WO2004069840A2 - Production of tetrahydroquinoline benzofurans - Google Patents

Abstract

The invention relates to methods for producing tetrahydro- 7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acids, selected tetrahydro-7 oxa-5-aza-benzo[c]fluorene-6-carboxylic acid derivatives, medicaments containing these compounds and to the use thereof for producing medicaments for certain indications, particularly for treating pain.

Description

 Patent application of Grünenthal GmbH, D-52078 Aachen (own sign G 3182)

5 Preparation of tetrahvdroquinoline benzofurans

The present invention relates to processes for preparing tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acids, selected tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives, drugs containing these compounds and their use for the preparation of

Medicines for certain indications, in particular for the treatment of pain.

The treatment of chronic and non-chronic pain is of great importance in medicine. There is a worldwide need for effective pain therapies for a patient-appropriate and goal-oriented treatment of chronic and non-chronic pain conditions, which is to be understood as the successful and satisfactory pain treatment for the patient. This can be seen in the large number of 20 scientific papers that have recently appeared in the field of applied analgesics or basic research on nociception.

Classic opioids such as morphine are effective in the treatment of severe to severe pain. Their use is however by the well-known

Side effects e.g. Respiratory depression, vomiting, sedation, constipation and tolerance development are limited. In addition, they are less effective in the case of neuropathic or incidental pain, in particular tumor patients.

30

Opioids develop their analgesic effect by binding to membrane-bound receptors, which belong to the family of the so-called G-protein

F \ PN \ PATEllT \ GRA 31β2 \ GRA3182_AUΞLAND_EN DOC coupled receptors belong. The biochemical and pharmacological characterization of subtypes of these receptors has now raised the hope that subtype-specific opioids have a different action / side-effect profile than eg morphine. Further pharmacological investigations have now made the existence of several subtypes of these opioid receptors (μ μ ₂ , κ _i5 κ ₂ , κ ₃ , δi and δ ₂ ) likely.

In addition, there are other receptors and ion channels that are significantly involved in the system of pain development and pain transmission. Of particular importance is the NMDA ion channel: it is a major part of the communication of synapses. This channel controls calcium ion exchange between the neuronal cell and its environment.

Knowledge of the physiological importance of ion channel-selective substances has been gained through the development of the patch-clamp technique. This clearly demonstrates the effect of NMDA antagonists on the influence of calcium ions in the cell interior. It also turned out that these substances have their own antinociceptive potential (e.g., ketamine). It is important that the mechanism of action is a completely different one, as for example in the case of opiates, because NMDA antagonists intervene directly in the crucial Caicium household of the cells in the pain transmission. Therefore, for the first time, it is possible to successfully carry out the treatment of neuropathic pain.

Various NMDA antagonists, in this case tetrahydroquinoline derivatives, have already been described in 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. In particular, in the patent applications a

GRA3182 Foreign countries de.doc Variety of possible indications indicated, among others, the pain therapy. However, the effectiveness and usability of these substances is still open, so that there is a need for further substances here.

An object underlying the invention was to provide a method for producing correspondingly analgesically active substances, in particular NMDA antagonists. Accordingly, the invention provides a process for the preparation of tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid of the general formula I,

wherein

R ¹ , R ² , R ³ and R ^{4 are} independently selected from

H, F, Cl, Br, I; C is cis-alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₁₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by N, S or O; Alkylaryl or Alkylheteroaryl, in each case monosubstituted or polysubstituted or

GRA3182 Foreign countries de.doc unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

C(O)R¹¹, C(O)OR¹¹, C(O)NR¹¹R¹¹ , NR¹¹R¹ OR ¹¹ ,

C (O) R ¹¹ , C (O) OR ¹¹ , C (O) NR ¹¹ R ¹¹ , NR ¹¹ R ¹

SS ((OO ₂₂ )) RR ¹¹¹¹ ooddeerr SSRR ¹¹¹¹ ,, \ wherein R ¹¹ and R ^{11 are} independently selected from

H; C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₁₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by N, S or O; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or

Heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

or

R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together

-CR ²³ = CH-CH-, -CR ²³ -CH = CH-, = CR ²³ -CH = CH-CH =, -CR ²³ = CH-CH = CH-, -CH = CR ²³ -CH = CH- or = CH-CR ²³ = CH-CH = form, with R ²³ selected from H, F, Cl, Br, I, OH or C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl or C ₂ -

C 1 -C 4 alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted;

R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently selected from

GRA3182 Foreign de doc H, F, Cl, Br, I; -C ₁₀ alkyl, C ₂ -Cι ₀ alkenyl or C ₂ -C ₁₀ alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted;

OR ¹⁸ , OC (O) R ¹⁸ , OC (S) R ¹⁸ , C (O) R ¹⁸ , C (O) OR ¹⁸ , C (S) R ¹⁸ ,

C (S) OR ¹⁸ , SR ¹⁸ , S (O) R ¹⁸ and S (O ₂ ) R ¹⁸ , respectively, wherein R ^{18 is} selected from

H; Ci-Cio-alkyl, C ₂ -Cι ₀ alkenyl or C ₂ -C ₁₀ alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or

Heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

NR ¹⁹ R ²⁰ , NR ¹⁹ C (O) R ²⁰ , C (NR ¹⁹ ) NR ²⁰ R ²¹ NR ¹⁹ C (S) R ²⁰ , C (S) NR ¹⁹ R ²⁰ or C (S) NR ¹⁹ NR ²⁰ R ²¹ or S (O ₂ ) NR ¹⁹ R ²⁰ , where

R ¹⁹ , R ²⁰ and R ^{21 are} independently selected from H, O; C ₁ -C ₈ -alkyl, C ₂ -C ₁₈ -alkenyl or C ₂ -C ₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case simply or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

GRA3182 Foreign countries de.doc or

R ¹⁹ and R ²⁰ or R ²⁰ and R ²¹ together form a C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or form a corresponding heterocycle in which at least one C atom in the ring by S , O or N is replaced; or

R ⁷ and R ⁸ , R ⁸ and R ⁹ or R ⁹ and R ¹⁰ together

-CR ²² = CH-CH-, -CR ²² -CH = CH-, = CR ²² -CH = CH-CH =, -CR ²² = CH-CH = CH-, -CH = CR ²² -CH = CH- or = CH-CR ²² = CH-CH = form, with R ²² selected from

H, F, Cl, Br, I, OH or Cι-Cι ₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₂ - Cio-alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted,

characterized in that an optionally substituted aniline of the formula II in which R ⁷ , R ⁸ , R ⁹ and R> 10 have the abovementioned meaning,

Glyoxylic acid or glyoxylic acid hydrate and

GRA3182 Foreign countries de.doc a benzofuran of the formula III in which R, R, R and R have the abovementioned meaning,

under microwave irradiation, preferably throughout the reaction time, in a suitable solvent in the presence of a Bronsted acid or Lewis acid simultaneously, wherein the olefin of the formula III and the glyoxylic acid or the Glyoxylsäurehydrat are used in excess.

For the purposes of this invention is meant by alkyl or cycloalkyl radicals saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons which may be unsubstituted or mono- or polysubstituted. In this case, C ₁ -C ₂ -alkyl is C ₁ -C ₂ -alkyl, C ₁ -C 3 -alkyl is C ₁ -C ₂ -alkyl or C 3 -alkyl, C ₁ -C 4 -alkyl is C ₁ -C 2, C 3 or C ₄ Alkyl, C _1-5 -alkyl for C ₁ , C 2, C 3, C 4 or C ₅ -alkyl, C _1-6 -alkyl for C ₁ , C 2, C 3, C 4, C ₅ or C 6 Alkyl, C _1-7 -alkyl for C 1, C 2, C 3, C 4, C 5, C 6 or C 7 -alkyl, C _1-8 -alkyl for C 1 -, C 2 -, C 3 -, C 4 -, C5, C6, C7 or C8 alkyl, d.io-alkyl for C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl and Cι _-18 -alkyl C1, C2, C3, C4, C5, C6, C7, C8, - C9-, C10-, C11, C12, C13, C14, C15 , C16, C17 or C18 alkyl. Next is _C3-4 - cycloalkyl means C3- or C4-cycloalkyl, C _3-5 cycloalkyl for C3, C4 or C5 cycloalkyl, _C3-6 cycloalkyl for C3, C4, C5 or C6 Cycloalkyl, C _3-7 -cycloalkyl for C 3, C 4, C 5, C 6 or C 7 -cycloalkyl, C _3-8 -cycloalkyl for C 3, C 4, C 5, C 6, C 7 or C 8 -cycloalkyl Cycloalkyl, C _4-5 -cycloalkyl for C4- or C5-

GRA3182 Foreign de doc Cycloalkyl, C _4-6 cycloalkyl for C 4, C 5 or C 6 cycloalkyl, C _4-7 cycloalkyl for C 4, C 5, C 6 or C 7 cycloalkyl, C _5-6 cycloalkyl for C 5 or C 6 -Cycloalkyl and C _5-7 cycloalkyl for C5, C6 or C7 cycloalkyl. With respect to cycloalkyl, the term also includes saturated cycloalkyls in which one or two carbon atoms are replaced by a heteroatom, S, N or O. However, the term cycloalkyl also includes, in particular, mono- or polysubstituted, preferably monounsaturated, unsaturated cycloalkyls without a heteroatom in the ring, as long as the cycloalkyl is not an aromatic system. The alkyl or cycloalkyl radicals 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, but also Adamantyl, CHF2, CF3 or CH2OH and pyrazolinone, oxopyrazolinone, [1, 4] dioxane or dioxolane.

