Substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds as NMDA-antagonists

Description

FIELD OF THE INVENTION

[0002] The present invention relates to substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds, and to processes for the production thereof, to pharmaceutical preparations containing these compounds and to the use thereof in treatment methods and for the production of pharmaceutical preparations for specific indications, in particular for the treatment of pain.

BACKGROUND OF THE INVENTION

[0003] The treatment of chronic and non-chronic pain is of great significance in medicine. There is a worldwide requirement for effective therapeutic methods for providing tailored and targeted treatment of chronic and non-chronic pain, this being taken to mean pain treatment which is effective and satisfactory from the patient's standpoint. This is clear from the large number of scientific papers relating to applied analgesia or to basic nociception research which have recently been published.

[0004] Conventional opioids such as morphine are highly effective in treating severe to extreme pain. However, the use thereof is limited by known side-effects, for example respiratory depression, vomiting, sedation, constipation and development of tolerance. Moreover, they are less effective in treating neuropathic or incidental pain, which is in particular experienced by tumor patients.

[0005] Opioids exert their analgesic effect by binding to membrane receptors belonging to the family of G protein-coupled receptors. The biochemical and pharmacological characterization of subtypes of these receptors has prompted hopes that subtype-specific opioids may have a effect/side-effect profile which differs from that of, for example, morphine. Further pharmacological investigations have now tentatively revealed the existence of various subtypes of these opioid receptors (μ1, μ2, κ1, κ2, κ3, δ1 and δ2). There are moreover further receptors and ion channels which play a substantial role in the system governing the genesis and transmission of pain. The NMDA ion channel plays a particularly important part as a substantial proportion of synaptic communication passes via this channel. This channel controls calcium ion exchange between the neuronal cell and its surroundings.

[0006] The development of the patch-clamp technique has made it possible to elucidate the physiological significance of ion channel-selective substances. It has thus been possible clearly to demonstrate the effect of NMDA antagonists on the influence of calcium ions within the cell. It has also been established that these substances themselves have their own antinociceptive potential (e.g. ketamine). One important fact is that their mode of action differs greatly from that of, for example, opiates, as NMDA antagonists act directly on the cell's calcium balance, which vitally determines the transmission of pain. For the first time, it is thus possible to treat neuropathic types of pain successfully.

[0007] Various NMDA antagonists, which in this case were tetrahydroquinoline compounds, have already been described in the articles J. Med. Chem. (1992) 35, 1954-1968, J. Med. Chem. (1992) 35, 1942-1953 and Med. Chem. Res. (1991) 1; 64-73 and the patent applications EP 386 839, WO 97/12879 A1, WO 98/07704 A1 and WO 98/42673 A1. Many possible indications, including inter alia pain therapy, were mentioned in these publications, especially in the patent applications. However, the efficacy and usability of these substances are as yet unclear and there is accordingly still a requirement for further substances.

SUMMARY OF THE INVENTION

[0008] One object underlying the invention was to provide analgesically active substances, in particular NMDA antagonists, which are suitable for treating pain, in particular including chronic and neuropathic pain. These substances should furthermore exhibit the fewest possible side-effects such as for example nausea, vomiting, dependency, respiratory depression or constipation. The present invention accordingly provides 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds corresponding to formula I

[0009] in the form as prepared or in the form of the acids or bases thereof or in the form of the salts thereof, in particular the physiologically acceptable salts, or in the form of the solvates thereof, in particular the hydrates; in particular in the form of the physiologically acceptable salts thereof with cations or bases or with anions or acids; optionally in the form of the racemates thereof, the pure stereoisomers thereof, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular of the enantiomers or diastereomers, in any desired mixing ratio;

[0010] in which

[0011] R1, R2, R3 and R4 are mutually independently selected from among

[0012] H, F, Cl, Br, I, CN, NO2; C1-C18 alkyl, C2-C18 alkenyl or C2-C18 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C3-C5 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one C atom in the ring is replaced by N, S or O; alkylaryl or alkylheteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; OR11, OC(O)R11, C(O)R11, C(O)OR11, C(O)NR11R11′, NR11R11′, S(O2)R11 or SR11, wherein R11 and R11′ are mutually independently selected from among

[0013] H; C1-C18 alkyl, C2-C18 alkenyl or C2-C18 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C3-C8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one C atom in the ring is replaced by N, S or O;

[0014] alkylaryl or alkylheteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;

[0015] R5 is selected from among

[0016] H; C1-C18 alkyl, C2-C18 alkenyl or C2-C18 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C3-C8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one C atom in the ring is replaced by N, S or O; alkylaryl or alkylheteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;

[0017] R6 is selected from among

[0018] R12 or ZR12 with Z=C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted, with R12 selected from among

[0019] H; C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C3-C8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one C atom in the ring is replaced by S, O or N; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;

[0020] C(O)R13, C(O)OR13, C(S)R13, C(S)OR13 or S(O2)R13 with R13 selected from among

[0021] H; C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C3-C8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one C atom in the ring is replaced by S, O or N;

[0022] alkylaryl or alkylheteroaryl, in each case mono- or polysubstituted or unsubstituted; aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted, in particular phenethyl, 1-adamantyl, 2-adamantyl, 1-naphthyl or 2-naphthyl, 2-, 3- or 4-pyridyl; or thiazolyl;

[0023] SR14 with R14 selected from among

[0024] aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or

[0025] C(O)NR15R16, C(O)NR15NR16R17, C(NR15)NR16R17, C(S)NR15R16 or C(S)NR15NR16R17, wherein R15, R16 and R17 are mutually independently selected from among

[0026] H; C1-C18 alkyl, C2-C18 alkenyl or C2-C18 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C3-C8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one C atom in the ring is replaced by S, O or N;

[0027] alkylaryl or alkylheteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;

[0028] R7, R8, R9 and R10 are mutually independently selected from among

[0029] H, F, Cl, Br, I, CN, NO2; C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted;

[0030] OR18, OC(O)R18, OC(S)R18, C(O)R18, C(O)OR18, C(S)R18, C(S)OR18, SR18, S(O)R18 or S(O2)R18, wherein R18 is selected from among

[0031] H; C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C3-C8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one C atom in the ring is replaced by S, O or N;

[0032] alkylaryl or alkylheteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;

[0033] NR19R20, NR19C(O)R20, C(NR19)NR20R21, NR19C(S)R20, C(S)NR19R20 or C(S)NR19NR20R21 or S(O2)NR19R20, wherein R19, R20 and R21 are mutually independently selected from among

[0034] H, O; C1-C18 alkyl, C2-C18 alkenyl or C2-C18 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C3-C8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one C atom in the ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or

[0035] R19 and R20 or R20 and R21 together form a C3-C8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one C atom in the ring is replaced by S, O or N; or

[0036] R7 and R8, R8 and R9 or R9 and R10 together

[0037] form ═CR22—CH═CH—CH═ or ═CH—CR22═CH—CH═, with R22 selected from among

[0038] H, F, Cl, Br, I, OH or C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted.

[0039] The 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compounds according to the invention exhibit a distinct analgesic action and are also NMDA antagonists, which selectively attack the glycine-binding site.

[0040] For the purposes of the present invention alkyl or cycloalkyl residues are taken to mean saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which may be unsubstituted or mono- or polysubstituted. C1-2 alkyl here denotes C1 or C2 alkyl, C1-3 alkyl denotes C1, C2 or C3 alkyl, C1-4 alkyl denotes C1, C2, C3 or C4 alkyl, C1-5 alkyl denotes C1, C2, C3, C4 or C5 alkyl, C1-6 alkyl denotes C1, C2, C3, C4, C5 or C6 alkyl, C1-7 alkyl denotes C1, C2, C3, C4, C5, C6 or C7 alkyl, C1-8 alkyl denotes C1, C2, C3, C4, C5, C6, C7 or C8 alkyl, C1-10 alkyl denotes C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl and C1-18 alkyl denotes C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17 or C18 alkyl. C3-4 cycloalkyl furthermore denotes C3 or C4 cycloalkyl, C3-5 cycloalkyl denotes C3, C4 or C5 cycloalkyl, C3-6 cycloalkyl denotes C3, C4, C5 or C6 cycloalkyl, C3-7 cycloalkyl denotes C3, C4, C5, C6 or C7 cycloalkyl, C3-8 cycloalkyl denotes C3, C4, C5, C6, C7 or C8 cycloalkyl, C4-5 cycloalkyl denotes C4 or C5 cycloalkyl, C4-6 cycloalkyl denotes C4, C5 or C6 cycloalkyl, C4-7 cycloalkyl denotes C4, C5, C6 or C7 cycloalkyl, C5-6 cycloalkyl denotes C5 or C6 cycloalkyl and C5-7 cycloalkyl denotes C5, C6 or C7 cycloalkyl. With regard to cycloalkyl, the term also includes saturated cycloalkyls in which one or 2 carbon atoms are replaced by a heteroatom S, N or O. The term cycloalkyl in particular, however, also includes mono- or polyunsaturated, preferably monounsaturated, cycloalkyls without a heteroatom in the ring, provided that the cycloalkyl does not constitute an aromatic system. The alkyl or cycloalkyl residues are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, as well as adamantyl, CHF2, CF3 or CH2OH and pyrazolinone, oxopyrazolinone, [1,4]-dioxane or dioxolane.

