to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease. The term “treating” also encompasses post-treatment care.
In some embodiments, administration of a compound of the invention, or pharmaceutically acceptable salt thereof, is effective in preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
The compounds of the invention may be used in human and veterinary medicine, which includes the treatment of companion animals, e.g. horses, dogs, cats, rabbits, guinea pigs, fishes e.g. koi, birds e.g. falcon; and livestock, e.g. cattle, poultry, pig, sheep, goat, donkey, yak and camel.
Pharmaceutical Compositions
The present invention further provides pharmaceutical compositions comprising a compound as described herein or a pharmaceutically acceptable salt thereof for use in medicine, e.g. in human or veterinary medicine. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.
An effective dose of the compounds according to the invention, or their salts, solvates or prodrugs thereof is used, in addition to physiologically acceptable carriers, diluents and/or adjuvants for producing a pharmaceutical composition. The dose of the active compounds can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the diseases to be treated, and similar factors. The daily dose can be given as a single dose, which is to be administered once, or be subdivided into two or more daily doses, and is as a rule 0.001-2000 mg. Particular preference is given to administering daily doses of 0.1-500 mg, e.g. 0.1-100 mg.
Suitable administration forms are topical or systemical including enteral, oral, rectal, and parenteral, as infusion and injection, intravenous, intra-arterial, intraperitoneal, intramuscular, intracardial, epidural, intracerebral, intracerebroventricular, intraosseous, intra-articular, intraocular, intravitreal, intrathecal, intravaginal, intracavernous, intravesical, subcutaneous, intradermal, transdermal, transmucosal, inhalative, intranasal, buccal, sublingual and intralesional preparations. Particular preference is given to using oral, parenteral, e.g. intravenous or intramuscular, intranasal preparations, e.g. dry powder or sublingual, of the compounds according to the invention. The customary galenic preparation forms, such as tablets, sugar-coated tablets, capsules, dispersible powders, granulates, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lip balms, mouthwashs, foams, pastes, tinctures, dermal patches and tapes, forms in occlusion or in combination with time release drug delivery systems, with electrophoretic dermal delivery systems including implants and devices, and with jet injectors, liposome and transfersome vesicles, vapors, sprays, syrups, juices or drops and eye drops, can be used.
Solid medicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminium stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gelatine, agar agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); preparations which are suitable for oral administration can comprise additional flavourings and/or sweetening agents, if desired.
Liquid medicinal forms can be sterilized and/or, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators. Examples of such additives are tartrate and citrate buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its non-toxic salts). High molecular weight polymers, such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.
Oily suspensions for parenteral or topical applications can be vegetable, synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Examples of such fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, inter alia. Silicone oils of differing viscosity, or fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, or fatty acids, such as oleic acid, are also suitable. It is furthermore possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil.
Suitable solvents, gelatinizing agents and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.
Cellulose ethers which can dissolve or swell both in water or in organic solvents, such as hydroxypropylmethyl cellulose, methyl cellulose or ethyl cellulose, or soluble starches, can be used as film-forming agents.
Mixtures of gelatinizing agents and film-forming agents are also perfectly possible. In this case, use is made, in particular, of ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. The following can be used as additional formulation aids: glycerol, paraffin of differing viscosity, triethanolamine, collagen, allantoin and novantisolic acid. Use of surfactants, emulsifiers or wetting agents, for example of Na lauryl sulphate, fatty alcohol ether sulphates, di-Na-N-lauryl-β-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono-/dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts can also be required for the formulation. Stabilizers, such as montmorillonites or colloidal silicic acids, for stabilizing emulsions or preventing the breakdown of active substances such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations.
Preparations for parenteral administration can be present in separate dose unit forms, such as ampoules or vials. Use is preferably made of solutions of the active compound, preferably aqueous solution and, in particular, isotonic solutions and also suspensions. These injection forms can be made available as ready-to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent.
Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilisates which are prepared before use using the suitable solvent or suspending agent.
Inhalable preparations can present as powders, solutions or suspensions. Preferably, inhalable preparations are in the form of powders, e.g. as a mixture of the active ingredient with a suitable formulation aid such as lactose.
The preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions.