In this case, in connection with alkyl and cycloalkyl the term substituted in the context of this invention the substitution of a hydrogen radical by F, Cl, Br, I, NH _2, SH or OH, it being understood by "polysubstituted" radicals that Substitution takes place both on different and on the same atoms repeatedly with the same or different substituents, for example, three times on the same carbon atom as in the case of CF ₃ or at different locations as in the case of -CH (OH) -CH = CH-CHCl _2. Particularly preferred substituents here are F, Cl and OH.

By the term (CH ₂ ) _3-6 is -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ - CH ₂ -CH ₂ -CH ₂ -CH ₂ - and CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ - to understand under (CH ₂ ) ι- is -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ -CH ₂ - to understand, etc.

GRA3182 Foreign de doc An aryl radical is understood as meaning ring systems having at least one aromatic ring but no heteroatoms in even one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which may be unsubstituted or monosubstituted or polysubstituted.

A heteroaryl radical is understood as meaning heterocyclic ring systems having at least one unsaturated ring which contain one or more heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur and may also be monosubstituted or polysubstituted.

Exemplary are from the group of heteroaryls furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1, 2,5 thiadiazol, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, Indole and quinazoline listed.

Substituted substitution of the aryl or heteroaryl with R ²⁶ , OR ^{26 is} a halogen, preferably F and / or Cl, a CF 3, a CN, a NO 2, a NR 24 R 25 _J ej _nem C- in connection with aryl and heteroaryl ug-alky! _(saturated). a C _j .g-alkoxy, a C .g-cycloalkoxy, a C .beta.-cycloalkyl or a C2_6-alkylene.

g-Alkyl-, einen Aryl- oder Heteroaryl- oder für einen über eine C-_j_3-Alkylen- Gruppe gebundenen Aryl- oder Heteroaryl-Rest, wobei diese Aryl undWhere is the rest R? for H, one

g-alkyl, an aryl or heteroaryl, or for a C _j _3-alkylene group bound aryl or heteroaryl radical, wherein these aryl and

Heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals,

the radicals R 4 and R 25 _(same or different, are H, a C _j _i _Q alkyl, preferably a _C-j alkyl, an aryl, a heteroaryl or a C -. ^ - Alkylene group bonded aryl or heteroaryl radical

GRA3182 Foreign countries de.doc where these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals,

or the radicals R ²⁴ and R ²⁵ together denote CH2CH2OCH2CH2, CH2CH ₂ NR ²⁷ CH ₂ CH 2 or (CH ₂₎ 3_ _6, and

Gruppe gebundenen Aryl- oder Heteroaryl-Rest, wobei diese Aryl und Heteroarylreste nicht selbst mit Aryl- oder Heteroaryl-Resten substituiert sein dürfen.the radical R ^{27 is} H, a C _j _ιo-alkyl, preferably a C ^ _ρ-alkyl, an aryl, or heteroaryl radical or a via one

Group-bonded aryl or heteroaryl radical, wherein these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals.

Another preferred subject of the invention is a method according to the invention, in which

as optionally substituted aniline, a compound of formula II, wherein

R ⁷ 'R ⁸ , R ⁹ and R ¹⁰ independently of one another are H, F, Cl, Br, I; C ₁ -C ₆ -alkyl, branched or unbranched, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Benzyl or phenyl, in each case monosubstituted or polysubstituted or unsubstituted;

OR ¹⁸ or C (0) OR ¹⁸ , where R ^{18 is} selected from

H; C is Cβ-alkyl, branched or unbranched, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or

GRA3182_Outland en.doc R ⁷ and R ⁸ , R ⁸ and R ⁹ or R ⁹ and R ¹⁰ together

-CH = CH-CH = CH- or -CH = CH-CH = CH- forms used.

Another preferred subject of the invention is a method according to the invention, in which

as optionally substituted aniline, a compound of formula II, wherein

R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently selected from

H, F, Cl, Br, 1, CH ₃ , C ₂ H ₅ , C ₃ H, C ₄ Hg, CF ₃ , CHF ₂ , CH ₂ F, OH, OCH ₃ , OC ₂ H ₅ , C (O) OH, C (O) OCH ₃ or C (O) OC ₂ H ₅ ,

preferably off

H, F, Cl, Br, I, CF ₃ , CHF ₂ , CH ₂ F or CH ₃ ,

in particular

R ⁸ and R ^{10 are} independently of each other, preferably both the same, selected from Cl or CF 3

and

R ⁹ and R ^{7 are} independently selected from H, F, Cl, Br, I, CF ₃ , CHF ₂ or CH ₂ F; preferably H, F, Cl, Br, I; especially H, inserts.

GRA3182 Foreign countries de.doc Another preferred subject matter of the invention is a process according to the invention in which the benzofuran is a compound of the formula III in which

R ¹ , R ² , R ³ and R ^{4 are} independently selected from

H, F, Cl, Br, I; C ₁ -C ₆ -alkyl, branched or unbranched, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by N, S or O; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

OR ¹¹ , OC (O) R ¹¹ , C (O) R ¹¹ , C (O) OR ¹¹ , C (O) NR ¹¹ R ^{11 '} or SR ¹¹ , wherein R ¹¹ and R ^{11 are} independently selected

H; Ci-C _δ -alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

or

R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together

-CR ²³ = CH-CH-, -CR ²³ -CH = CH-, -CR ²³ = CH-CH = CH- or - CH = CR ²³ -CH = CH- form, with R ²³ selected from

GRA3182 Foreign de doc H, F, Cl, Br, I, OH or CC ₄ alkyl, branched or unbranched, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted;

starts.

Another preferred subject matter of the invention is a process according to the invention in which the benzofuran is a compound of the formula III in which

R ¹ , R ² , R ³ and R ^{4 are} independently selected from

H, F, Cl, Br, I; CF ₃ , CHF ₂ , CH ₂ F, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ Hg; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Benzyl or phenyl, in each case monosubstituted or polysubstituted or unsubstituted;

OH, OCH ₃ , OC ₂ H ₅ , OC ₃ H ₅ , C (O) OH, C (O) OCH ₃ , C (O) OC ₂ H ₅ , C (O) OC ₃ H ₇

or

R and R, R and R or R and R in common

Form -CH = CH-CH-, -CH-CH = CH-, -CH = CH-CH = CH- or -CH = CH-CH = CH-,

starts.

Another preferred subject matter of the invention is a process according to the invention in which the optionally substituted aniline of the formula II, the glyoxylic acid or the

GRA3182 Foreign countries de.doc Glyoxylsäurehydrat and the benzofuran of formula III in a molar ratio of 1: 1, 5-3: 1, 5-3.

Another preferred subject matter of the invention is a process according to the invention in which the process is carried out in the presence of a Lewis acid,

preferably a triflate (a trifluoromethanesulfonic acid salt), in particular a lanthanum, (for example scandium) or indium triflate, particularly preferably an indium triflate,

or

in the presence of a polymer-bound Lewis acids or

Clay minerals, preferably montmorillonite, performs.

Another preferred subject matter of the invention is a process according to the invention in which acetonitrile is used as the solvent.

Another preferred subject matter of the invention is a process according to the invention in which the reaction is carried out at a temperature in the range from 40 to 80 ° C., preferably from 50 to 60 ° C.

Another preferred subject matter of the invention is a process according to the invention in which the solvent is removed or the poorly soluble compound of the general formula I is filtered off in order to isolate the compound of the general formula I.

Another preferred subject matter of the invention is a process according to the invention in which the purification of the

GRA3182 Foreign de doc Compound of the general formula I with a suitable solvent, preferably with a non-polar organic solvent, which washes the isolated compound and / or recrystallizes the compound.

Another preferred subject matter of the invention is a process according to the invention in which the solvent used for washing is hexane or acetonitrile.

Another preferred subject matter of the invention is a process according to the invention in which the corresponding salt is formed by adding a base, preferably sodium hydroxide, potassium hydroxide or lithium hydroxide, in particular sodium hydroxide, to the isolated and optionally purified compound of general formula I.

Another preferred subject of the invention is a process according to the invention for the preparation of 1, 3-dichloro-5,6,6a, 1 1 b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, at which 3,5-dichloroaniline, glyoxylic acid or

Glyoxylsäurehydrat and benzofuran.

For the preparation of the salts, in particular of the physiologically tolerated salts with cations or bases, the procedure is as follows:

One equivalent of a compound according to formula I is suspended in a little water and one equivalent of 1 normal aqueous lye, for example NaOH or KOH, is added. With poor solubility, so much methanol is added dropwise until complete solution occurs. After stirring at room temperature, the mixture is concentrated in a rotary evaporator, the remaining solution is frozen at low temperatures in a mixture of isopropanol / dry ice and freeze-dried. The salts,

GRA3182 Foreign de doc in particular the carboxylic acids, preferably the sodium or potassium salts, are obtained as mostly colorless solids.