[0041] In relation to alkyl and cycloalkyl, it is here understood that, unless explicitly stated otherwise, for the purposes of the present invention, substituted means the substitution of a hydrogen residue by F, Cl, Br, I, NH2, SH or OH, wherein “polysubstituted” residues should be taken to mean that substitution is performed repeatedly both on different and the same atoms with identical or different substituents, for example three times on the same C atom as in case of CF3 or on different sites as in the case of —CH(OH)—CH═CH—CHCl2. Particularly preferred substituents are here F, Cl and OH.

[0042] The term (CH2)3-6 should be taken to mean —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—CH2— and CH2—CH2—CH2—CH2—CH2—CH2—, while the term (CH2)1-4 should be taken to mean —CH2—, —CH2—CH2—, —CH2—CH2—CH2— and —CH2—CH2—CH2—CH2—, etc.

[0043] An aryl residue is taken to mean ring systems comprising at least one aromatic ring, but without a heteroatom in even one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H fluorenyl or anthacenyl residues, which may be unsubstituted or mono- or polysubstituted.

[0044] A heteroaryl residue is taken to mean heterocyclic ring systems comprising at least one unsaturated ring, which contain one or more heteroatoms from the group comprising nitrogen, oxygen and/or sulfur and may also be mono- or polysubstituted. Examples from the group of heteroaryls which may be mentioned are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and quinazoline.

[0045] In relation to aryl and heteroaryl, substituted is taken to mean the substitution of the aryl or heteroaryl with R23, OR23, a halogen, preferably F and/or Cl, a CF3, a CN, an NO2, an NR24R25, a C1-6 alkyl (saturated), a C1-6 alkoxy, a C3-8 cycloalkoxy, a C3-8 cycloalkyl or a C2-6 alkylene.

[0046] The residue R23 here denotes H, a C1-10 alkyl, preferably a C1-6 alkyl, an aryl or heteroaryl or an aryl or heteroaryl residue attached via a C1-3 alkylene group, wherein these aryl and heteroaryl residues may not themselves be substituted with aryl or heteroaryl residues.

[0047] The residues R24 and R25 may be identical or different and denote H, a C1-10 alkyl, preferably a C1-6 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl attached via a C1-3 alkylene group, wherein these aryl and heteroaryl residues may not themselves be substituted with aryl or heteroaryl residues, or the residues R24 and R25 together mean CH2CH2OCH2CH2, CH2CH2NR26CH2CH2 or (CH2)3-6.

[0048] The residue R26 denotes H, a C1-10 alkyl, preferably a C1-6 alkyl, an aryl or heteroaryl residue or an aryl or heteroaryl residue attached via a C1-3 alkylene group, where these aryl and heteroaryl residues may not themselves be substituted with aryl or heteroaryl residues.

[0049] The term salt should be taken to mean any form of the active substance according to the invention, in which the latter assumes ionic form or bears a charge and is coupled with a counterion (a cation or anion) or is in solution. These should also be taken to mean complexes of the active substance with other molecules and ions, in particular complexes which are complexed by means of ionic interactions.

[0050] For the purposes of the present invention, a physiologically acceptable salt with cations or bases is taken to mean salts of at least one of the compounds according to the invention, usually a (deprotonated) acid, as the anion with at least one, preferably inorganic, cation, which is physiologically acceptable, in particular for use in humans and/or mammals. Particularly preferred salts are those of the alkali and alkaline earth metals, as are those with NH4+, most particularly preferred are (mono-) or (di-)sodium, (mono-) or (di-)potassium, magnesium or calcium salts.

[0051] For the purposes of the present invention, a physiologically acceptable salt with anions or acids is taken to mean salts of at least one of the compounds according to the invention, usually protonated, for example on the nitrogen, as the cation with at least one anion, which is physiologically acceptable, in particular for use in humans and/or mammals. In particular, for the purposes of the present invention, the physiologically acceptable salt is taken to be the salt formed with a physiologically acceptable acid, namely salts of the particular active substance with inorganic or organic acids which are physiologically acceptable, in particular for use in humans and/or mammals. Examples of physiologically acceptable salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro-1,6-benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid. The hydrochloride salt is particularly preferred.

[0052] The present application preferably provides substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds of the formula I, in which R6 is selected from among

[0053] H; C1-C10 alkyl, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted; preferably H, CH3 or C2H5, in particular H.

[0054] The present application preferably also provides substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds of the formula I, in which R5 is selected from among

[0055] H; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; phenyl, benzyl, or phenethyl, mono- or polysubstituted or unsubstituted, preferably H, CH3 or C2H5, in particular H.

[0056] The present application preferably also provides substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compounds of the formula I, in which R7, R8, R9 and R10 are mutually independently selected from among

[0057] H, F, Cl, Br, I, CN, NO2; C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted;

[0058] OR18, C(O)R18, C(O)OR18 or SR18, wherein R18 is selected from among H; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl, mono- or polysubstituted or unsubstituted,

[0059] R7, R8, R9 and R10 are preferably mutually independently selected from among

[0060] H, F, Cl, Br, I, CN; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted;

[0061] OR18 or SR18, with R18 selected from among

[0062] H; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; phenyl, mono- or polysubstituted or unsubstituted,

[0063] in particular R7, R8, R9 and R10 are mutually independently selected from among H, F, Cl, Br, I, CN; CH3, CF3, t-butyl, i-butyl, OH, —OCH3, —OCF3, —SCH3, —O-phenyl.

[0064] It is particularly preferred in this connection if

[0065] R7, R8 and R10 mean H and R9 means Cl or

[0066] R7 and R9 mean H and R8 and R10 mean Cl,

[0067] preferably, R7 and R9 mean H and R8 and R10 mean Cl.

[0068] The present application particularly preferably provides substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compounds of the formula I, in which

[0069] R5=H,

[0070] R6=H,

[0071] R7=H,

[0072] R8=Cl,

[0073] R9=H and

[0074] R10=Cl.

[0075] The present application preferably also provides substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds of the formula I, in which R1, R2, R3 or R4 are mutually independently selected from among

[0076] H, F, Cl, Br, I, CN, NO2; C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted;

[0077] OR11, OC(O)R11, C(O)R11, C(O)OR11, C(O)NR11R11′, NR11R11′, S(O2)R11 or SR11, wherein R11and R11′ are mutually independently selected from among

[0078] H; C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted;

[0079] preferably

[0080] H, F, Cl, Br, I, CN, NH2, NO2; C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted;

[0081] OR11, C(O)OR11 or SR11, wherein R11 is selected from among

[0082] H; C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted;

[0083] in particular

[0084] H, F, Cl, Br, I, CN, NH2; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; SH; OR11 or C(O)OR11, wherein R11 is selected from among

[0085] H; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted;

[0086] or particularly preferably

[0087] H, F, Cl, Br, I, CN, NH2, CH3, C2H5, n-propyl, i-propyl, i-butyl, sec.-butyl, n-butyl, t-butyl, CF3, CHF2, SH, OH, OCH3, OC2H5, C(O)OH, C(O)OCH3 or C(O)OC2H5.

[0088] The present invention in particular provides the following substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compounds or the salts thereof:

[0089] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid,

[0090] 1,3-Dichloro-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid,

[0091] 1,3-Dichloro-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid,

[0092] 1,3-Dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid,

[0093] 1,3-Dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid,

[0094] 1,3-Dichloro-8-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid,

[0095] 1,3,8-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid,

[0096] 8-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid,

[0097] 8-Iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid,

[0098] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6,8-dicarboxylic acid,

[0099] 1,3-Dichloro-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid,

[0100] 1,3-Dichloro-10-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid,

[0101] 1,3,10-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid,

[0102] 10-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid,

[0103] 10-Iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid,

[0104] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6,10-dicarboxylic acid or

[0105] 1,3-Dichloro-10-cyano-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid,

[0106] preferably 1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid.