As indicated above, the compounds of the invention may be administered as a combination therapy, as sequence therapy or as simultaneous combination therapy, with further active agents, e.g. therapeutically active compounds useful in the treatment of the above indicated disorders. These therapeutically active compounds may include but are not limited to chemotherapeutic agents such as nucleoside and nucleobase analogs, e.g. Cytarabin, Gemcitabine, Azathioprine, Mercaptopurine, Fluorouracil, Thioguanine, Azacitidine, Capecitabine, Doxifluridine; such as platinum-based drugs, e.g. Cisplatin, Oxaliplatin, Carboplatin and Nedaplatin; such as anthracyclines, e.g. Doxorubicin, Epirubicin, Valrubicin, Idarubicin, Daunorubicin, Sabarubicin, Pixantrone and Mitoxantrone; such as peptide antibiotics, e.g. Actinomycin and Bleomycin; such as alkylating agents e.g. Mechlorethamine, Chlorambucil, Melphalan, Nitrosoureas, Dacarbazine, Temozolomide and Cyclophosphamide; such as antimitotic agents including taxanes and vinca alkaloids, e.g. Docetaxel, Paclitaxel, Abraxane, Cabazitaxel, Vinblastine, Vindesine, Vinorelbine and Vincristine; such as topoisomerase inhibitors, e.g. Irinotecan, Topotecan, Teniposide and Etoposide; such as other cytostatic agents e.g. Hydroxyurea and Methotrexate; such as proteasome inhibitors, e.g Bortezomib, Ixazomib; and other targeted therapeutic agents such as kinase inhibitors, cell cycle inhibitors, regulators i.e. inhibitors and activators of signaling pathways including growth factor signaling, cytokine signaling, NF-kappaB signaling, AP1 signaling, JAK/STAT signaling, EGFR signaling, TGF-beta signaling, Notch signaling, Wnt signaling, Hedgehog signaling, hormone and nuclear receptor signaling, e.g. Erlotinib, Lapatinib, Dasatinib, Imatinib, Afatinib, Vemurafenib, Dabrafenib, Nilotinib, Cetuximab, Trametinib, Palbociclib, Cobimetinib, Cabozantinib, Pegaptanib, Crizotinib, Olaparib, Panitumumab, Cabozantinib, Ponatinib, Regorafenib, Entrectinib, Ranibizumab, Ibrutinib, Trastuzumab, Rituximab, Alemtuzumab, Gefitinib, Bevacizumab, Lenvatinib, Bosutinib, Axitinib, Pazopanib, Everolimus, Temsirolimus, Ruxolitinib, Tofacitinib, Sorafenib, Sunitinib, Aflibercept, Vandetanib; Vismodegib and Sonidegib; retinoids such as retinol, tretinoin, isotretinoin, alitretinoin, bexarotene, tazarotene, acitretin, adapalene and etretinate; hormone signaling modulators including estrogen receptor modulators, androgen receptor modulators and aromatase inhibitors e.g. Raloxifene, Tamoxifen, Fulvestrant, Lasofoxifene, Toremifene, Bicalutamide, Flutamide, Anastrozole, Letrozole and Exemestane; histone deacetylase inhibitors, e.g. Vorinostat, Romidepsin, Panobinostat, Belinostat and Chidamide; and Ingenol mebutate; and other Notch enhancers not encompassed by the compounds of the present invention, e.g. Valproic acid, Resveratrol, hesperetin, chrysin, phenethyl isothiocyanate, thiocoraline, N-methylhemeanthidine chloride and Notch Signaling-activating peptides or antibodies; and immune response modulating agents including immune checkpoint inhibitors e.g. Imiquimod, Ipilimumab, Atezolizumab, Ofatumumab, Rituximab, Nivolumab and Pembrolizumab; and anti-inflammatory agents including glucocorticoids and non-steroidal anti-inflammatory drugs, e.g. cortisol-based preparations, Dexamethason, Betamethason, Prednisone, Prednisolone, Methylprednisolone, Triamcinolon-hexacetonid, Mometasonfuroat, Clobetasolpropionat, acetylsalicylic acid, salicylic acid and other salicylates, Diflunisal, Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Loxoprofen, Flurbiprofen, Oxaprozin, Indomethacin, Ketorolac, Tolmetin, Diclofenac, Etodolac, Aceclofenac, Nabumetone, Sulindac, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, Celecoxib, Parecoxib, Etoricoxib and Firocoxib; and ACE inhibitors; and beta-blockers; and myostatin inhibitors; and PDE-S inhibitors; and antihistamines. For a combination therapy, the active ingredients may be formulated as compositions containing several active ingredients in a single dose form and/or as kits containing individual active ingredients in separate dose forms. The active ingredients used in combination therapy may be co-administered or administered separately.