A further object underlying the invention was to provide analgesic substances, in particular NMDA antagonists, which are suitable for the treatment of pain - in particular also chronic and neuropathic pain. In addition, these substances should have as few side effects as possible, e.g. Nausea, vomiting, addiction, respiratory depression or constipation. Accordingly, the invention provides a tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of the general formula VI,

VI

wherein

R ¹ , R ² , R ³ and R ^{4 are} independently selected from

H, F, Cl, Br, I; C 1 -C ₈ -alkyl, C ₂ -C ₁₈ -alkenyl or C ₂ -C ₁₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted,

GRA3182 Foreign countries de.doc 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 monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

OR ¹¹ , OC (O) R, C (O) R ¹¹ , C (O) OR, C (O) NR ¹¹ R ¹¹ , NR ¹¹ R ¹

SS ((OO ₂₂ )) RR ¹¹¹¹ ooddeerr SSRR ¹¹¹¹ ,, \ where R ¹¹ and R ^{11 'are} independently selected from

H; C ₁ -C ₁₈ -alkyl, C ₂ -C ₁₈ -alkenyl or C ₂ -C ₁₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by N, S or O; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

or

R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together are -CR ²³ = CH-CH-, -CR ²³ -CH = CH-, = CR ²³ -CH = CH-CH =, -CR ²³ = CH-

CH = CH-, -CH = CR ²³ -CH = CH- or = CH-CR ²³ = CH-CH = form, with R ²³ selected from

H, F, Cl, Br, I, OH or C Cιo-alkyl, C ₂ -C ₁₀ -alkenyl or C ₂ - C-io-alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted;

R ⁵ is H;

GRA3182 Foreign countries de.doc R ⁷ and R ^{9 are} independently selected from

H, F, Cl, Br, I; dC ₁₀ alkyl, C ₂ alkenyl or C ₂ -Cιo--Cι ₀ alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted;

OR ¹⁸ , OC (O) R ¹⁸ , OC (S) R ¹⁸ , C (O) R ¹⁸ , C (O) OR ¹⁸ , C (S) R ¹⁸ , C (S) OR ¹⁸ , SR ¹⁸ , S ( O) R ¹⁸ or S (O ₂ ) R ¹⁸ , wherein R ^{18 is} selected from

H; d-Cio-alkyl, C ₂ -Cι ₀ alkenyl or C ₂ -C ₁₀ alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

NR ¹⁹ R ²⁰ , NR ¹⁹ C (O) R ²⁰ , C (NR ¹⁹ ) NR ²⁰ R ²¹ NR ¹⁹ C (S) R ²⁰ , C (S) NR ⁹ R ²⁰ or C (S) NR ¹⁹ NR ²⁰ R ²¹ or S (O ₂ ) NR ¹⁹ R ²⁰ , wherein R ¹⁹ , R ²⁰ and R ^{21 are} independently selected from H, O; C ₁ -C ₈ -alkyl, C ₂ -C ₁₈ -alkenyl or C ₂ -d ₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case simply or polysubstituted or unsubstituted; Aryl or

G A3182 Foreign countries de.doc Heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

or

R and R ^ü or R and R together form a C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or form a corresponding heterocycle in which at least one C atom in the ring by S, O or N is replaced; or

optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, in particular of the physiologically tolerated salts, or in the form of their solvates, in particular the hydrates.

The 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention have a marked analgesic effect and are also NMDA antagonists which attack selectively at the glycine binding site.

The term salt means any form of the active ingredient according to the invention in which it assumes an ionic form or is charged and is coupled with a counterion (a cation or anion) or is in solution. These also include complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions.

For the purposes of the present invention, the term "physiologically acceptable salt" means salts of at least one of the compounds according to the invention

GRA3182 Foreign countries de.doc Compounds that are physiologically compatible - especially when used in humans and / or mammals. In particular, physiologically acceptable salts with cations or bases or physiologically acceptable salts with anions or acids are meant.

In the context of this invention, the term "physiologically compatible salt with cations or bases" refers to salts of at least one of the compounds according to the invention-usually a (deprotonated) acid-as an anion having at least one, preferably inorganic, cation which is physiologically-in particular when used in humans and or

Mammal - are compatible. Particularly preferred are the salts of the alkali and alkaline earth metals but also with NH ⁺ , but especially (mono-) or (di-) sodium, (mono-) or (di) potassium, magnesium or calcium salts.

In the context of this invention, the term "physiologically acceptable salt with anions or acids" is understood as meaning salts of at least one of the compounds according to the invention-usually, for example, nitrogen-protonated-as a cation having at least one anion which is physiologically-in particular when used in humans and / or Mammal - are compatible. In particular, for the purposes of this invention, it is understood to mean the salt formed with a physiologically acceptable acid, namely salts of the respective active ingredient with inorganic or organic acids, which are physiologically compatible - in particular when used in humans and / or mammals.

A preferred subject of the application is a tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of the formula VI according to the invention, in which

R ¹ , R ² , R ³ or R ^{4 are} independently selected from

GRA3182 Foreign countries de.doc H, F, Cl, Br, I; C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted;

NR->1^ι 1^π rR->1^π 1'OR> 1 "1, Mr

NR-> 1 ^ι 1 ^π rR-> 1 ^π 1 '

SS ((OO ₂₂ )) RR ¹¹¹¹ ooddeerr SSRR ¹¹¹¹ ,, \ where R ¹¹ and R ^{11 'are} independently selected from

H; C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted;

preferably R ¹ , R ² , R ³ or R ^{4 are} independently selected from

H, F, Cl, Br, I; C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl or C ₂ -C ₄ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted;

OR ¹¹ , C (O) OR ¹¹ or SR ¹¹ , wherein R ^{11 is} selected from

H; CC ₄ alkyl, C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted;

in particular R ¹ , R ² , R ³ or R ⁴ are selected independently of one another

H, F, Cl, Br, I; C 1 -C 4 -alkyl, branched or unbranched, simply ooddeerr mmeehhrrffaacchh ssuubbssttiittuuiertrt ooddeerr uunnssuubbssttiittuiert; SH; OR ¹¹ or C (O) OR ¹¹ , wherein R ^{11 is} selected from

GRA3182 Foreign de doc H; C 1 -C ₄ -alkyl, branched or unbranched, monosubstituted or polysubstituted or unsubstituted;

or more preferably R ¹ , R ² , R ³ or R ^{4 are} independently selected from

H, F, Cl, Br, I, CH ₃ , C ₂ H ₅ , n-propyl, i-propyl, i-butyl, sec-butyl, n-butyl, t-butyl, CF ₃ , CHF ₂ , SH OH, OCH ₃ , OC ₂ H ₅ , C (O) OH C (O) OCH ₃ or C (O) OC ₂ H ₅ ,

R ⁵ is H,

R ⁷ and R ^{9 are} independently selected from

H, F, Cl, Br, I; C 1 -C 4 -alkyl, branched or unbranched, monosubstituted or polysubstituted or unsubstituted;

OR ¹⁸ or SR ¹⁸ , with R ¹⁸ selected from

H, -CC-alkyl, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; Phenyl, monosubstituted or polysubstituted or unsubstituted,

preferably R ⁷ and R ^{9 are} independently selected from

H, F, Cl, Br, I, CH _3, CF _3, OH, -OCH _3,

in particular R ⁷ and R ^{9 are} selected from H.

Another object of the invention was to provide analgesic substances, in particular NMDA antagonists, available for pain therapy - especially

GRA3182 Foreign countries de.doc chronic and neuropathic pain - suitable. In addition, these substances should have as few side effects as possible, such as nausea, vomiting, dependence, respiratory depression or constipation. Accordingly, the invention provides a tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid of the general formula I,

wherein

R ¹ , R ² , R ³ and R ^{4 are} independently selected from

H or phenyl, monosubstituted or polysubstituted or unsubstituted;

or

R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together

-CR ²³ = CH-CH-, -CR ²³ -CH = CH-, = CR ²³ -CH = CH-CH =, -CR ²³ = CH-CH = CH-, -CH = CR ²³ -CH = CH- or = CH-CR ²³ = CH-CH = form, with R ²³ selected from H, F, Cl, Br, I, OH or CC ₄ alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted;

R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently selected from

H, F, Cl, Br, I; d-Cio-alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -Cιo-alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted;

GRA3182 Foreign countries de.doc OR ^18, OC (O) R ^18, OC (S) R ^18, C (O) R ^18, C (0) OR ^18, C (S) R ^18, C (S) OR ^18, SR ^18, S ( O) R ¹⁸ or S (O ₂ ) R ¹⁸ , wherein R ^{18 is} selected from

H; CrCio-alkyl, C ₂ alkenyl or C ₂ -Cι _{0 0} -Cι alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

NR ¹⁹ R ²⁰ , NR ¹⁹ C (O) R ²⁰ , C (NR ¹⁹ ) NR ²⁰ R ²¹ NR ¹⁹ C (S) R ²⁰ ,

C (S) NR ¹⁹ R ²⁰ or C (S) NR ¹⁹ NR ²⁰ R ²¹ or S (O ₂ ) NR ¹⁹ R ²⁰ , wherein R ¹⁹ , R ²⁰ and R ^{21 are} independently selected from H, O; C ₁ -C ₈ -alkyl, C ₂ -d ₈ -alkenyl or C ₂ -C ₁₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case simple or polysubstituted or unsubstituted; Aryl or

Heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted;

or

R ¹⁹ and R ²⁰ or R ²⁰ and R ²¹ together form a C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, mono- or polysubstituted

GRA3182 Foreign countries de.doc substituted or unsubstituted, form or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; or

optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, in particular the physiologically tolerable

Salts, or in the form of their solvates, especially the hydrates.

A preferred subject of the application is accordingly a tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid according to the invention according to general formula I, in which

R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently selected from

H, F, Cl, Br, I; CC ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted;

OR ¹⁸ , C (O) R ¹⁸ , C (O) OR ¹⁸ or SR ¹⁸ , wherein R ^{18 is} selected from H; dC ₄ -AlkyI, branched or unbranched, mono- or polysubstituted or unsubstituted; Aryl, monosubstituted or polysubstituted or unsubstituted,

preferably R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently selected from

H, F, Cl, Br, I; C 1 -C 4 -alkyl, branched or unbranched, monosubstituted or polysubstituted or unsubstituted;

GRA3182 Foreign countries de.doc OR ¹⁸ or SR ¹⁸ , with R ¹⁸ selected from

H, C 1 -C ₄ -alkyl, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; Phenyl, monosubstituted or polysubstituted or unsubstituted,

in particular R, R, R and R are selected independently of one another

H, F, Cl, Br, I; CH ₃ , CF ₃ , t-butyl, i-butyl, OH, -OCH ₃ , -OCF ₃ , -

SCH ₃ , -O-phenyl,

particularly preferred

R ⁷ and R ^{9 are} H and R ⁸ and R ^{10 are} Cl.