[0107] Particularly preferred compounds are the free carboxylic acids or the salts of the substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compounds according to the invention of the formula I in the form of the alkali metal salts thereof, preferably the potassium or sodium salts, or in the form of inorganic acid salts, preferably the hydrochloride.

[0108] The present invention also provides processes for the production of the salts according to the invention of a substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound.

[0109] Various processes for the preparation of tetrahydroquinolines, the parent substance of the compounds according to the invention, are described in the literature:

[0110] a solid phase approach (WO 98/34111),

[0111] multistage processes (WO 98/42673; Bioorganic and Medicinal Chemistry Letters vol. 2, p. 371, 1992; Journal of Heterocyclic Chemistry vol. 25, p. 1831, 1988; Journal of the Chemical Society, Perkin Transactions 1 (1989), page 2245) or

[0112] a Lewis acid-catalyzed “single vessel” process (Journal of the Chemical Society, Chemical Communications, 1999, p. 651; Journal of the American Chemical Society, vol. 118, p. 8977, 1996).

[0113] However, all these processes clearly exhibit some disadvantages.

[0114] Unlike these processes, the “basic process” described herein is a trifluoroacetic acid-mediated, preferably “single vessel” process, in which one aromatic amine component, one aldehyde component and one electron-rich olefin component react together.

[0115] The basic process involves initially producing 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds of the formula I with R6=H, while the other residues have one of the above-stated meanings. In this process, anilines corresponding to formula II, in which R7, R8, R9 and R10 mutually independently each and have one of the meanings already stated for formula I or are provided with a protective group,

[0116] are reacted with glyoxalic acid esters or glyoxalic acid of the formula III and a benzofuran according to IV, in which R1, R2, R3, R4 and R5 mutually independently each have one of the meanings already stated for formula I or are provided with a protective group, in the presence of trifluoroacetic acid at between 0° C. and 100° C. It is preferred in this connection that the duration of the reaction is 0.25-12 h, preferably at most 2 h. It is also preferred that the reaction proceeds at a temperature of between 20 and 40° C., preferably room temperature, and/or preferably the reaction is a single-vessel reaction.

[0117] A decisive advantage of the process according to the invention is that the process is highly selective and gives good yields by means of a domino reaction (imine formation followed by an aza Diels-Alder reaction).

[0118] By dispensing with the necessity of carrying out a linkage or elimination step, as in the case of the solid phase approach, and also with the necessity of purifying the intermediates, as in the case of the described solution chemistry, the process according to the invention differs with regard both to its simplicity to perform and its purification method. The products may for the most part be obtained in high purity by repeated washing with nonpolar solvents, such as for example n-hexane. Otherwise, they are purified by means of column chromatography. In particular, compounds of the formula I may be obtained in diastereomerically pure form by washing processes with nonpolar solvents, such as for example n-hexane, or by crystallization of the salts thereof.

[0119] In general, in a favorable form of the production process, once formation of a compound of the formula I is complete, the compound is converted into a compound with a base or acid, which may already contain the desired cation or anion, and the resultant salt is then purified.

[0120] Most of the reagents used in the process, in particular of the formulae II, III and IV, are commercially available or may be produced by simple synthesis steps known to the person skilled in the art. After the basic process, the products obtained according to the basic process may be converted in accordance with methods known to the person skilled in the art into derived products according to the invention of the formula I, wherein the hydrogen on R6 is initially substituted.

[0121] Accordingly, if the intended products are substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds of the formula I with R6=alkylformyl, acyl, sulfenyl and sulfonyl, once the basic reaction has been performed, the reaction product may be reacted with appropriate chloro- or fluoroformates, acid chlorides, sulfenyl chlorides and sulfonyl chlorides in the presence of a base, preferably triethylamine, pyridine or NaOH, at a temperature of between 0-20° C. in water, dioxane/water or THF/water mixtures (J. Org. Chem. 1989, 54, 5574-5580). Similarly, if the intended products are substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds of the formula I with R6=C(S)NR15R16, once the basic reaction has been performed, the reaction product may be reacted with a thionation reagent, preferably Lawesson's reagent (2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiaphosphetane), in organic solvents, preferably THF or toluene, at a temperature of 30-50° C.

[0122] Alternatively, if the intended products are substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds of the formula I with R6=C(O)NR15R16 or C(S)NR15R16, once the basic reaction has been performed, the reaction product may be reacted with potassium cyanate or potassium isothiocyanate in water at temperatures of up to 100° C. or with organic isocyanates or isothiocyanates in alcohols, preferably methanol, ethanol or isopropanol at temperatures of up to boiling point. Furthermore, if the intended products are substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds of the formula I with R6=C(NR15)NR16R17, once the basic reaction has been performed, the reaction product may be reacted with O-methylisoureas or S-methylisothioureas under alkaline conditions, preferably in ethanolic or methanolic NaOH or KOH, at temperatures of 20-50° C.

[0123] Furthermore, if the intended products are substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds of the formula I with R6=C(O)NR15R16, once the basic reaction has been performed, the reaction product may also be reacted with 2-propanone semicarbazone in water/glacial acetic acid at 30-60° C.

[0124] Similarly, if the intended products are substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds of the formula I with R6=C(S)NR15R16, once the basic reaction has been performed, the reaction product may be reacted with CS2 and hydrazines in water/NaOH at 30-60° C.

[0125] As the final possibility which will be mentioned in this connection, if the intended products are substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds of the formula I with R6=alkyl, benzyl or phenethyl, once the basic reaction has been performed, the reaction product may be reacted with a corresponding alkylation halide, benzyl halide or phenethyl halide and a suitable base, preferably sodium hydride or potassium tert.-butylate, in a solvent, for example ethanol, between 0 and 100° C. (J. Org. Chem. 1947, 12, 760; Zh. Obshch. Khim. 1942, 12, 418).

[0126] Under many of the stated reaction conditions, OH, SH and NH2 groups may possibly enter into unwanted secondary reactions. It is thus preferred to provide said groups with protective groups or, in the case of NH2, to replace them with NO2 and, before the final product is purified, to eliminate the protective group or reduce the NO2 group. The present application accordingly also provides a modification of the above-described process, in which, in the starting compounds, at least one OH group has been replaced by an OSi(Ph)2tert.-butyl group, at least one SH-group has been replaced by an S-p-methoxybenzyl group and/or at least one NH2 group has been replaced by an NO2 group and, before the final product is purified, at least one, preferably all, of the OSi(Ph)2tert.-butyl group(s) is/are eliminated with tetrabutylammonium fluoride in tetrahydrofuran and/or at least one, preferably all, of the p-methoxybenzyl group(s) is/are eliminated with a metal amide, preferably sodium amide, and/or at least one, preferably all, of the NO2 group(s) is/are reduced to NH2.

[0127] Furthermore, under certain circumstances, carboxylic acid or thiocarboxylic acid groups are not stable under the reaction conditions, such that it is preferred to use the methyl ester thereof in the reactions and subsequently to saponify the product of the process with KOH solution or NaOH solution in methanol at 40° C.-60° C. The present invention accordingly also provides a modification of the above-described process in which, before the final product is purified, a product of the process with at least one C(O)OCH3, OC(O)OCH3 and/or C(S)OCH3 group is saponified with KOH solution or NaOH solution in methanol or ethanol at 0° C.-100° C., preferably 40° C.-60° C.

[0128] It may accordingly also be favorable when producing substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compounds of the formula I with R5=H to use starting products of the formula III for the basic process, in which R5≠H and R5 is preferably alkyl, in particular CH3 and C2H5. According to the basic process and also the subsequent reactions which possibly follow, the reaction product is saponified with an appropriate base, preferably NaOH or KOH, in ethanol or methanol, at temperatures of between 0-100° C., preferably 40° C.-60° C. (Organikum, 1990, p. 418).