The compounds of the invention may be administered as antibody-drug conjugates.
The compounds of the invention may be administered in combination with surgery, cryotherapy, electrodessication, radiotherapy, photodynamic therapy, laser therapy, chemotherapy, targeted therapy, immunotherapy, gene therapy, antisense therapy, cell-based transplantation therapy, stem cell therapy, physical therapy and occupational therapy.
Chemical Synthesis
Ac Acetyl
aq Aqueous
Alk Alkyl
Bn Benzyl
BRSM Based on Recovered Starting Material (yield)
Bu Butyl
mCPBA meta chloroperoxybenzoic acid
NMR Nuclear Magnetic Resonance Spectroscopy
DCE 1,2-dichloroethane
DCM Dichloromethane
DIBAL-H Diisobutylaluminium hydride
DMF N,N-dimethylformamide
DMSO Dimethyl sulfoxide
DMAP Dimethylaminopyridine
Equiv Equivalent
ESI Electron Spray Ionization
EDC N-(3dimethylaminopropyl)-N′-ethylcarbodimide
HOBt 1-hydroxybenzotriazole
HATU Hexafluorophosphate azabenzotriazole tetramethyl uronium
Et Ethyl
LiHMDS Lithium bis(trimetylsilyl)amide
Me Methyl
Ms Methanesulfonyl
PE Petroleum Ether
PG Protecting group
PTSA p-Toluenesulfonic acid
sat Saturated
TBAF Tetrabutylammonium Fluoride
Tf Trifluoromethanesulfonyl
THF Tetrahydrofuran
TLC Thin Layer Chromatography
TMS Trimethylsilyl
Ts p-Toluenesulfonyl
UV Ultraviolet
General Considerations
The compounds listed in Table 93 and Table 94 have been identified by TLC using pre-coated silica TLC sheets and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, toluene, triethylamine or acetic acid as eluent, preferably as binary or tertiary solvent mixtures thereof. UV light at a wavelength of 254 or 366 nm, and/or common staining solutions such as phosphomolybdic acid, potassium permanganate, or ninhydrin were used to visualize the compounds. Reactions were also monitored for completion this way. Reactions were run under inert atmosphere unless otherwise stated. Dry solvents were used wherever required. All reactions were stirred using a stir plate and magnetic stir bar.
The compounds listed in Table 93 have furthermore been identified by mass spectrometry using formic acid in the mobile phase for detection of positive ions, while no additive was used for negative ions. Ammonium Carbonate was used if the molecule was difficult to ionize in negative mode. Representative compounds and those which showed poor ionization in mass spectrometry were also identified by nuclear magnetic resonance spectroscopy (Table 94). Chemical shifts (6) were reported in parts per million (ppm) relative to residual solvent peaks rounded to the nearest 0.01 ppm for proton and 0.1 ppm for carbon (ref.: CHCl3 [1H: 7.26 ppm, 13C: 77.2 ppm], DMSO [1H: 2.50 ppm, 13C: 39.5 ppm]). Coupling constants (J) were reported in Hz to the nearest 0.1 Hz. Peak multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), hept (heptet), m (multiplet), and br (broad).
Synthesis of Described Compounds:
The aforementioned compounds of the invention falling under the scope of formula I can be synthesized and purified by those persons skilled in the art and are preferably synthesized according to the general procedures (A to R) mentioned herein as illustrated in Scheme 1.
Analytical Data
The following compounds were synthetized according to the aforementioned protocols and characterized via mass spectrometry (Table 93) or NMR (Table 94).
1H-NMR
1H NMR (400 MHz, CDCl3) δ 7.41-7.33 (m, 4H), 7.05-6.96 (m, 4H), 4.32
1H NMR (400 MHz, CDCl3) δ 7.93-7.76 (m, 3H), 7.62-7.46 (m, 6H), 7.32
1H NMR (400 MHz, CDCl3) δ 7.38-7.30 (m, 4H), 7.02-6.91 (m, 4H), 4.24
1H NMR (400 MHz, CDCl3) δ 7.62-7.55 (m, 2H), 7.25-7.21 (m, 2H), 7.02-
1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 2H), 7.35-7.30 (m, 2H), 6.97-
1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.12-7.98 (m, 2H), 7.80 (d, J =
1H NMR (400 MHz, CDCl3) δ 8.05-7.95 (m, 2H), 7.61 (d, J = 2.3 Hz, 1H),
1H NMR (400 MHz, CDCl3) δ 8.02-7.91 (m, 2H), 6.99-6.89 (m, 6H), 4.32
1H NMR (400 MHz, CDCl3) δ 8.00-7.92 (m, 2H), 7.10 (d, J = 2.2 Hz, 1H),
For illustrative purposes the synthesis and characterisation of the following examples are described in detail.