The 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention have a marked analgesic effect and are also NMDA antagonists which attack selectively at the glycine binding site.

A preferred subject matter of the application is a tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to the invention represented by the general formulas I or VI in which the compound is in the form of its alkali metal salts, preferably Potassium or sodium salts present.

The substituted tetra-hydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives according to the invention are toxicologically harmless, so that they are suitable as pharmaceutical active substance in medicaments.

Another object of the invention is therefore also a medicament containing as active ingredient at least one inventive substituted tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to the

GRA3182 Foreign de doc general formulas I or VI in the illustrated form or in the form of the acid or base or in the form of its salts, in particular the physiologically tolerated salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; and optionally containing suitable additives and / or adjuvants and / or optionally further active ingredients.

The medicaments according to the invention can be administered as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, patches or aerosols and contain, in addition to at least one substituted tetrahydro-7-oxa derivative according to the invention. 5-aza-benzo [c] fluorene-6-carboxylic acid derivative, depending on the galenic form, optionally carrier materials, fillers, solvents, diluents, dyes and / or binders. The choice of excipients and the amounts to be used depend on whether the drug is oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or topical, for example on skin infections, mucous membranes and on the eyes, to be applied. For oral administration, preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable, for parenteral, topical and inhalative administration solutions, suspensions, readily reconstitutable dry preparations and sprays. Substituted tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives according to the invention in a depot in dissolved form or in a plaster, optionally with the addition of skin penetration-promoting agents, are suitable percutaneous administration preparations. Orally or percutaneously applicable preparation forms, the substituted according to the invention

GRA3182 Foreign countries de.doc Delayed release of tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid derivatives. The amount of drug to be administered to the patient varies depending on the weight of the patient, the mode of administration, the indication and the severity of the disease. Usually, 2 to 500 mg / kg of at least one substituted tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of the general formula I or VI according to the invention are applied.

The substituted tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives according to the invention are preferably used for the treatment of pain, in particular chronic and neuropathic pain, but also in migraine, so that a further subject of the invention is the use of at least one substituted Tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to general formula I or VI in the form shown or in the form of the acid or base or in the form of its salts, in particular the physiologically acceptable salts, or in the form his solvates, especially the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment of pain, in particular neuropathic and / or chronic pain, and / or for the treatment of migraine.

From the affinity to the NMDA receptor, there are further fields of application, since NMDA antagonists are known i.a. have a neuroprotective effect and therefore can also be used well in conditions associated with neurodegeneration and damage, such as Parkinson's disease and Huntington's disease, etc. Further indications of the NMDA antagonists according to the invention are

GRA3182 Foreign countries de.doc Epilepsy, glaucoma, osteoporosis, ototoxicity, withdrawal symptoms associated with alcohol and / or drug abuse, stroke, and related cerebral ischaemias, cerebral infarctions, cerebral edema, hypoxia, anoxia, as well as anxiolysis and anesthesia. Another object of the invention is therefore the use of at least one substituted tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to general formula I or VI according to the invention; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment / prophylaxis of / in epilepsy, Parkinson's disease, Huntington's disease, glaucoma, ototoxicity, withdrawal symptoms in alcohol and / or drug abuse, stroke, cerebral ischaemias, cerebral infarctions, cerebral edema, hypoxia, anoxia and / or anxiolysis and / or anesthesia.

Surprisingly, it has been found that the substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivative according to the invention are also very suitable for other indications, in particular for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea. A further subject of the application is therefore the use of at least one substituted tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to general formula I or VI according to the invention; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates;

GRA3182 Foreign de doc in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea

But in other indications, the compounds of the invention are effective. A further subject of the application is therefore the use of at least one substituted tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to general formula I or VI according to the invention; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment / prophylaxis of schizophrenia, Alzheimer's disease, psychosis due to increased levels of amino acids, AIDS dementia, encephalomyelitis, Tourette's syndrome, perinatal asphyxia, inflammatory and allergic reactions, depression, drug and / or alcohol abuse, gastritis, Diabetes, cardiovascular diseases, respiratory diseases, cough and / or mental illness.

A further subject of the invention is a method for treating a non-human mammal or human that requires treatment of medically relevant symptoms

GRA3182 Foreign de doc Administration of a therapeutically effective dose of a substituted tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of the invention according to general formula I or VI; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; or a drug of the invention. The invention particularly relates to corresponding methods for the treatment of pain, in particular of neuropathic and / or chronic pain and / or for the treatment of migraines for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea, for the treatment / prophylaxis of / in epilepsy, for morbus Parkinson's disease, Huntington's disease, glaucoma, osteoporosis, ototoxicity, withdrawal symptoms in alcohol and / or drug abuse, stroke, cerebral ischemia, cerebral infarctions, cerebral edema, hypoxia, anoxia and / or anxiolysis and / or anesthesia or for the treatment / prophylaxis of / at Schizophrenia, Alzheimer's disease, psychosis due to elevated levels of amino acids, AIDS dementia, encephalomyelitis, Tourette's syndrome, perinatal asphyxia, inflammatory and allergic reactions, depression, drug and / or alcohol abuse, gastritis, diabetes, cardiovascular disease, respiratory disease, cough and / or mental illness.

In the following, the invention will be further illustrated by examples without being limited thereto.

GRA3182 Foreign countries de.doc Examples

The following examples show compounds of the invention as well as their presentation and efficacy studies conducted therewith.

The following information generally applies:

The chemicals and solvents used have been purchased commercially from the traditional suppliers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, etc.) or are synthesized according to general manufacturing methods known to those skilled in the art. In particular, some of the benzofurans, but also other compounds used before the basic synthesis described below as synthesis blocks synthesized by known synthesis procedures 1 The thin-layer chromatographic studies were with HP! ._ Finished plates, silica gel 60 F 254, E. Merck, Darmstadt, carried out. The yields of the compounds produced are not optimized.

The analysis was carried out by ESI mass spectrometry.

The connections are numbered, whereby the information in parentheses always corresponds to the number of the assigned connection.

Example 1: Finding Suitable Catalysts:

a)

The use of Iium triflate as a catalyst in the lino-Diels-Alder reaction of in situ formed 2-aza-1,3-bis with cyclic enol ethers has been described by Sandu et al. (Gadwal, JS Sandhu; Chem. Soc, Perkin Trans. 1 (2000), 2827-2829). A reaction of 2-aza-1, 3-serve with suitable reactants such as olefins or

GRA3182 Foreign countries de.doc heteroaromatic systems has not been described yet.

It was necessary to check whether indium triflate was suitable as a catalyst for the reaction according to the invention (see Examples 2 and 3) and it was surprisingly found that this catalyst is suitable for the direct synthesis of 5,6,6a, 11b-tetrahydro-7-oxa 5-aza-benzo [c] fluorene-6-carboxylic acids could be used. In this case, aniline (1 equivalent), glyoxylic acid (1, 5 equivalents) and benzofuran (3 equivalents) were irradiated with 10 mol% indium triflate as a catalyst in closed vessels with microwaves. In a one-step synthesis, the desired heterocycles could be prepared reproducibly in a few minutes, almost quantitatively and in analytically pure form (Scheme).

Table 1 shows the yields in the preparation of various compounds according to Example 4 (see below).

Catalyst, CH ₃ CN

Micro elle

scheme

GRA3182 Foreign de doc b)

Another possibility for the synthesis of tetrahydroquinolines is the use of heterogeneous catalysts such as polymer-bound Lewis acids or clay minerals. The advantage of these catalysts is the easy separability from the reaction mixture or the separation of unreacted starting materials from the product. Although the 5,6,6a, 1 1 b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acids represent a very poorly soluble class of substance, a method was developed with which the heterocycles can be synthesized using could be prepared from heterogeneous catalysts.

Under the influence of microwave radiation, aniline, glyoxylic acid, benzofuran and montmorillonite were used as KSF

Heterogeneous catalyst to the 5,6,6a, 1 1 b-tetrahydro-7-oxa-5-aza- benzo [c] fluorene-6-carboxylic acids implemented. The solid is filtered off and unreacted starting materials and by-products are removed by washing with the reaction medium, e.g. Acetonitrile, separated. The sparingly soluble product remained bound to the catalyst and could with a polar solvent such. As acetone, are washed out of the montmorillonite. After concentrating the acetone phase and drying in a high vacuum, the product was isolated for analysis. Table 1 shows the yields in the preparation of various compounds according to Example 4 (see below).

GRA3182 Foreign countries de.doc

Table 1: Yields in the three-component synthesis with benzofurans as dienophile.

GRA3182 Foreign countries de.doc Further studies have focused on the utility of transition metal catalysts such as the lanthanide triflates (S.Kobayashi, H. Ishitani, S. Nagayama, Synthesis (1995), 1952-1202).

Ytterbium (III) triflate, scandium (III) triflate, and cerium (IV) triflate could be added to the 5,6,6a, 1 under the reaction conditions described for indium triflate (same equivalents of starting materials, same mol% of catalyst, and exposure to microwave radiation) 1 b-Tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acids are reacted. The work-up and isolation of the products was carried out under identical conditions as described for the reaction of indium (III) triflate. The products were received cleanly. ,

Table 2: Yields in the three-component synthesis with benzofurans as dienophile and transition metal triflates as catalysts.

d) As a fourth possibility for the discovery of new catalysts for the synthesis of 5,6,6a, 1 1 b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acids were some main group salts and Brönstedt Acids.