[0129] In order to produce the salts, in particular the physiologically acceptable salts, with cations or bases, the following method is used: one equivalent of a compound of the formula I, preferably an imino acid, or a carboxylic acid, in particular with R3=H, is suspended in a little water and one equivalent of 1 normal aqueous alkali solution, for example NaOH or KOH, is added. If solubility is poor, methanol is added dropwise until complete dissolution is achieved. After stirring at room temperature, the mixture is evaporated in a rotary evaporator, the remaining solution is frozen at low temperatures in a mixture of isopropanol/dry ice and freeze-dried. The salts, in particular the imino acids or carboxylic acids, preferably the sodium or potassium salts, are obtained as mainly colorless solids. Alternatively, it is also possible to produce the potassium or sodium salts with potassium or sodium trimethylsilanolate (E. D. Laganis, B. L. Chenard; Tetrahedron Letters 25, 5831-5834 (1984)). In this case, potassium or sodium trimethylsilanolate is dissolved under nitrogen in an organic solvent (for example, dichloromethane, toluene or THF) and the ester or the acid is added in a single portion. The reaction mixture is stirred for two or more hours at room temperature and filtered out. The mainly colorless solid is washed and dried under a vacuum. The potassium or sodium salts are obtained as solids.

[0130] The substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compounds according to the invention are toxicologically safe, such that they are suitable as a pharmaceutically active ingredient in pharmaceutical preparations.

[0131] The present invention accordingly also provides a pharmaceutical preparation containing as active ingredient at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to the invention of the formula I in the form as prepared or in the form of the acid or base or in the form of the salts thereof, in particular the physiologically acceptable salts, or in the form of the solvates thereof, in particular the hydrates; in particular in the form of the physiologically acceptable salts thereof with cations or bases or with anions or acids; optionally in the form of the racemates thereof, of the pure stereoisomers thereof, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; and optionally containing suitable additives and/or auxiliary substances and/or optionally further active ingredients.

[0132] The pharmaceutical preparations according to the invention may be administered in the form of solutions for injection, drops or succi, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, dressings or aerosols and, in addition to the at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to the invention, they also optionally contain, depending upon the pharmaceutical presentation, excipients, fillers, solvents, diluents, colorants and/or binders. Selection of the auxiliary substances and the quantities thereof which are to be used depends upon whether the pharmaceutical preparation is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example onto infections of the skin, mucous membranes or eyes. Preparations in the form of tablets, coated tablets, capsules, granules, drops, succi and syrups are suitable for oral administration, while solutions, suspensions, easily reconstitutible dried preparations and sprays are suitable for parenteral, topical and inhalatory administration. Substituted 5,6,6a-11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds according to the invention in a depot in dissolved form or in a dressing, optionally with the addition of skin penetration promoters, are examples of suitable percutaneous formulations. Orally or percutaneously administrable preparations may release the substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds according to the invention in a delayed manner. The quantity of active substance to be administered to the patient varies as a function of patient weight, mode of administration, the indication and the severity of the condition. Conventionally, 2 to 500 mg/kg of at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to the invention of the formula I are administered.

[0133] The substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compounds according to the invention are preferably used for treating pain, in particular chronic and neuropathic pain, but also for migraine, such that the present invention also provides the use of at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to the invention of the formula I in the form as prepared or in the form of the acid or base or in the form of the salts thereof, in particular the physiologically acceptable salts, or in the form of the solvates thereof, in particular the hydrates; in particular in the form of the physiologically acceptable salts thereof with cations or bases or with anions or acids; optionally in the form of the racemates thereof, the pure stereoisomers thereof, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; for the production of a pharmaceutical preparation for the treatment of pain, in particular of neuropathic and/or chronic pain, and/or for the treatment of migraine.

[0134] Further applications arise from the affinity with the NMDA receptor, as NMDA antagonists are known, inter alia, to have a neuroprotective action and are thus well suited to use with clinical pictures associated with neurodegeneration and nerve damage, such as Parkinson's disease and Huntington's chorea etc. Further indications of the NMDA antagonists according to the invention are epilepsy, glaucoma, osteoporosis, ototoxicity, the withdrawal symptoms associated with alcohol and/or drug abuse, stroke and the associated cerebral ischemia, cerebral infarcts, cerebral edema, hypoxia, anoxia, together with use for anxiolysis and in anesthesia. The present invention accordingly also provides the use of at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to the invention of the formula I; in the form as prepared or in the form of the acid or base or in the form of the salts thereof, in particular the physiologically acceptable salts, or in the form of the solvates thereof, in particular the hydrates; in particular in the form of the physiologically acceptable salts thereof with cations or bases or with anions or acids; optionally in the form of the racemates thereof, the pure stereoisomers thereof, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; for the production of a pharmaceutical preparation for the treatment/prevention of epilepsy, Parkinson's disease, Huntington's chorea, glaucoma, ototoxicity, withdrawal symptoms associated with alcohol and/or drug abuse, stroke, cerebral ischemia, cerebral infarcts, cerebral edema, hypoxia, anoxia and/or for anxiolysis and/or anesthesia.

[0135] It has surprisingly been found that the substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to the invention is also highly suitable for further indications, in particular for the treatment of urinary incontinence, pruritus, tinnitus and/or diarrhea. The present application accordingly also provides the use of at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to the invention of the formula I; in the form as prepared or in the form of the acid or base or in the form of the salts thereof, in particular the physiologically acceptable salts, or in the form of the solvates thereof, in particular the hydrates; in particular in the form of the physiologically acceptable salts thereof with cations or bases or with anions or acids; optionally in the form of the racemates thereof, the pure stereoisomers thereof, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; for the production of a pharmaceutical preparation for the treatment of urinary incontinence, pruritus, tinnitus and/or diarrhea.

[0136] The compounds according to the invention are, however, also effective for other indications. The present application accordingly also provides the use of at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to the invention of the formula I; in the form as prepared or in the form of the acid or base or in the form of the salts thereof, in particular the physiologically acceptable salts, or in the form of the solvates thereof, in particular the hydrates; in particular in the form of the physiologically acceptable salts thereof with cations or bases or with anions or acids; optionally in the form of the racemates thereof, the pure stereoisomers thereof, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; for the production of a pharmaceutical preparation for the treatment/prevention of schizophrenia, Alzheimer's disease, psychoses due to elevated amino acid levels, AIDS dementia, encephalomyelitis, Tourette's syndrome, perinatal asphyxia, inflammatory and allergic reactions, depression, drug and/or alcohol abuse, gastritis, diabetes, cardiovascular disease, respiratory diseases, coughing and/or mental illnesses.

[0137] The present invention also provides a method for the treatment of a non-human mammal or hum an requiring the treatment of medically relevant symptoms by administration of a therapeutically effective dose of a substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to the invention of the formula I; in the form as prepared or in the form of the acid or base or in the form of the salts thereof, in particular the physiologically acceptable salts, or in the form of the solvates thereof, in particular the hydrates; in particular in the form of the physiologically acceptable salts thereof with cations or bases or with anions or acids; optionally in the form of the racemates thereof, the pure stereoisomers thereof, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; or of a pharmaceutical preparation according to the invention. The invention in particular relates to a corresponding method for the treatment of pain, in particular of neuropathic and/or chronic pain and/or for the treatment of migraine, for the treatment of urinary incontinence, pruritus, tinnitus and/or diarrhea, for the treatment/prevention of epilepsy, Parkinson's disease, Huntington's chorea, glaucoma, osteoporosis, ototoxicity, the withdrawal symptoms associated with alcohol and/or drug abuse, stroke, cerebral ischemia, cerebral infarcts, cerebral edema, hypoxia, anoxia and/or for anxiolysis and/or anesthesia or for the treatment/prevention of schizophrenia, Alzheimer's disease, psychoses due to increased amino acid levels, AIDS dementia, encephalomyelitis, Tourette's syndrome, perinatal asphyxia, inflammatory and allergic reactions, depression, drug and/or alcohol abuse, gastritis, diabetes, cardiovascular diseases, respiratory diseases, coughing and/or mental illnesses.

[0138] The following Examples are provided to illustrate the invention and are not intended to, nor should they be understood to be, limiting.

EXAMPLES

[0139] The following Examples illustrate compounds according to the invention and the preparation thereof and efficacy testing performed with said compounds.

[0140] The following general comments apply:

[0141] The chemicals and solvents used were purchased from conventional suppliers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI etc.) or were synthesized by general production methods known to the person skilled in the art. In particular, some of the benzofurans, together with some others of the compounds used, were synthesized as synthesis building blocks using known synthetic methods prior to the basic synthesis described below. Thin-layer chromatography was performed with pre-coated silica gel 60 F 254 HPTLC plates from E. Merck, Darmstadt. The yields of the compounds produced are not optimized.

[0142] Analysis was performed by ESI mass spectroscopy.

[0143] The compounds are numbered, the value in brackets in principle corresponding to the number of the assigned compound.