To 4-(4-butylphenoxy)benzoic acid (104 mg, 0.38 mmol, 1 equiv), suspended in stirred toluene (1.85 mL, 0.2 M), under argon, was added first SOCl2 (67 μL, 0.93 mmol, 2.5 equiv) then DMF (0.3 μL, 3.7 μmol, 1 mol %) and the mixture was heated to 80° C. for 3 h. The reaction mixture was then evaporated to dryness and the resulting residue placed under argon again and redissolved in THF (1.85 mL, 0.2 M). To this was added in order, trimethylamine (0.13 mL, 0.93 mmol, 2.5 equiv), DMAP (0.45 mg, 3.7 μmol, 1 mol %) and methansulfonamide (42.3 mg, 0.45 mmol, 1.2 equiv) and the suspension was stirred for 16 h. The reaction was then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether/AcOEt) to yield 118 mg of 4-(4-butylphenoxy)-N-(methylsulfonyl)benzamide (88%).
MS: m/z [M−H]−, calc for [C18H20NO4S]−=346.11; found 346.24.
1H-NMR (300 MHz DMSO-d6) δ 12.03 (s, 1H), 7.97 (d, J=8.9 Hz, 2H), 7.32-7.24 (m, 2H), 7.08-6.97 (m, 4H), 3.36 (s, 3H), 2.66-2.56 (m, 2H), 1.58 (tt, J=8.8, 6.8 Hz, 2H), 1.41-1.24 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).
13C-NMR (75 MHz, DMSO-d6) δ 166.1, 162.1, 153.2, 139.4, 131.4, 130.5, 126.3, 120.4, 117.2, 41.8, 34.6, 33.6, 22.2, 14.3.
To 6-(4-cyclohexylphenoxy)nicotinic acid (50 mg, 0.17 mmol, 1 equiv), suspended in stirred toluene (0.85 mL, 0.2 M), under argon, was added first SOCl2 (31 μL, 0.43 mmol, 2.5 equiv) then DMF (0.14 μL, 1.7 μmol, 1 mol %) and the mixture was heated to 80° C. for 3 h. The reaction mixture was then evaporated to dryness and the resulting residue placed under argon again and redissolved in THE (0.85 mL, 0.2 M). To this was added in order, trimethylamine (9.4 μL, 0.68 mmol, 2.5 equiv), DMAP (0.2 mg, 1.7 μmol, 1 mol %) and morpholine (20 μL, 0.23 mmol, 1.5 equiv) and the suspension was stirred for 16 hours. The reaction was then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether/AcOEt) to yield 45 mg of (6-(4-cyclohexylphenoxy)pyridin-3-yl)(morpholino)methanone (71%).
MS: m/z [M+H]+, calc for [C22H27N2O3]+=367.20; found 367.32.
1H-NMR (300 MHz, CDCl3) δ 8.20 (d, J=2.3 Hz, 1H), 7.73 (dd, J=8.6, 2.2 Hz, 1H), 7.18 (d, J=7.7 Hz, 2H), 7.06-6.92 (m, 2H), 6.87 (d, J=8.5 Hz, 1H), 3.63 (s, 8H), 2.50-2.37 (m, 1H), 1.89-1.62 (m, 5H), 1.38-1.08 (m, 5H).
13C-NMR (75 MHz, CDCl3) δ 167.7, 164.7, 151.2, 146.6, 145.1, 139.5, 128.1, 125.5, 121.0, 111.3, 66.8, 53.4, 44.0, 34.5, 26.9, 26.1.