GRA3182 Foreign countries de.doc Lithium tetrafluoroborate has been used successfully in the reaction of 2-aza-1,3-bis with cyclic enol ethers by Yadav et al. (JS Yadav, BV Subba Reddy, C. Reddy Madhuri, G. Sabitha, Synthesis (2001), 1065-1068 and similarly positive results have been obtained using bismuth (III) salts such as bismuth trichloride (BV Subba Reddy, R. Srinivas, J, S, Yadav, T. Ramalingam, Synth.Commun., 31, 1075-1080 (2001); G. Sabitha, EV Reddy, JS Yadav, Synthesis (2001), 1979-1984, G. Sabitha, E. Venkata Reddy, C. Maruthi, A. Ravi Sankar, Tetrahedron Lett., 43, 1 573-1575 (2002);

G. Sabitha, E. Venkata Reddy, J.S. Yadav, K.V.S. Rama Krishna, A. Ravi Sankar; Tetrahedron Lett. 43, 4029-2032 (2002)) and bismuth (II) triflate (Laurent-Robert, B. Garrigues, J. Dubac, Synlett (2000), 160-1562).

In addition to the main group salts bismuth trichloride, lithium tetrafluoroborate and tin chloride, boric acid under the reaction conditions described above (same equivalents of the starting materials, same mol% catalyst and exposure to microwave radiation). The use of boric acid could yield some advantages in the work-up of the reaction mixture over all other catalysts described. Boric acid is very soluble in water and not harmful to the environment and could therefore easily be washed out with water when isolating the products.

Surprisingly, the desired 5,6,6a, 1 1 b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acids could also be isolated in good yields and high purity in these reactions (Table 3).

GRA3182 Foreign de doc

TABLE 3 Yields in the three-component synthesis with benzofurans as dienophile and main group salts as catalysts.

Example 2: Synthesis of Benzofuran THCs

General

The chemicals and solvents used were purchased commercially from the traditional suppliers (Acros, Aldrich, Avocado, Fluka, Lancaster, Merck).

The reactions under microwave irradiation are carried out in a laboratory microwave of the make MLS ETHOS 600 from MLS GmbH (D-88299 Leutkirch, Auenweg 37, Germany). Thin-layer chromatography was performed on RP-8-TLC plates with fluorescence indicator (Merck, Darmstadt) with the following

Eluent mixture carried out: methanol / water / NaCl; 12: 5: 3rd The detection was carried out by staining in the iodine chamber.

The 1 H NMR spectra were measured using the Rheinstetten 300 MHz spectrometer (Avance DPX 300 MHz) from Bruker Analytik GmbH, Silberstreifen 4, D-76287.

GRA3182 Foreign countries de.doc The ESI-MS spectra were measured with a device from Thermoquest, Analyst Systems GmbH, Boschring 12, D-63329 Egelsbach (device name Finnigan LCQ).

GC analysis was carried out using the HP 6890 gas chromatograph (with PTV injector) and a Hewlett-Packard coupled mass detector 5973. (Mass Selective Detector).

The benzofurans used (5-methylbenzofuran, 5-phenylbenzofuran, 5-methoxybenzofuran, 5-chlorobenzofuran, 5-bromobenzofuran, 5-ethoxycarbonylbenzofuran, 7-methylbenzofuran, 7-ethylbenzofuran, 7-phenylbenzofuran, 7-methoxybenzofuran, 7-chlorobenzofuran, (naphthofuran ?, 4,6-dimethylbenzofuran, 4,7-dimethylbenzofuran, 5,7-dimethylbenzofuran, 5-chloro-6-methylbenzofuran) were prepared according to the procedure described by Barker et al. (P. Barker, P. Finke, K. Thompson, Synthetic Communications 19, 257-265 (1994) or (4-methylbenzofuran, 6-methylbenzofuran) according to the method of Acardi et al. (A. Acardi, F. Marinelli, S. Cacchi, Synthesis (1986), 749-751 and A. Arcadi, S. Cacchi, M. Del Rosario, G. Fabrizi, F. Marinelli, J. Org. Chem. 61, 9280-9288 (1996)).

Example 3:

Synthesis of THC-Benzofurans by Three-Compound Synthesis

General working instructions

a) Process 1: salts as catalyst

GRA3182 Foreign countries de.doc 3,5-Dichloroaniline (10 mmol) and glyoxylic acid hydrate (15 mmol) were dissolved in 20 ml acetonitrile, catalyst (10 mol%) and the benzofuran (30 mmol) added (sealable, pressure stable Teflon tube) and within 90 seconds heated in the microwave with 800 watts of power to 50 ° C and left for ten minutes at this temperature. After the reaction, the vessel was placed in ice-water, carefully opened and filtered off. The solid was washed three times with 30 ml of acetonitrile and dried in a high vacuum. A colorless crystal mass was obtained, which was reagent grade. From the mother liquor and the washing phases, further substance could be isolated after rotation and reprecipitation from acetonitrile.

b) Method 2: montmorillonite KSF as catalyst

3,5-dichloroaniline (10 mmol), glyoxylic acid hydrate (15 mmol) and benzofuran (30 mmol) were dissolved in 20 ml acetonitrile, montmorillonite KSF (3.5 g / 63.3 mmol based on aniline) was added (sealable, pressure-stable Teflon Vial) and heated within 90 seconds in the microwave with 800 watts of power to 50 ° C and left for ten minutes at this temperature. After the reaction, the vessel was placed in ice-water, gently opened, filtered off and the montmorillonite was washed with 30 ml of acetonitrile. Subsequently, the montmorillonite is washed with 50 ml of acetone to elute the product bound to the catalyst. The acetone is removed on a rotary evaporator and the resulting solid dried under high vacuum. The product was obtained analytically pure as a colorless solid. From the acetonitrile phases, further material could be isolated after rotation and reprecipitation from acetonitrile.

GRA3182 Foreign de doc The characterization of the isolated products was carried out by ^ H NMR spectroscopy and ESI mass spectrometry.

Example 4): According to the compounds according to the invention, prepared in Examples 2 and 3, with analysis data:

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

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.89 ppm (s, 1H, CH); 5.22 ppm (d, 1H, J = 9.83 Hz, CH); 5.71 ppm (d, 1H, J = 10.58 Hz, CH); 6.72-6.75 ppm (m, 2H, 2 x aryl-CH); 6.90 ppm (s, 1H, aryl-CH); 7.01 ppm (s, 1H, aryl-CH); 7.07 ppm (t, 1H, J = 7.55 Hz, aryl CH); 7.33 ppm (d, 1H, J = 7.55 Hz, aryl-CH); 13.26 ppm (s (broad), 1H, COOH).

ESI-MS for C16H11CI2NO3, calculated: 338.18 g / mol; found (positive mode): 336.0 (MH ⁺ ), 290.0 (MH ⁺ -CO ₂ ), 218.0 (MH ⁺ - C ₈ H ₆ O); (negative mode): 334.0 (MH). ,

Connection 2)

1,3-Bis- (trifluoromethyl) -5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ¹ H-NMR (de-DMSO / TMSext.) : δ = 3.81 ppm (d, 1H, J = 3.02 Hz,

CH);

5.28 ppm (d, 1H, J = 9.79 Hz, CH); 5.83 ppm (d, 1H, J = 10.55

Hz, CH);

6.42 ppm (s, 1H, NH), 6.69-6.75 ppm (m, 3H, 3 x aryl-H); 7.06 ppm (m, 1H, J = 4.52 Hz, aryl-H); 7.37 ppm (s, 1H, aryl-H); 7.64 ppm (s, 1H, aryl H); 13, 27 ppm (s (broad), 1H, COOH).

GRA3182 Foreign countries de.doc ESI-MS Calcd for Cι ₈ HιιFβN0 _3l calculated: 403.28 g / mol; found (positive mode): 404.0 (MH ⁺ ), 358.4 (MH ⁺ -CO ₂ ); (negative mode): 402.0 (MH), 358.1 (MH-C0 ₂ ).

Compound 3)

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

¹ H-NMR (de-DMSO / TMSext.): Δ = 2.07 ppm (s, 3H, 8-CH3); 3.85 ppm (d, 1H, J = 2.64 Hz, CH); 5.20 ppm (d, 1H, J = 10.17 Hz,. CH); 5.70 ppm (d, 1H, J = 10.55 Hz, CH); 6.09 ppm (s, 1H, NH); 6.63 ppm (t, 1H, J = 7.53 Hz, aryl-H); 6.89 ppm (d, 1H, J = 1.88 Hz, aryl-H); 6.91 ppm (s, 1H, aryl H); 6.98 ppm (d, 1H, J = 1.89 Hz, aryl-H); 7.12 ppm (d, 1H, J = 7.54 Hz, aryl-H). ESI-MS for C ₁₇ Hι ₃ Cl ₂ NO ₃ , calculated: 350.20 g / mol; found (positive mode): 350.0 (MH ⁺ ), 304.2 (MH ⁺ -CO ₂ ); 218.0 (MH ⁺ - C ₉ H ₈ O); (negative mode): 348.1 (MH), 303.9 (MH-CO ₂ ).

Connection 4)

1, 3-dichloro-8-ethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza be ^'nzo [c] fluoren-6-carboxylic acid

¹ H-NMR (de-DMSO / TMSext.): Δ = 1.11 ppm (t, 3H, J = 7.54 Hz,

CH ₃ );

2.46 ppm (m, 2H, J = 7.16 Hz, CH ₂ ); 3.86 ppm (d, 1H, J = 2.63

Hz, CH); 5.23 ppm (d, 1H, J = 10.18 Hz, CH); 5.70 ppm (d, 1H, J = 10.55

Hz, CH); 6.08 ppm (s, 1H, NH); 6.65 ppm (t, 1H, J = 7.53 Hz,

Aryl-H);

6.89 ppm (d, 1H, J = 2.26 Hz, aryl-H); 6.92 ppm (s, 1H, aryl-H);

6.98 ppm (d, 1H, J = 1.88 Hz, aryl-H); 7.09 ppm (d, 1H, J = 7.53 Hz, aryl-H); 13.20 ppm (s (broad), 1H, CO ₂ H).