Example 0

[0144] Basic process

[0145] a) One equivalent each of aniline compound and trifluoroacetic acid are dissolved in 6 ml/mmol of acetonitrile with stirring at room temperature, and then 1.1 equivalents of ethyl glyoxalate (50% in toluene) or 1.1 equivalents glyoxylic acid monohydrate are added. After ten minutes, 3 equivalents of the benzofuran component are added and the course of the reaction is monitored by thin-layer chromatography (mobile solvent system diethyl ether/hexane, 1:1). The reaction is complete after 2 hours (TLC monitoring). The reaction batch is combined with an excess of saturated aqueous sodium hydrogencarbonate solution and the organic phase is extracted three times with diethyl ether. The organic phase is washed to neutrality with water, dried over magnesium sulfate, filtered, washed with diethyl ether and, after evaporation, isolated by recrystallization or silica gel chromatography. The 5,6,6a, lb-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid esters are characterized by ESI mass spectrometry.

[0146] b) Optional Subsequent Preparation of the Free 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acids.

[0147] The above-described 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid ester (1 equivalent) is dissolved in 4 ml/mmol of ethanol and combined with 1.2 equivalents of aqueous 6N sodium hydroxide solution and stirred at room temperature. The course of the ester saponification is monitored by thin-layer chromatography (mobile solvent system diethyl ether/hexane, 1:1) and is complete after 30 minutes (TLC monitoring). The reaction mixture is evaporated in a rotary evaporator, redissolved in approximately 10 ml of water and adjusted to pH 1 with 32% HCl. The aqueous solution is extracted five times with diethyl ether and, after drying over magnesium sulfate, is evaporated.

[0148] Automated method

[0149] A stirrer was placed in a round-bottomed glass tube (diameter 16 mm, length 125 mm) with a thread and the tube sealed using a screw lid with septum. The tube was placed in a stirring block, which had been adjusted to 20° C. The following reagents were then added in succession by pipette:

[0150] 1 ml of a solution of trifluoroacetic acid, 0.1 M, and aniline component, 0.1 M, in acetonitrile;

[0151] 1 ml of a 0.11 M solution of the aldehyde in acetonitrile;

[0152] 1 ml of a 0.3 M solution of the benzofuran in acetonitrile.

[0153] In this connection, aldehyde should be taken to mean both the glyoxalic acid and the glyoxalic ester, preferably the alkyl ester, in particular the ethyl or methyl ester. The reaction mixture was stirred for 10 hours at 20° C. in one of the stirring blocks. The reaction solution was then filtered. The tube was then rinsed twice with 1.5 ml portions of a 7.5% NaHCO3 solution.

[0154] The reaction mixture was combined with 2 ml of ethyl acetate on a vortexer and shaken. The mixture was briefly centrifuged to form a phase boundary. The phase boundary was detected optically and the organic phase removed by pipette. In the next step, the aqueous phase was again combined with 2 ml of ethyl acetate, shaken, centrifuged and the organic phase removed by pipette. The combined organic phases were dried over 2.4 g of MgSO4 (pellets). The solvent was removed in a vacuum centrifuge.

[0155] The free 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid or ester was characterized by ESI mass spectrometry.

[0156] In principle, in the case of compounds with R3≠H, both the automated and the normal basic process may be followed by saponification in accordance with methods known to the person skilled in the art, such as for example with KOH solution or NaOH solution in methanol or ethanol at 0° C.-100° C., preferably at 40° C.-60° C.

Example 1

[0157]

[0158] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (1)

[0159] Compound 1 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and the unsubstituted benzofuran, the resultant ester subsequently being saponified.

Example 2

[0160]

[0161] 1,3-Dichloro-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (2)

[0162] Compound 2 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 5-methoxybenzofuran, the resultant ester subsequently being saponified.

Example 3

[0163]

[0164] 1,3-Dichloro-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (3)

[0165] Compound 3 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 7-methylbenzofuran, the resultant ester subsequently being saponified.

Example 4

[0166]

[0167] 1,3-Dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (4)

[0168] Compound 4 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxylic acid ethyl ester and 7-ethylbenzofuran, the resultant ether subsequently being saponified.

Example 5

[0169]

[0170] 1,3-Dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid (5)

[0171] Compound 5 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 7-methoxybenzofuran, the resultant ester subsequently being saponified.

Example 6

[0172]

[0173] 1,3-Dichloro-8-fluoro-5,6,6a,1 lb-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (6)

[0174] Compound 6 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 7-fluorobenzofuran, the resultant ester subsequently being saponified.

Example 7

[0175]

[0176] 1,3,8-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (7)

[0177] Compound 7 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 7-chlorobenzofuran, the resultant ester subsequently being saponified.

Example 8

[0178]

[0179] 8-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (8)

[0180] Compound 8 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 7-bromobenzofuran, the resultant ester subsequently being saponified.

Example 9

[0181]

[0182] 8-Iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (9)

[0183] Compound 9 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 7-iodobenzofuran, the resultant ester subsequently being saponified.

Example 10

[0184]

[0185] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6,8-dicarboxylic acid (10)

[0186] Compound 10 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and benzofuran-7-carboxylic acid, the resultant ester subsequently being saponified.

Example 11

[0187]

[0188] 1,3-Dichloro-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (11)

[0189] Compound 11 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 5-methylbenzofuran, the resultant ester subsequently being saponified.

Example 12

[0190]

[0191] 1,3-Dichloro-10-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (12)

[0192] Compound 12 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 5-fluorobenzofuran, the resultant ester subsequently being saponified.

Example 13

[0193]

[0194] 1,3,10-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (13)

[0195] Compound 13 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 5-chlorobenzofuran, the resultant ester subsequently being saponified.

Example 14

[0196]

[0197] 10-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (14)

[0198] Compound 14 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 5-bromobenzofuran, the resultant ester subsequently being saponified.

Example 15

[0199]

[0200] 10-Iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (15)

[0201] Compound 15 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 5-iodobenzofuran, the resultant ester subsequently being saponified.

Example 16

[0202]

[0203] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6,10-dicarboxylic acid (16)

[0204] Compound 16 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and benzofuran-5-carboxylic acid, the resultant ester subsequently being saponified.

Example 17

[0205]

[0206] 1,3-Dichloro-10-cyano-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid (17)

[0207] Compound 17 was produced in accordance with the basic process according to Example 0 from 3,5-dichloroaniline, glyoxalic acid ethyl ester and 5-cyanobenzofuran, the resultant ester subsequently being saponified.

Example 18

General preparation of the salts with cations by way of example of the compounds according to Examples 1-17.

[0208] One equivalent of the compound according to one of Examples 1 to 17, preferably an imino acid, is suspended in a little water and one equivalent of 1 normal aqueous alkali solution, preferably NaOH or KOH, is added. If solubility is poor, methanol is added dropwise until complete dissolution is achieved. After 30 minutes' stirring at room temperature, the mixture is evaporated in a rotary evaporator, the remaining solution is frozen at −60° C. in a mixture of isopropanol/dry ice and freeze-dried. The salts, in particular of the imino acids, preferably the sodium or potassium salts, are obtained as generally colorless solids.

[0209] Alternatively, it is also possible to produce the potassium or sodium salts with potassium or sodium trimethylsilanolate (E. D. Laganis, B. L. Chenard; Tetrahedron Letters 25, 5831-5834 (1984)). Potassium or sodium trimethylsilanolate is dissolved under nitrogen in an organic solvent (for instance, dichloromethane, toluene or THF) and the ester or acid is added in a single portion. The reaction mixture is stirred for four hours at room temperature and filtered. The generally colorless solid is washed with diethyl ether and dried under a vacuum. The potassium or sodium salts are obtained as solids.

[0210] The compounds according to Example 19 to 35 are sodium salts, produced in accordance with these example instructions, of compounds 1 to 17, while the compounds according to Examples 36 to 52 are the correspondingly produced potassium salts.

Example 19

[0211]

[0212] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylate; sodium salt (19)

[0213] Compound 19 was produced by the process according to Example 18 from compound 1.

Example 20

[0214]

[0215] 1,3-Dichloro-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; sodium salt (20)

[0216] Compound 20 was produced by the process according to Example 18 from compound 2.

Example 21

[0217]

[0218] 1,3-Dichloro-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; sodium salt (21)

[0219] Compound 21 was produced by the process according to Example 18 from compound 3.

Example 22

[0220]

[0221] 1,3-Dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; sodium salt (22)

[0222] Compound 22 was produced by the process according to Example 18 from compound 4.

Example 23

[0223]

[0224] 1,3-Dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylate; sodium salt (23)

[0225] Compound 23 was produced by the process according to Example 18 from compound 5.

[0226] 1,3-Dichloro-8-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; sodium salt (24)

[0227] Compound 24 was produced by the process according to Example 18 from compound 6.