To 4-(4-cyclohexylphenoxy)benzoic acid (60 mg, 0.2 mmol, 1 equiv), suspended in stirred toluene (0.8 mL, 0.2 M), under argon, was added first SOCl2 (37 μL, 0.0.5 mmol, 2.5 equiv) then DMF (0.15 μL, 2.0 μmol, 1 mol %) and the mixture was heated to 80° C. for 3 h. The reaction mixture was then evaporated to dryness and the resulting residue placed under argon again and redissolved in THF (0.8 mL, 0.2 M). To this was added in order, trimethylamine (57 μL, 0.5 mmol, 2.5 equiv), DMAP (0.24 mg, 2.0 μmol, 1 mol %) and cyanamide (12.6 mg, 0.3 mmol, 1.5 equiv) and the suspension was stirred for 16 h. The reaction was then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether/AcOEt) to yield 15.4 mg of N-cyano-4-(4-cyclohexylphenoxy)benzamide (24%).
MS: m/z [M−H]−, calc for [C20H19N2O2]−=319.15; found 319.28.
1H-NMR, (300 MHz, CDCl3) δ 7.93 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.23-6.85 (m, 4H), 3.37 (brs, 1H), 2.59-2.51 (m, 1H) 1.91-1.63 (m, 5H), 1.57-1.12 (m, 5H).
13C-NMR, (75 MHz, CDCl3) δ 166.5, 161.8, 152.7, 144.2, 130.8, 128.4, 124.8, 119.9, 117.1, 110.0, 43.1, 34.0, 26.3, 25.5.
To 4-(4-(2-methoxyethyl)phenoxy)benzoic acid (125 mg, 0.46 mmol, 1 equiv), suspended in stirred toluene (2.3 mL, 0.2 M), under argon, was added first SOCl2 (84 μL, 1.15 mmol, 2.5 equiv) then DMF (0.35 μL, 4.6 μmol, 1 mol %) and the mixture was heated to 80° C. for 3 h. The reaction mixture was then evaporated to dryness and the resulting residue placed under argon again and redissolved in THE (2.3 mL, 0.2 M). To this was added in order, trimethylamine (144 μL, 1.13 mmol, 2.5 equiv), DMAP (0.56 mg, 4.6 μmol, 1 mol %) and N-methylhydroxylamine hydrochloride (58 mg, 0.69 mmol, 1.5 equiv) and the suspension was stirred for 16 h. The reaction was then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether/AcOEt) to yield 103.1 mg of N-hydroxy-4-(4-(2-methoxyethyl)phenoxy)-N-methylbenzamide (74%).
MS: m/z [M+H]+, calc for [C17H20NO4]+=302.14; found 302.17.
1H-NMR, (300 MHz, CDCl3) δ 10.00 (s, 1H), 7.73-7.61 (m, 2H), 7.37-7.20 (m, 2H), 7.07-6.82 (m, 4H), 3.55 (t, J=6.8 Hz, 2H), 3.26 (s, 3H), 3.25 (s, 3H), 2.82 (t, J=6.8 Hz, 2H).
13C-NMR, (75 MHz, CDCl3) δ 168.6, 159.2, 154.3, 135.6, 131.2, 130.9, 129.5, 119.9, 117.1, 73.2, 58.3, 37.9, 35.1.
To 6-(4-cyclohexylphenoxy)nicotinonitrile (41 mg, 0.15 mmol, 1 equiv), dissolved in THF/MeOH (1:1, 1.5 mL, 0.1 M), at 0° C. under argon and stirring, was added NaH (6.6 mg, 0.17 mmol, 1.1 equiv, 60% in oil). After 4 h, the ice bath was removed and cyanamide (9.5 mg, 0.23 mmol, 1.5 equiv) was added and the mixture stirred for a further 16 h. The reaction was then partitioned between AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether/AcOEt/MeOH) to yield 32 mg of N′-cyano-6-(4-cyclohexylphenoxy)nicotinimidamide (67%).
MS: m/z [M+H]+, calc for [C20H22N3O]+=320.18; found 320.27.
1H-NMR (300 MHz, DMSO-d6) δ 7.79 (d, J=8.9 Hz, 2H), 7.25-7.17 (m, 2H), 7.07-6.94 (m, 4H), 3.83 (s, 2H), 2.63-2.41 (m, 1H), 1.94-1.55 (m, 5H), 1.48-1.16 (m, 5H).
13C-NMR (75 MHz, DMSO-d6) δ 152.9, 144.9, 129.3, 129.3, 128.4, 124.4, 120.1, 117.4, 116.4, 113.3, 77.5, 44.0, 34.6, 26.9, 26.1.