GRA3182 Foreign countries de.doc ESI-MS for C ₁₈ H ₁₅ Cl ₂ NO ₃ , calculated: 364.23 g / mol; found (positive mode): 364.1 (MH ⁺ ), 318.3 (MH ⁺ -CO ₂ ); 218.0 (MH ⁺ - CιoH ₁₀ O); (negative mode): 362.2 (MH), 318.2 (MH-CO ₂ ).

Compound 5)

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

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.93 ppm (d, 1H, J = 2.64 Hz,

CH); 5.30 ppm (d, 1H, J = 10.17 Hz, CH); 5.76 ppm (d, 1H, J = 10.55

Hz, CH); 6.19 ppm (s, 1H, NH); 6.85 ppm (t, 1H, J = 7.54 Hz,

Aryl-H);

6.98 ppm (d, 1H, J = 1.88 Hz, aryl-H); 7.02 ppm (d, 1H, J = 1.89

HZ, aryl-H); 7.23 - 7.41 ppm (m, 6H, 6 x aryl-H); 7.66 ppm (d, 1H, J = 7.16 Hz, aryl-H); 13.36 ppm (s (broad), 1H, COOH).

ESI-MS for C ₂₂ Hι ₅ CI ₂ NO ₃ , calculated: 412.28 g / mol; found

(positive mode): 412.1 (MH ⁺ ), 366.4 (MH ⁺ -CO ₂ ); 218.0 (MH ⁺ -

CH ₁₀ O); (negative mode): 410.4 (MH), 366.2 (MH-CO ₂ ).

Compound 6)

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

¹ H NMR (d ₆ -DMSO / TMS _ex t.): Δ = 3.74 ppm (s, 3H, OCH ₃ ); 3.88 ppm (d, 1H, J = 2.26 Hz, CH); 5.22 ppm (d, 1H, J = 10.18 Hz, CH); 5.73 ppm (d, 1H, J = 10.18 Hz, CH); 6.13 ppm (s, 1H, NH);

6.68 ppm (t, 1H, J = 7.53 Hz, aryl-H); 6.76 ppm (s, 1H, aryl-H);

6.78 ppm (s, 1H, aryl-H); 6.87 ppm (d, 1H, J = 1.88 Hz, aryl-H);

6.92 ppm (s, 1H, aryl-H); 6.94 ppm (s, 1H, aryl-H); 7.01 ppm (d,

1H, J = 2.26 Hz, aryl-H); 13.25 ppm (s (broad), 1H, COOH). ESI-MS for Cι ₇ Hι ₃ CI ₂ NO ₄ , calculated: 366.2 g / mol; found

(positive mode): 366.0 (MH ⁺ ), 320.1 (MH ⁺ -CO ₂ ); 218.0 (MH ⁺ -

C ₉ H ₈ O ₂ ); (negative mode): 364.2 (MH), 320.3 (MH-C0 ₂ ).

G A3182 Foreign de doc Connection 7)

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

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.92 ppm (d, 1H, J = 2.27 Hz, CH);

5.33 ppm (d, 1H, J = 10.17 Hz, CH); 5.83 ppm (d, 1H, J = 10.18 Hz, CH); 6.18 ppm (s, 1H, NH); 6.76 ppm (t, 1H, J = 7.54 Hz, aryl-H);

6.92 ppm (d, 1H, aryl-H); 7.02 ppm (d, 1H, J = 1.50 Hz, aryl-H); 7.16 ppm (d, 1H, J = 7.92 Hz, aryl-H); 7.25 ppm (d, U, J = 7.53 Hz, aryl-H); 13.37 ppm (s (broad), 1H, COOH). ESI-MS for C ₇ H ₁₃ Cl ₂ NO ₄ , calculated: 370.62 g / mol; found (positive mode): 372.1 (MH ⁺ ); (negative mode): 368.0 (MH), 326.0 (MH-CO ₂ ).

Compound 8)

7,9-dichloro-6b, 11,12,12a-tetrahydro-13-oxa-11-aza-dibenzo [a, g] fluorene-12-carboxylic acid ¹ H-NMR (de-DMSO / TMSext.): Δ = 3.98 ppm (d, 1H, J = 2.64 Hz,

CH);

5.42 ppm (d, 1H, J = 10.55 Hz, CH); 5.06 ppm (d, 1H, J = 10.55

Hz, CH); 6.16 ppm (s, 1H, NH); 6.93 ppm (d, 1H, J = 1.88 Hz,

Aryl-H); 7.00 ppm (d, 1H, J = 2.27 Hz, aryl-H); 7.32 ppm (d, 1H, J = 8.67 Hz, aryl-H); 7.42 ppm (s, 1H, aryl-H); 7.44-7.47 ppm

(m, 2H, 2 x aryl-H); 7.75-7.83 ppm (m, 2H, 2 x aryl-H); 13.37 ppm (s (broad), 1H, COOH).

ESI-MS for C ₂ oHι ₃ CI ₂ NO ₃ , calculated: 386.24 g / mol; found

(positive mode): 386.0 (MH ⁺ ), 340.2 (MH ⁺ -CO ₂ ), 217.9 (MH ⁺ - C ₁₂ H ₈ O); (negative mode): 384.3 (MH), 340.2 (MH-CO ₂ ).

GRA3182 Foreign countries de.doc Compound 9)

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

¹ H-NMR (de-DMSO / TMSext.): Δ = 2.14 ppm (s, 3H, 10-CH _3); 3.86 ppm (d, 1H, J = 2.26 Hz, CH); 5.18 ppm (d, 1H, J = 9.79 Hz, CH); 6.68 ppm (d, 1H, J = 10.17 Hz, CH); 6.09 ppm (s, 1H, NH); 6.60 ppm (d, 1H, J = 8.29 Hz, aryl-H); 6.87 ppm (d, 1H, J = 8.66 Hz, aryl-H); 6.90 ppm (d, 1H, J = 2.26 Hz, aryl-H); 7.00 ppm (d, 1H, J = 1.89 Hz, aryl-H); 7.11 ppm (s, 1H, aryl-H); 13.24 ppm (s (broad), 1H, COOH).

ESI-MS for C ₁₇ H ₁₃ Cl ₂ Nθ ₃ , calculated: 350.20 g / mol; found (positive mode): 350.1 (MH ⁺ ), 304.2 (MH ⁺ -CO ₂ ), 218.0 (MH ⁺ - C ₉ H ₈ O); (negative mode): 348.1 (MH), 312.1 (MH-CO ₂ ).

Connection 10)

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

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.95 ppm (d, 1H, J = 2.26 Hz,

CH); 5.29 ppm (d, 1H, J = 9.80 Hz, CH); 5.79 ppm (d, 1H, J = 10.17 Hz, CH);

6.19 ppm (s, 1H, NH); 6.85 ppm (d, 1H, J = 8.29 Hz, aryl-H); 6.96 ppm (d, 1H, J = 1.89 Hz, aryl-H); 7.04 ppm (d, 1H, J = 1.88 Hz, aryl-H); 7.28 ppm (t, 1H, J = 6.78 Hz, aryl H); 7.37-7.45 ppm (m, 5H, 5x aryl-H); 7.58 ppm (s, 1H, aryl-H); 13.36 ppm (s (broad), 1H, COOH).

ESI-MS for C ₂₂ Hι ₅ CI ₂ NO ₃ , calculated: 412.28 g / mol; found (positive mode): 412.3 (MH ⁺ ), 366.3 (MH ⁺ -CO ₂ ), 218.0 (MH ⁺ - C ₁₄ H ₁₀ O); (negative mode): 410.1 (MH), 366.1 (MH-CO ₂ ).

Connection 11)

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

GRA3182 Foreign de doc ¹ H-NMR (de-DMSO / TMSext.): Δ = 3.61 ppm (s, 3H, 10-OCH ₃ ); 3.88 ppm (d, 1H, J = 2.64 Hz, CH); 5.18 ppm (d, 1H, J = 10.17 Hz, CH); 5.68 ppm (d, 1H, J = 10.18 Hz, CH); 6.14 ppm (s, 1H, NH); 6.65 ppm (s, 2H, 2 x aryl-H); 6.91 ppm (s, 2H, 2 x aryl-H); 7.02 ppm (d, 1H, J = 1.51 Hz, aryl-H); 13.27 ppm (s (broad), 1H, COOH).

ESI-MS for C ₁₇ H ₁₃ Cl ₂ N03, calculated: 366.19 g / mol; found (positive mode): 366.0 (MH ⁺ ), 320.1 (MH ⁺ -CO ₂ ); (negative mode): 365.4 (MH).

Connection 12)

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

¹ H-NMR (de-DMSO / TMSext.): Δ = 1.27 ppm (t, 3H, J = 6.78 Hz, CH ₃ );

3.94 ppm (d, 1H, J = 2.26 Hz, CH); 4.21 ppm (m, 1H, J = 1.88

Hz, J = 7.54 Hz, OCH ₂ ); 4.24 ppm (m, 1H, J = 1.88 Hz, J = 7.16

Hz, OCH ₂ );

5.28 ppm (d, 1H, J = 10.18 Hz, CH); 5.84 ppm (d, 1H, J = 10.18 Hz, CH); 6.18 ppm (s, 1H, NH); 6.85 ppm (d, 1H, J = 8.29 Hz,

Aryl-H); 6.97 ppm (d, 1H, J = 1.88 Hz, aryl-H); 7.03 ppm (d, 1H,

J = 1.88 Hz, aryl-H); 7.75 ppm (d, 1H, J = 8.29 Hz, aryl-H); 7.93 ppm (s, 1H, aryl-H); 13.36 ppm (s (broad), 1H, COOH).