[0228] 1,3,8-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; sodium salt (25)

[0229] Compound 25 was produced by the process according to Example 18 from compound 7.

Example 26

[0230]

[0231] 8-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylate; sodium salt (26)

[0232] Compound 26 was produced by the process according to Example 18 from compound 8.

Example 27

[0233]

[0234] 8-Iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; sodium salt (27)

[0235] Compound 27 was produced by the process according to Example 18 from compound 9.

Example 28

[0236]

[0237] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6,8-dicarboxylate; disodium salt (28)

[0238] Compound 28 was produced by the process according to Example 18 from compound 10.

Example 29

[0239]

[0240] 1,3-Dichloro-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; sodium salt (29)

[0241] Compound 29 was produced by the process according to Example 18 from compound 11.

Example 30

[0242]

[0243] 1,3-Dichloro-10-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; sodium salt (30)

[0244] Compound 30 was produced by the process according to Example 18 from compound 12.

Example 31

[0245]

[0246] 1,3,10-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylate; sodium salt (31)

[0247] Compound 31 was produced by the process according to Example 18 from compound 13.

Example 32

[0248]

[0249] 10-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylate; sodium salt (32)

[0250] Compound 32 was produced by the process according to Example 18 from compound 14.

Example 33

[0251]

[0252] 10-Iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; sodium salt (33)

[0253] Compound 33 was produced by the process according to Example 18 from compound 15.

Example 34

[0254]

[0255] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6,10-dicarboxylate; disodium salt (34)

[0256] Compound 34 was produced by the process according to Example 18 from compound 16.

Example 35

[0257]

[0258] 1,3-Dichloro-10-cyano-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; sodium salt (35)

[0259] Compound 35 was produced by the process according to Example 18 from compound 17.

Example 36

[0260]

[0261] 1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; potassium salt (36)

[0262] Compound 36 was produced by the process according to Example 18 from compound 1.

Example 37

[0263]

[0264] 1,3-Dichloro-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; potassium salt (37)

[0265] Compound 37 was produced by the process according to Example 18 from compound 2.

Example 38

[0266]

[0267] 1,3-Dichloro-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; potassium salt (38)

[0268] Compound 38 was produced by the process according to Example 18 from compound 3.

Example 39

[0269]

[0270] 1,3-Dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate potassium salt (39)

[0271] Compound 39 was produced by the process according to Example 18 from compound 4.

Example 40

[0272]

[0273] 1,3-Dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylate potassium salt (40)

[0274] Compound 40 was produced by the process according to Example 18 from compound 5.

Example 41

[0275]

[0276] 1,3-Dichloro-8-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; potassium salt (41)

[0277] Compound 41 was produced by the process according to Example 18 from compound 6.

Example 42

[0278]

[0279] 1,3,8-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; potassium salt (42)

[0280] Compound 42 was produced by the process according to Example 18 from compound 7.

Example 43

[0281]

[0282] 8-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; potassium salt (43)

[0283] Compound 43 was produced by the process according to Example 18 from compound 8.

Example 44

[0284]

[0285] 8-Iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; potassium salt (44)

[0286] Compound 44 was produced by the process according to Example 18 from compound 9.

Example 45

[0287]

[0288] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6,8-dicarboxylate; dipotassium salt (45)

[0289] Compound 45 was produced by the process according to Example 18 from compound 10.

Example 46

[0290]

[0291] 1,3-Dichloro-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; potassium salt (46)

[0292] Compound 46 was produced by the process according to Example 18 from compound 11.

Example 47

[0293]

[0294] 1,3-Dichloro-10-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; potassium salt (47)

[0295] Compound 47 was produced by the process according to Example 18 from compound 12.

Example 48

[0296]

[0297] 1,3,10-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylate; potassium salt (48)

[0298] Compound 31 was produced by the process according to Example 18 from compound 13.

Example 49

[0299]

[0300] 10-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; potassium salt (49)

[0301] Compound 49 was produced by the process according to Example 18 from compound 14.

Example 50

[0302]

[0303] 10-Iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylate; potassium salt (50)

[0304] Compound 50 was produced by the process according to Example 18 from compound 15.

Example 51

[0305]

[0306] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6,10-dicarboxylate; dipotassium salt (51)

[0307] Compound 51 was produced by the process according to Example 18 from compound 16.

Example 52

[0308]

[0309] 1,3-Dichloro-10-cyano-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylate; potassium salt (52)

[0310] Compound 52 was produced by the process according to Example 18 from compound 17.

Example 53

General Preparation of the Salts with Anions by way of Example of the Hydrochloride Salt of the Compounds According to Examples 1-17.

[0311] One equivalent of the compound according to one of Examples 1 to 17 is dissolved in approximately 10 ml of 2-butanone per gram of substance. Half a mol equivalent of water is then added, followed by 1.1 mol equivalents of chlorotrimethylsilane. Then the mixture is stirred overnight. If no hydrochloride was formed on cooling to approximately 4° C., the precipitation batch was resuspended in twice the volume of water, washed with three small portions of ether, the aqueous phase was alkalized with a small volume of approximately 30% sodium hydroxide solution and extracted three times with ether (“acid-base extraction”). These final extracts were in turn combined and subjected to another hydrochloride precipitation.

[0312] The compounds according to Examples 54 to 70 are the hydrochloride salts, produced in accordance with these example instructions, of compounds 1 to

Example 54

[0313]

[0314] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; hydrochloride salt (54)

[0315] Compound 54 was produced by the process according to Example 53 from compound 1.

Example 55

[0316]

[0317] 1,3-Dichloro-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid; hydrochloride salt (55)

[0318] Compound 55 was produced by the process according to Example 53 from compound 2.

Example 56

[0319]

[0320] 1,3-Dichloro-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid; hydrochloride salt (56)

[0321] Compound 56 was produced by the process according to Example 53 from compound 3.

Example 57

[0322]

[0323] 1,3-Dichloro-8-ethyl-5,6,6a,11 b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; hydrochloride salt (57)

[0324] Compound 57 was produced by the process according to Example 53 from compound 4.

Example 58

[0325]

[0326] 1,3-Dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; hydrochloride salt (58)

[0327] Compound 58 was produced by the process according to Example 53 from compound 5.

Example 59

[0328]

[0329] 1,3-Dichloro-8-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; hydrochloride salt (59)

[0330] Compound 59 was produced by the process according to Example 53 from compound 6.

Example 60

[0331]

[0332] 1,3,8-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; hydrochloride salt (60)

[0333] Compound 60 was produced by the process according to Example 53 from compound 7.

Example 61

[0334]

[0335] 8-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; hydrochloride salt (61)

[0336] Compound 61 was produced by the process according to Example 53 from compound 8.

Example 62

[0337]

[0338] 8-Iodo-1,3-dichloro-5,6,6a,1 b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; hydrochloride salt (62)

[0339] Compound 62 was produced by the process according to Example 53 from compound 9.

Example 63

[0340]

[0341] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6,8-dicarboxylic acid; hydrochloride salt(63)

[0342] Compound 63 was produced by the process according to Example 53 from compound 10.

Example 64

[0343]

[0344] 1,3-Dichloro-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; hydrochloride salt (64)

[0345] Compound 64 was produced by the process according to Example 53 from compound 11.

Example 65

[0346]

[0347] 1,3-Dichloro-10-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid; hydrochloride salt (65)

[0348] Compound 65 was produced by the process according to Example 53 from compound 12.

Example 66

[0349]

[0350] 1,3,10-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; hydrochloride salt (66)

[0351] Compound 66 was produced by the process according to Example 53 from compound 13.

Example 67

[0352]

[0353] 10-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid; hydrochloride salt (67)

[0354] Compound 67 was produced by the process according to Example 53 from compound 14.

Example 68

[0355]

[0356] 10-Iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid; hydrochloride salt (68)

[0357] Compound 68 was produced by the process according to Example 53 from compound 15.

Example 69

[0358]

[0359] 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6,10-dicarboxylic acid; hydrochloride salt (69)

[0360] Compound 69 was produced by the process according to Example 53 from compound 16.

Example 70

[0361]

[0362] 1,3-Dichloro-10-cyano-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; hydrochloride salt (70)

[0363] Compound 70 was produced by the process according to Example 53 from compound 17.

Example 71

[0364] Receptor Binding (Glycine-Binding Site of the NMDA Receptor Channel)

[0365] The investigation for determining the affinity of the compounds according to the invention of the formula I towards the glycine-binding site of the NMDA receptor channel was performed on brain membrane homogenates (homogenate of the cortex and hippocampus area from male rat brain, Wistar strain) [B. M. Baron, B. W. Siegel, B. L. Harrison, R. S. Gross, C. Hawes and P. Towers, Journal of Pharmacology and Experimental Therapeutics, vol. 279, p. 62, 1996].