(3r,5r,7r)-1-(4-(4-bromophenoxy)phenyl)adamantane (100 mg, 0.26 mmol, 1 equiv) was dissolved in dry THF (1.3 mL, 0.2 M) under argon and stirring and the resulting solution was cooled to −78° C. with a dry ice/acetone bath. nBuLi (0.11 mL, 0.26 mmol, 1.0 equiv, 2.3 M in pentane) was then added dropwise and the mixture left to stir at that temperature for 30 min then at −50° C. for another 30 min. The mixture was then cooled back down to −78° C. A solution of 2-methyl-N-(2,2,2-trifluoroethylidene)propane-2-sulfinamide (79 mg, 0.39 mmol, 1.5 equiv) in THF (0.39 mL, 1 M) was added dropwise and the reaction was stirred 1 hour before allowed to return to room temperature slowly overnight. The reaction was then partitioned between AcOEt and NH4Cl aq sat., the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether/AcOEt) to yield 81 mg of N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (62%).
MS: m/z [M+H]+, calc for [C28H35F3NO2S]+=506.23; found 506.70.
1H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 4H), 7.03-6.95 (m, 4H), 4.83 (qd, J=7.1, 3.5 Hz, 1H), 3.88 (d, J=3.5 Hz, 1H), 2.10 (p, J=3.5 Hz, 3H), 1.91 (d, J=2.9 Hz, 6H), 1.83-1.68 (m, 6H), 1.23 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 159.29, 153.59, 147.36, 130.78, 126.31, 125.24, 124.53 (q, J=281.3 Hz), 119.39, 117.93, 59.87 (q, J=30.4 Hz), 56.31, 43.33, 36.76, 35.91, 28.95, 22.41.
19F NMR (376 MHz, CDCl3) δ −74.56 (d, J=7.2 Hz).
To a solution of N-(3-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (31 mg, 0.065 mmol, 1 equiv) in THF (0.32 mL, 0.2 M) was added HCl (0.8 mL, 0.5 M in MeOH, 6 equiv) and the reaction was left to stir till completion. The reaction was then partitioned between AcOEt and NaHCO3 aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient DCM/MeOH) to yield 17.4 mg of 3-(6-(4-((adamantan-1-yl)phenoxy)pyridin-3-yl)oxetan-3-amine (71%).
MS: m/z [M+H]+, calc for [C24H29N2O2]+=377.22; found 377.34.
1H-NMR, (300 MHz, DMSO-d6) δ 8.33 (dd, J=2.6, 0.7 Hz, 1H), 8.02 (dd, J=8.6, 2.6 Hz, 1H), 7.50-7.36 (m, 2H), 7.14-6.96 (m, 3H), 4.70 (d, J=6.3 Hz, 2H), 4.64 (d, J=6.3 Hz, 2H), 2.65 (brs, 2H), 2.18-1.99 (m, 3H), 1.96-1.83 (m, 6H), 1.75 (s, 6H).
13C-NMR, (75 MHz, DMSO-d6) δ 162.6, 152.3, 147.4, 144.9, 138.0, 136.4, 126.4, 121.0, 111.3, 85.7, 57.6, 43.2, 36.6, 35.9, 28.8.
To a solution of N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (360 mg, 0.71 mmol, 1 equiv) in THE (7.2 mL, 0.1 M) was added Cs2CO3 (464 mg, 1.42 mmol, 2 equiv). After 30 min, iodomethane (0.089 mL, 1.42 mmol, 2 equiv) was added. The mixture then heated for a further 16 h at 50° C. The reaction was then partitioned between AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether/AcOEt) to yield 300 mg of N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide (81%).
MS: m/z [M+H]+, calc for [C29H37F3NO2S]+=520.25; found 520.69.
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=8.6 Hz, 2H), 7.37-7.32 (m, 2H), 7.02-6.96 (m, 4H), 4.92 (q, J=8.6 Hz, 1H), 2.71 (s, 3H), 2.11 (s, 3H), 1.91 (d, J=2.9 Hz, 6H), 1.85-1.71 (m, 6H), 1.20 (s, 9H).
19F NMR (376 MHz, CDCl3) δ −67.23 (d, J=8.2 Hz).
To N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfinamide (300 mg, 0.58 mmol, 1 equiv), dissolved in THE (5.8 mL, 0.1 M) was added HCl (2.3 mL, 1.15 mmol, 0.5 M in MeOH, 2 equiv) and the reaction was left to stir till completion. Then either the reaction was evaporated to dryness to yield 255 mg of 1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoro-N-methylethan-1-amine as HCl salt (Quantitative).