ESI-MS for C ₁₉ Hι ₅ Cl ₂ NO ₅ , calculated: 408.24 g / mol; found (negative mode): 407.0 (MH), 365.0 (MHC ₂ H ₅ O).

Connection 13)

1, 3,10-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ¹ H-NMR (de-DMSO / TMSext.): Δ = 3.90 ppm (d, 1H, J = 1.89 Hz, CH); 5.24 ppm (d, 1H, J = 9.80 Hz, CH); 5.76 ppm (d, 1H, J = 10.55 Hz, CH);

GRA3182 Foreign countries de.doc 6.17 ppm (s, 1H, NH); 6.77 ppm (d, 1H, J = 8.66 Hz, aryl-H); 6.93 ppm (d, 1H, J = 1.89 Hz, aryl-H); 7.03 ppm (d, 1H, J = 1.88 Hz, aryl-H); 7.11 ppm (d / d, 1H, J = 1.88 Hz, J = 8.29 Hz, aryl-H); 7.26 ppm (s, 1H, aryl-H); 13.38 ppm (s (broad), 1H, COOH). ESI-MS for C16H10Cl3NO3, calculated: 370.62 g / mol; found

(negative mode): 370.1 (MH), 332.2 (MH-CO ₂ ).

Connection 14)

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

¹ H NMR (d ₆ -DMSO / TMS _ext .): Δ = 3.90 ppm (d, 1H, J = 2.63 Hz,

CH);

5.25 ppm (d, 1H, J = 10.17 Hz, CH); 5.76 ppm (d, 1H, J = 10.18

Hz, CH); 6.17 ppm (s, 1H, NH); 6.73 ppm (d, 1H, J = 8.29 Hz, aryl-H); 6.93 ppm (d, 1H, J = 2.26 Hz, aryl-H); 7.04 ppm (d, 1H,

J = 2.26 Hz, aryl-H); 7.23 ppm (d / d, 1H, J = 2.26 Hz, J = 8.67 Hz,

Aryl-H); 7.38 ppm (s, 1H, aryl-H); 13.33 ppm (s (broad), 1H,

COOH).

ESI-MS for C ₁₆ HιoBrCl ₂ Nθ ₃ , calculated: 415.07 g / mol; found (positive mode): 415.9 (MH ⁺ ), 370.0 (MH ⁺ -CO ₂ ); (Negative mode):

414.1 (MH), 370.0 (MHCO ₂ ).

Compound 15)

1, 3-dichloro-8,10-dimethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid

¹ H NMR (d ₆ -DMSO / TMSeχt.): Δ = 2.02 ppm (s, 3H, CH ₃ ); 2.10 ppm (s, 3H, CH _3); 3.87 ppm (d, 1H, J = 2.63 Hz, CH); 5.17 ppm (d, 1H, J = 10.17 Hz, CH); 5.66 ppm (d, 1H, J = 10.17 Hz, CH); 6.09 ppm (s, 1H, NH); 6.72 ppm (s, 1H, aryl-H); 6.89 ppm (s, 1H, aryl H); 6.93 ppm (d, 1H, J = 1.89 Hz, aryl-H); 6.99 ppm (d, 1H, J = 1.88 Hz, aryl-H); 13.23 ppm (s (broad), 1H, COOH).

GRA3182 Foreign countries de.doc ESI-MS for C ₁₈ Hι ₅ CI ₂ NO ₃ , calculated: 364.23 g / mol; found (positive mode): 364.2 (MH ⁺ ), 318.3 (MH ⁺ -CO ₂ ), 218.0 (MH + -Cι ₀ H ₁₀ O); (negative mode): 362.3 (MH), 318.1 (MH-CO ₂ ).

Connection 16)

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

¹ H-NMR (de-DMSO / TMSext.): Δ = 1.84 ppm (s, 3H, CH ₃ ); 2.02 ppm

(s, 3H, CH _3); 3.58 ppm (d, 1H, J = 3.77 Hz, CH); 5.30 ppm (d, 1H, J = 9.80 Hz, CH); 5.64 ppm (d, 1H, J = 9.79 Hz, CH); 5.97 ppm (s, 1H, NH); 6.39 ppm (d, 1H, J = 7.54 Hz, aryl-H); 6.77 ppm

(d, 1H, J = 7.53 Hz, aryl-H);

6.98 ppm (d, 1H, J = 1.88 Hz, aryl-H); 7.01 ppm (d, 1H, J = 1.89

Hz, aryl-H); 13.11 ppm (s (broad), 1H, COOH). ESI-MS for C ₁₈ Hι ₅ CI ₂ NO ₃ , calculated: 364.23 g / mol; found

(negative mode): 362.4 (MH), 318.1 (MH-CO ₂ ).

Connection 17)

1, 3-dichloro-9,11-dimethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza be ^'nzo [c] fluoren-6-carboxylic acid

¹ H-NMR (d6-DMSO / TMS _e χt.): Δ = 1.85 ppm (s, 3H, CH ₃ ); 2.13 ppm (s, 3H, CH _3); 3.57 ppm (d, 1H, J = 3.76 Hz, CH); 5.23 ppm (d, 1H, J = 9.79 Hz, CH); 5.64 ppm (m, 1H, J = 10.17 Hz, CH); 5.97 ppm (s, 1H, NH); 6.30 ppm (s, 1H, aryl-H); 6.35 ppm (s, 1H, aryl H); 6.97 ppm (d, 1H, J = 1.88 Hz, aryl-H); 7.05 ppm (d, 1H, J = 1.88 Hz, aryl-H); 13.10 ppm (s (broad), 1H, COOH). ESI-MS for Cι ₈ Hι ₅ C! ₂ NO ₃ calculated: 364.23 g / mol; found (positive mode): 336.2 (MH ⁺ -K), 290.2 (MH ⁺ -CO ₂ ); found (negative mode): 362.3 (MH).

GRA3182 Foreign countries de.doc Compound 18)

1,3,10-trichloro-9-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid

¹ H-NMR (de-DMSO / TMSext.): Δ = 2.20 ppm (s, 3H, 9-CH ₃ ); 3.92 ppm (d, 1H, J = 2.26 Hz, CH); 5.20 ppm (d, 1H, J = 10.17 Hz, CH); 5.73 ppm (d, 1H, J = 9.79 Hz, CH); 6.17 ppm (s, 1H, NH); 6.78 ppm (s, 1H, aryl-H); 6.95 ppm (d, 1H, J = 1.89 Hz, aryl-H); 7.03 ppm (d, 1H, J = 1.89 Hz, aryl-H); 7.24 ppm (s, 1H, aryl-H); 13.31 ppm (s (broad), 1H, COOH). ESI-MS for C ₁₇ H ₁₂ Cl ₃ NO ₃ , calculated: 384.65 g / mol; found (negative mode): 384.2 (MH), 338.4 (MH-CO ₂ ).

Connection 19)

1, 3-dichloro-9-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid

Connection 20)

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

Example 4: Compounds from the synthesis of alkali salts with analytical data

Connection 21)

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

Yield: 100% of theory

¹ H NMR (d ₆ -DMSO / TMS _ext .): Δ = 3.32 ppm (m, 1H, CH); 5.03 ppm (d, 1H, J = 9.82 Hz, CH); 5.68 ppm (d, 1H, J = 9.82 Hz, CH); 5.79 ppm (s, 1H, NH); 6.63 ppm (d, 1H, J = 8.31 Hz, aryl-H); 6.68 ppm

GRA3182 Foreign countries de.doc (t, 1H, J = 7.56 Hz, aryl-H); 6.74 ppm (s, 1H, aryl-H); 6.89 ppm (s, 1H aryl-H); 7.03 ppm (t, 1H, J = 7.56 Hz, aryl-H); 7.38 ppm (d, 1H, J = 7.56 Hz, aryl-H).

ESI-MS for C ₁₆ HιoCl ₂ LiNO ₃ , calculated: 3342.10 g / mol; found (negative mode): 334.3 (MH-Li).

Connection 22)

1, 3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt. Yield: 100% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.32 ppm (m, 1H, CH); 5.05 ppm (d, 1H, J = 9.82 Hz, CH); 5.69 ppm (d, 1H, J = 9.82 Hz, CH); 5.76 ppm (s, 1H, NH); 6.63 ppm (d, 1H, J = 8.31 Hz, aryl-H); 6.67 ppm (t, 1H, J = 7.56 Hz, aryl-H); 6.73 ppm (s, 1H, aryl-H); 6.91 ppm (s, 1H, aryl H); 7.03 ppm (t, 1H, J = 8.31 Hz, aryl-H); 7.39 ppm (d, 1H, J = 7.56 Hz, aryl-H).

ESI-MS for C ₈ H ₁₀ Cl ₂ KNO ₃ , calculated: 375.28 g / mol; found (negative mode): 334.3 (MIC), 290.2 (MIC-CO ₂ ).

Connection 23)

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

Yield: 94% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.47 ppm (s, 1H, CH); 5.09 ppm (d, 1H, J = 9.82 Hz, CH); 5.69 ppm (d, 1H, J = 9.82 Hz, CH); 5.90 ppm (s, 1H, NH); 6.68 ppm (d, 1H, J = 8.31 Hz, aryl-H); 6.71 ppm

(d, 1H, J = 7.55 Hz, aryl-H); 6.80 ppm (s, 1H, aryl-H); 6.95 ppm

(s, 1H, aryl-H); 7.05 ppm (t, 1H, J = 7.56 Hz, aryl-H); 7.37 ppm

(d ^' , 1H, J = 7.56 Hz, aryl-H). ESI-MS for C ₁₈ Hι ₀ CI ₂ KNO ₃ , calculated: 375.28 g / mol; found

(negative mode): 334.3 (MIC), 290.2 (MIC-CO ₂ ).