[0366] To this end, the cortex and hippocampus were dissected out of freshly harvested rat brains and homogenized with ice cooling in 5 mmol/l of TRIS-acetate buffer, 0.32 mol/l of sucrose, pH 7.4 (10 ml/g fresh weight) using a Potter homogenizer (Braun/Melsungen, 10 piston strokes at 500 rpm) and then centrifuged for 10 minutes at 1,000 g and 4° C. The first supernatant was collected and the sediment again homogenized with ice cooling with 5 mmol/l of TRIS-acetate buffer, 0.32 mol/i of sucrose, pH 7.4 (5 ml/g of original fresh weight) with the Potter homogenizer (10 piston strokes at 500 rpm) and centrifuged for 10 minutes at 1,000 g and 4° C. The resultant supernatant was combined with the supernatant from the first centrifugation and centrifuged at 17,000 g for 20 minutes at 4° C. The supernatant after this centrifugation was discarded and the membrane sediment was resuspended with 5 mmol/l of TRIS-acetate buffer, pH 8.0 (20 ml/g of original fresh weight) and homogenized with 10 piston strokes at 500 rpm. The membrane homogenate was then incubated for 1 hour at 4° C. and centrifuged for 30 minutes at 50,000 g and 4° C. The supernatant was discarded and the centrifuge tubes containing the membrane sediment were sealed with Parafilm and frozen for 24 hours at −20° C. On the following day, the membrane sediment was thawed and resuspended with ice-cold 5 mmol/l TRIS-acetate buffer, 0.1% saponin (wt./vol.), pH 7.0 (10 ml/g of original fresh weight) and homogenized with 10 piston strokes at 500 rpm and then centrifuged for 20 minutes at 50,000 g and 4° C. The resultant supernatant was discarded and the sediment resuspended in a small volume with 5 mmol/l of TRIS-acetate buffer, pH 7.0 (approximately 2 ml/g of original fresh weight) redissolved and again homogenized with 10 piston strokes at 500 rpm. After determination of the protein content, the membrane homogenate was adjusted with 5 mmol/l TRIS-acetate buffer, pH 7.0, to a protein concentration of 10 mg of protein/ml and frozen in aliquots until used for testing. The receptor binding test was performed by thawing aliquots, diluting them 1:10 with 5 mmol/l TRIS-acetate buffer, pH 7.0, homogenizing them with ice-cooling with 10 piston strokes at 500 rpm with the Potter homogenizer (10 piston strokes at 500 rpm) and centrifuging them for 60 minutes at 55,000 g at 4° C. The supernatant was decanted and the membrane sediment adjusted with ice-cold 50 mmol/l TRIS-acetate buffer, pH 7.0, to a protein concentration of 1 mg/ml and again homogenized with 10 piston strokes at 500 rpm and kept in suspension in an ice bath with stirring on a magnetic stirrer. This membrane homogenate was used in the receptor binding test in a quantity of 100 μl per 1 ml batch (0.1 mg of protein/ml in the final batch). In the binding test, the buffer used was 50 mmol/l TRIS-acetate buffer, pH 7.0, and the radioactive ligand was 1 nmol/l of (3H)-MDL 105.519 (B. M. Baron et al. 1996). The level of non-specific binding was determined in the presence of 1 mmol/l of glycine.

[0367] In further batches, the compounds according to the invention were added in concentration series and the displacement of the radioactive ligand from its specific binding at the glycine-binding site of the NMDA receptor channel was determined. Each of the triplicate batches was incubated for 120 minutes at 4° C. and then harvested by filtration through glass fiber filter mats (GF/B) in order to determine the radioactivity bound to the membrane homogenate. The radioactivity retained on the glass fiber filters was measured in the β counter by addition of scintillating material.

[0368] The affinity of the compounds according to the invention towards the glycine-binding site of the NMDA receptor channel was calculated as an IC50 value (concentration with 50% displacement of the radioactive ligand from its specific binding site) in accordance with the mass-action law by means of nonlinear regression and is stated in Table 1 after conversion (using the Cheng-Prussoff equation) as a Ki value (mean of three independent tests) or as the percentage of the previously bound radioactive ligand (see above) which is displaced from its specific binding site at a concentration of 10 μmol/l of the substance according to the invention under test.

1TABLE 1Glycine-binding site of the NMDA receptorchannelExampleKi (μmol/l)Displacement (%, 10 μmol/l)10.053100

Example 72

[0369] Formaldehyde Test, Rat

[0370] The investigations to determine the antinociceptive action of the compounds according to the invention of the formula I were carried by the formaldehyde test on male rats (Sprague-Dawley, 150-170 g). In the formaldehyde test, a distinction is drawn between the first (early) phase (0-15 min after formaldehyde injection) and the second (later) phase (15-60 min after formaldehyde injection) (D. Dubuisson, S. G. Dennis, Pain 4, 161-174 (1977)). The early phase, being a direct response to the formaldehyde injection, is considered to be a model for acute pain, while the late phase is considered to be a model for persistent (chronic) pain (T. J. Coderre, J. Katz, A. L. Vaccarino, R. Melzack, Pain, Vol. 52, p. 259, 1993). The compounds according to the invention were investigated in the second phase of the formaldehyde test in order to obtain information concerning the effects of the substances in chronic/inflammatory pain.

[0371] A nociceptive reaction was induced in the freely mobile test animals by a single, subcutaneous formaldehyde injection (50 μl, 5%) into the dorsal side of the rear hind paw, the reaction being classed according to one of the following behavioral parameters: lifting and holding up the affected paw (score 1), shaking or twitching (score 2), licking and biting (score 3). The differential behavior induced by the formaldehyde injection was recorded by observing the animals in the late phase of the formaldehyde test and assigned a variable weighting in the evaluation. Normal behavior, in which the animal places an even load on all four paws, was recorded as a score of 0. The time of administration before the formaldehyde injection was selected as a function on the mode of administration of the compounds according to the invention (intraperitoneal: 15 min; intravenous: 5 min). After injection of the substances, which are antinociceptively active in the formaldehyde test, the described behaviors (score 1-3) of the animals are reduced or even eliminated. A comparison was made with control animals which had received vehicle (solvent) before administration of the formaldehyde. The nociceptive behavior was calculated as a “pain rate” (PR). The various behavioral parameters were differently weighted (factor of 0, 1, 2, 3). The calculation was carried out in accordance with the following equation at sub-intervals of 3 min:

PR
=[(T0×0)+(T1×1)+(T2×2)+(T3×3)]/180,

[0372] wherein T0, T1, T2, and T3 in each case correspond to the time in seconds for which the animal exhibited behavior 0, 1, 2 or 3. Substance and vehicle groups in each case comprises n=10 animals. On the basis of the calculated PR values, the effect of the substance was determined as a percentage change relative to the control. The ED50 calculations were carried out by regression analysis. All the compounds according to the invention exhibited moderate to strong inhibition of the formaldehyde-induced nociception.

[0373] The following Table summarizes the results from selected investigations in the rat formaldehyde test.

2TABLE 2CompoundMode of administrationED501i.v.7.27 mg/kg

Example 73

Parenteral Administration Form

[0374] 38.5 g of compound 1 were dissolved in 11 of water for injection at room temperature and then adjusted to isotonic conditions by addition of anhydrous glucose for injection.

[0375] The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.