MS: m/z [M+H]+, calc for [C25H29F3NO]+=416.22; found 416.69.
1H NMR (400 MHz, CDCl3) δ 11.04 (brs, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.43-7.33 (m, 2H), 7.08 (d, J=8.4 Hz, 2H), 7.05-6.96 (m, 2H), 4.71-4.36 (m, 1H), 2.69 (s, 3H), 2.14 (s, 3H), 1.94 (d, J=2.9 Hz, 6H), 1.88-1.73 (m, 6H).
To 1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride (50 mg, 0.12 mmol, 1 equiv) in DCM (1.2 mL, 0.1 M) was added mCPBA (35 mg, 0.144 mmol, 70%, 1.2 equiv) and the mixture was stirred at room temperature for 30 min. The reaction mixture was then partitioned between AcOEt and aq. sat. NaHCO3, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether/AcOEt) to yield 44.5 mg of N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-N-methylhydroxylamine (86%).
1H NMR (400 MHz, CDCl3) δ 7.41-7.33 (m, 4H), 7.05-6.96 (m, 4H), 4.32 (q, J=7.6 Hz, 1H), 2.87 (s, 3H), 2.16-2.07 (m, 3H), 1.92 (d, J=2.9 Hz, 6H), 1.85-1.67 (m, 6H).
19F NMR (376 MHz, CDCl3) δ −67.82 (d, J=7.5 Hz).
13C NMR (101 MHz, CDCl3) δ 159.24, 153.61, 147.38, 131.35, 126.33, 124.40, 124.18 (q, J=282.5 Hz), 119.37, 117.73, 74.70 (q, J=29.0 Hz), 50.31, 43.34, 36.76, 35.92, 28.96.
To 1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoro-N-methylethan-1-amine hydrochloride (20 mg, 0.05 mmol, 1 equiv) in acetonitrile (0.25 mL, 0.2 M) was added formaldehyde (0.025 mL, 0.29 mmol, 6 equiv, 37% w/w in water) followed by NaBH3CN (6.1 mg, 0.10 mmol, 2 equiv). The reaction mixture was stirred till completion before being partitioned between AcOEt and aq. sat. NaHCO3, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient DCM/MeOH) to yield 15 mg of 1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoro-N,N-dimethylethan-1-amine (75%).
MS: m/z [M+H]+, calc for [C26H31F3NO]+=430.27; found 430.71.
1H NMR (400 MHz, CDCl3) δ 7.39-7.28 (m, 4H), 7.04-6.93 (m, 4H), 3.95 (q, J=8.7 Hz, 1H), 2.36 (s, 6H), 2.10 (s, 3H), 1.91 (d, J=2.9 Hz, 6H), 1.85-1.69 (m, 6H).
19F NMR (376 MHz, CDCl3) δ −67.30.
To a stirred solution under argon of 4-(4-cyclohexylphenoxy)benzaldehyde (50 mg, 0.18 mmol, 1 equiv) in toluene (0.9 mL, 0.2 M) was added dimethylamine (0.18 mL, 0.36 mmol, 2 equiv) followed by TMSCN (0.05 mL, 0.36 mmol, 2 equiv) and the reaction was stirred for 16 h. The reaction was then partitioned between AcOEt and NaHCO3 aq sat. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether/AcOEt) to yield 29 mg of 2-(4-(4-cyclohexylphenoxy)phenyl)-2-(dimethylamino)acetonitrile (48%).
MS: m/z [M+H]+, calc for [C22H27N2O]+=335.21; found 335.31.
1H-NMR, (300 MHz, CDCl3) δ 7.46-7.32 (m, 2H), 7.16-7.07 (m, 2H), 6.99-6.82 (m, 4H), 4.75 (s, 1H), 2.43 (ddt, J=11.7, 8.2, 5.0 Hz, 1H), 2.27 (s, 6H), 1.87-1.61 (m, 5H), 1.42-1.24 (m, 5H).
13C NMR (75 MHz, CDCl3) δ 158.5, 154.2, 143.8, 129.3, 128.1, 119.3, 118.3, 115.0, 62.5, 43.9, 41.7, 34.6, 26.9, 26.1.
| Number | Date | Country | Kind |
|---|---|---|---|
| 18190769.2 | Aug 2018 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2019/072633 | 8/23/2019 | WO |