Claims

1. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound corresponding to formula I
2. The compound of claim 1, wherein said compound is present in the form of a free base.
3. The compound of claim 1, wherein said compound is present in the form of a salt with a base.
4. The compound of claim 1, wherein said compound is present in the form of a pure enantiomer.
5. The compound of claim 1, wherein said compound is present in the form of a pure diastereoisomer.
6. The compound of claim 1, wherein said compound is present in the form of a mixture of stereoisomers.
7. The compound of claim 1, wherein said compound is present in the form of a racemic mixture.
8. The compound of claim 1, wherein said compound is present in the form of a solvate.
9. The compound of claim 1, wherein said compound is present in the form of a hydrate.
10. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to claim 1, wherein R6 represents H; C1-C10 alkyl, either unsubstituted or mono- or polysubstituted; or phenyl, either unsubstituted or mono- or polysubstituted.
11. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to claim 10, wherein R6 represents H, CH3 or C2H5.
12. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to claim 1, wherein R5 represents H; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; or phenyl, benzyl, or phenethyl, mono- or polysubstituted or unsubstituted.
13. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to claim 12, wherein R5 represents H, CH3 or C2H5.
14. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to one of claim 1, wherein R7, R8, R9 and R10 independently represent H, F, Cl, Br, I, CN, NO2; C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; or OR18, C(O)R18, C(O)OR18 or SR18, wherein R18 represents H; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; aryl, mono- or polysubstituted or unsubstituted.
15. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to claim 14, wherein R7, R8, R9 and R10 independently represent H, F, Cl, Br, I, CN; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; or OR18 or SR18, wherein R18 represents H; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; phenyl, mono- or polysubstituted or unsubstituted.
16. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to claim 15, wherein R7, R8, R9 and R10 independently represent H, F, Cl, Br, I, CN; CH3, CF3, t-butyl, i-butyl, OH, —OCH3, —OCF3, —SCH3, or —O-phenyl.
17. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to claim 1, wherein R7, R8 and R10 represent H and R9 represents Cl or R7 and R9 represent H and R8 and R10 represent Cl.
18. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to claim 1, wherein R5=H, R6=H, R7=H, R8=Cl, R9=H and R10=Cl.
19. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to claim 1, wherein at least one of R1, R2, R3 and R4 independently represent H, F, Cl, Br, I, CN, NO2; C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; or OR11, OC(O)R11, C(O)R11, C(O)OR11, C(O)NR11R11′, NR11R11′, S(O2)R11 or SR11, wherein R11 and R11′ independently represent H; C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted.
20. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to claim 19, wherein at least one of R1, R2, R3 and R4 independently represent H, F, Cl, Br, I, CN, NH2, NO2; C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; or OR11, C(O)OR11 or SR11, wherein R11 represents H; C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted.
21. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to claim 19, wherein at least one of R1, R2, R3 and R4 independently represent H, F, Cl, Br, I, CN, NH2; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; or SH; OR11 or C(O)OR11, wherein R11 represents H; C1-C4 alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted.
22. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to claim 19, wherein at least one of R1, R2, R3 and R4 independently represent H, F, Cl, Br, I, CN, NH2, CH3, C2H5, n-propyl, i-propyl, i-butyl, sec.-butyl, n-butyl, t-butyl, CF3, CHF2, SH, OH, OCH3, OC2H5, C(O)OH, C(O)OCH3 or C(O)OC2H5.
23. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to claim 1, wherein said compound is selected from the group consisting of: 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 1,3-Dichloro-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 1,3-Dichloro-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 1,3-Dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 1,3-Dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 1,3-Dichloro-8-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 1,3,8-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 8-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 8-Iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6,8-dicarboxylic acid; 1,3-Dichloro-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 1,3-Dichloro-10-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 1,3,10-Trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 10-Bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 10-Iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid; 1,3-Dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6,10-dicarboxylic acid or 1,3-Dichloro-10-cyano-5,6,6a,11 b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid, or a salt thereof with a physiologically acceptable acid.
24. A substituted 5,6,6a,1 b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to claim 23, wherein said compound is 1,3-Dichloro-5,6,6a,1 b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid or a salt thereof with a physiologically acceptable acid.
25. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to claim 1, wherein said compound is present as an alkali metal salt or an inorganic acid salt.
26. A substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c]fluorene-6-carboxylic acid compound according to claim 25, wherein said alkali metal salt is a potassium or sodium salt, and wherein said inorganic acid salt is a hydrochloride salt.
27. A process for producing a substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound corresponding to formula I of claim 1 wherein R6═H,
28. The process of claim 27, wherein said step of reacting is carried out at a temperature between 0° C. and 100° C.
29. The process of claim 27, wherein at least one of R1, R2, R3, R4, R5, R7, R8, R9 or R10 are independently provided with a protective group.
30. The process of claim 27, wherein the duration of the reaction is 0.25-12 hours.
31. The process of claim 27, wherein the duration of the reaction is no longer than 2 hours.
32. The process of claim 27, wherein the reaction is carried out at a temperature of between 20 and 40° C.
33. The process of claim 32, wherein the reaction is carried out at room temperature.
34. The process of claim 27, wherein the reaction is a single-vessel reaction.
35. A process for producing a substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound according to formula 1 of claim 1, wherein R6≠H,
36. A process according to claim 27, wherein in at least one of the aniline corresponding to formula II, the glyoxalic acid ester or glyoxalic acid compound corresponding to formula III or the benzofuran corresponding to formula IV, R1, R2, R3, R4, R5, R7, R8, R9 or R10 are independently provided with a protective group, said protective group being selected from the group consisting of OSi(Ph)2tert.-butyl to replace an OH group; p-methoxybenzyl to replace an SH-group and NO2 to replace an NH2 group and before a purification step, at least one OSi(Ph)2tert.-butyl group is cleaved with tetrabutylammonium fluoride in tetrahydrofuran; at least one S-p-methoxybenzyl group is cleaved with a metal amide or at least one NO2 group is reduced to NH2.
37. A process according to claim 36, wherein said metal amide is sodium amide.
38. A process according to claim 36, wherein, before purification, all OSi(Ph)2tert.-butyl groups are cleaved with tetrabutylammonium fluoride in tetrahydrofuran; all S-p-methoxybenzyl groups are cleaved with a metal amide or all NO2 groups are reduced to NH2.
39. A process according to claims 27, wherein a product of the process with at least one C(O)OCH3 or C(S)OCH3 group or a product of the process wherein R5=C1-4 alkyl, is saponified with KOH solution or NaOH solution in methanol or ethanol at a temperature of from 0° C. to 100° C.
40. A process according to claim 39, wherein said temperature is from 40° C. to 60° C.
41. A process according to claim 39, wherein in said product of the process R5=CH3 or C2H5.
42. A pharmaceutical composition, comprising: at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compound corresponding to formula I of claim 1 or a salt thereof with a physiologically tolerated acid and an auxiliary agent.
43. The pharmaceutical composition of claim 42, wherein said compound is present in the form of a free base.
44. The pharmaceutical composition of claim 42, wherein said compound is present in the form of a salt with a base.
45. The pharmaceutical composition of claim 42, wherein said compound is present in the form of a pure enantiomer.
46. The pharmaceutical composition of claim 42, wherein said compound is present in the form of a pure diastereoisomer.
47. The pharmaceutical composition of claim 42, wherein said compound is present in the form of a mixture of stereoisomers.
48. The pharmaceutical composition of claim 42, wherein said compound is present in the form of a racemic mixture.
49. The pharmaceutical composition of claim 42, wherein said compound is present in the form of a solvate.
50. The pharmaceutical composition of claim 42, wherein said compound is present in the form of a hydrate.
51. A method of alleviating pain in a mammal, said method comprising administering to said mammal an effective pain alleviating amount of a compound according to claim 1.
52. The method of claim 49, wherein said pain is neuropathic or chronic pain.
53. The method of claim 49 wherein said pain is pain from a migraine.
54. A method of treating urinary incontinence, pruritus, tinnitus or diarrhea in a mammal, said method comprising administering to said mammal an effective amount of a compound according to claim 1.
55. A method of treating or inhibiting epilepsy, Parkinson's disease, Huntington's chorea, glaucoma, osteoporosis, ototoxicity, the withdrawal symptoms associated with alcohol or drug abuse, stroke, cerebral ischaemia, cerebral infarcts, cerebral oedema, hypoxia, anoxia or for anxiolysis or anaesthesia in a mammal, said method comprising administering to said mammal an effective amount of a compound according to claim 1.
56. A method of treating or inhibiting schizophrenia, Alzheimer's disease, psychosis due to increased amino acid levels, AIDS dementia, encephalomyelitis, Tourette's syndrome, perinatal asphyxia, inflammatory and allergic reactions, depression, drug or alcohol abuse, gastritis, diabetes, cardiovascular diseases, respiratory diseases, coughing or mental illnesses said method comprising administering to said mammal an effective amount of a compound according to claim 1.

Priority Claims (1)

Number	Date	Country	Kind
101 37 487.9	Aug 2001	DE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of International Patent Application No. PCT/EP02/08886, filed Aug. 5, 2002, designating the United States of America, and published in German as WO 03/014124 A1, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on Federal Republic of Germany Patent Application No. DE 101 37 487.9, filed Aug. 3, 2001.

Continuations (1)

	Number	Date	Country
Parent	PCT/EP02/08886	Aug 2002	US
Child	10770126	Feb 2004	US

Substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds as NMDA-antagonists

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Priority Claims (1)

CROSS-REFERENCE TO RELATED APPLICATIONS

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