GRA3182 Foreign countries de.doc Connection 24)

1,3-Bis- (trifluoromethyl) -5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt

Yield: 98% of theory ¹ H-NMR (de-DMSO / TMSext.): Δ = 3.14 ppm (s, 1H, CH); 5.13 ppm

(d, 1H, J = 9.82 Hz, CH); 5.79 ppm (d, 1H, J = 10.57 Hz, CH);

6.10 ppm (s, 1H, NH); 6.63 ppm (m, 2H, aryl-H); 6.70 ppm (d,

1H, J = 7.56 Hz, aryl-H); 7.01 ppm (t, 1H, J = 7.56 Hz, aryl-H);

7.20 ppm (s, 1H, aryl-H); 7.55 ppm (s, 1H, aryl-H). ESI-MS for Ci ₈ H ₁₀ F ₆ NNaO ₃ , calculated: 425.26 g / mol; found

(negative mode): 402.2 (MH-Na), 358.3 (MH-Na-CO ₂ ).

Connection 25)

1,3-Dichloro-8-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt. Yield: 94% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 2.06 ppm (s, 3H, CH ₃ ); 3.31 ppm (d, 1H, CH); 5.02 ppm (d, 1H, J = 10.58 Hz, CH); 5.67 ppm (d, 1H, J = 10.57 Hz, CH); 5.74 ppm (s, 1H, NH); 6.57 ppm (t, 1H, J = 7.56 Hz, aryl-H); 6.70 ppm (s, 1H, aryl-H); 6.85 ppm (d, 1H, J = 7.55 Hz, aryl H); 6.87 ppm (s, 1H, aryl); 7.22 ppm (d, 1H, J = 7.55 Hz, aryl-H).

ESI-MS for C ₁₇ Hι ₃ Cl ₂ NNaO ₃ , calculated: 373.29 g / mol; found (positive mode): 352.1 (MH ⁺ -Na), 304.3 (MH ⁺ -Na-CO ₂ ); (negative mode): 348.2 (MH-Na), 304.3 (MH-Na-CO ₂ ).

Connection 26)

1,3-Dichloro-8-ethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt. Yield: 100% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 1.09 ppm (t, 3H, J = 7.56 Hz, CH ₃ ); 2.44 ppm (q, 2H, J = 7.56 Hz, CH ₂ ); 3.31 ppm (d, 1H, CH);

GRA3182 Foreign countries de.doc 5.04 ppm (d, 1H, J = 9.82 Hz, CH); 5.68 ppm (d, 1Y, J = 9.82 Hz, CH); 5.75 ppm (s, 1H, NH); 6.60 ppm (t, 1H, J = 7.55 Hz, aryl-H); 6.72 ppm (s, 1H, aryl-H); 6.87 ppm (m, 2H, 2 x aryl-H); 7.19 ppm (d, 1H, J = 7.55 Hz, aryl-H). ESI-MS for C ₈ H ₁₅ Cl ₂ NNaO ₃ , calculated: 364.23 g / mol; found (positive mode): 364.0 (MH ⁺ -Na), 318.3 (MH ⁺ -Na-CO ₂ ); (negative mode): 362.2 (MH-Na), 317.9 (MH-Na-CO ₂ ).

Compound 27) 1,3-Dichloro-8-phenyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt Yield: 94% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.31 ppm (m, 1H, CH); 5.12 ppm (d, 1H, J = 9.82 Hz, CH); 5.73 ppm (d, 1H, J = 9.82 Hz, CH); 5.83 ppm (s, 1H, NH); 6.78 ppm (t, 2H, J = 7.55 Hz, aryl-H); 6.93 ppm

(s, 1H, aryl-H); 7.25 ppm (d, 1H, J = 7.55 Hz, aryl-H); 7.29 ppm (t, 1H, J = 7.55 Hz, aryl-H); 7.32 ppm (d, 1H, J = 7.55 Hz, aryl H); 7.37 ppm (t, 2H, J = 7.55 Hz, aryl-H); 7.69 ppm (d, 2H, J = 8.31 Hz, aryl-H). ESI-MS for C ₂₂ Hι ₄ Cl ₂ NNaO ₃ , calculated: 434.28 g / mol; found (negative mode): 410.3 (MH-Na), 366.3 (MH-Na-CO ₂ ).

Connection 28)

1,3-Dichloro-8-methoxy-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt. Yield: 100% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.31 ppm (m, 1H, CH); 3.71 ppm (s, 3H, OCH ₃ ); 5.06 ppm (d, 1H, J = 9.82 Hz, CH); 5.69 ppm (d, 1H, J = 9.82 Hz, CH); 5.81 ppm (s, 1H, NH); 6.63 ppm (t, 1H, J = 7.56 Hz, aryl-H); 6.74 ppm (m, 2H, 2 x aryl-H); 6.91 ppm (s, 1H, aryl H); 6.99 ppm (d, 1H, J = 7.56 Hz, aryl-H).

GRA3182 Foreign countries de.doc ESI-MS for C ₁₇ H ₁₂ Cl ₂ NNaO 4, calculated: 366.20 g / mol; found (negative mode): 364.1 (MH-Na), 320.0 (MH-Na-CO ₂ ).

Compound 29) 1, 3,8-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-

6-carboxylic acid, sodium salt

Yield: 95% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.31 ppm (m, 1H, CH); 5.14 ppm

(d, 1H, J = 9.82 Hz, CH); 5.78 ppm (d, 1H, J = 9.82 Hz, CH); 5.80 ppm (s, 1H, NH); 6.70 ppm (t, 1H, J = 7.55 Hz, aryl-H); 6.73 ppm

(d, 1H, J = 1.51 Hz, aryl-H); 6.92 ppm (d, 1H, J = 2.27 Hz, aryl-

H); 7.11 ppm (d, 1H, J = 7.55 Hz, aryl H); 7.35 ppm (d, 1H, J =

7.55 Hz, aryl H).

ESI-MS for C ₁₇ H ₁₂ Cl ₂ NNaO ₄ , calculated: 366.20 g / mol; found (negative mode): 364.1 (MH-Na), 320.0 (MH-Na-CO ₂ ).

Connection 30)

7,9-dichloro-6b, 11,12,12a-tetrahydro-13-oxa-11-aza-dibenzo [a, g] fluorene-12-carboxylic acid, sodium salt Yield: 100% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.31 ppm (m, 1H, CH); 5.24 ppm (d, 1H, J = 9.82 Hz, CH); 5.76 ppm (s, 1H, NH); 5.92 ppm (d, 1H, J = 9.78 Hz, CH); 6.74 ppm (s, 1H, aryl-H); 6.87 ppm (s, 1H, aryl-H); 7.25 ppm (d, 1H, J = 8.31 Hz, aryl-H); 7.41 ppm (m, 2H, J = 3.78 Hz, 2 x aryl-H);

7.52 ppm (d, 1H, J = 8.31 Hz, aryl H); 7.77 ppm (m, 1H, J = 5.29 Hz, aryl-H); 7.79 ppm (m, 1H, J = 6.04 Hz, aryl-H). ESI-MS for C ₂ oH ₁₂ Cl ₂ NNaO ₃ , calculated: 408.24 g / mol; found (negative mode): 384.2 (MH-Na), 3340.1 (MH-Na-CO ₂ ).

GRA3182 Foreign countries de.doc Compound 31)

1,3-dichloro-10-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt. Yield: 98% of theory ¹ H-NMR ( d ₆ -DMSO / TMS _ex t.): δ = 2.13 ppm (s, 3H, 10-CHs); 3.31 ppm (m, 1H, CH); 4.99 ppm (d, 1H, J = 9.82 Hz, CH); 5.63 ppm (d, 1H, J = 9.82 hz, CH); 5.73 ppm (s, 1H, NH); 6.51 ppm (d, 1H, J = 8.31 Hz, aryl-H); 6.72 ppm (s, 1H, aryl-H); 6.83 ppm (d, 1H, J = 8.31 Hz, aryl-H); 6.88 ppm (s, 1H, aryl-H); 7.17 ppm (s, 1H, Aryi-H).

ESI-MS for C ₁₇ H ₁₂ Cl ₂ NNaO ₃ , calculated: 350.2 g / mol; found (positive mode): 350.1 (MH ⁺ -Na), 304.3 (MH ⁺ -Na-CO ₂ ); (negative mode): 348.4 (MH-Na).

Connection 32)

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

Yield: 89% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.31 ppm (m, 1H, CH); 5.11 ppm (di 1H, J = 9.82 Hz, CH); 5.75 ppm (d, 1H, J = 9.82 Hz, CH); 5.79 ppm (s, 1H, NH); 6.73 ppm (m, 2H, 2 x aryl-H); 6.91 ppm (s, 1H, aryl H); 7.26 ppm (t, 1H, J = 6.80 Hz, aryl-H); 7.34 ppm (d, 1H, J = 8.31 Hz, aryl-H); 7.39 ppm (t, 2H, J = 8.31 Hz, 2 x aryl-H); 7.44 ppm (d, 2H, J = 7.55 Hz, aryl-H); 7.66 ppm (s, 1H, aryl-H). ESI-MS for C ₂₂ Hι ₄ Cl ₂ NNaO ₃ , calculated: 434.28 g / mol; found (negative mode): 410.3 (MH-Na), 366.2 (MH-Na-CO ₂ ).

Connection 33)

1,3-dichloro-10-methoxy-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt Yield: 92%

GRA3182 Foreign countries de.doc ¹ H-NMR (de-DMSO / TMSext.): Δ = 3.31 ppm (m, 1H, CH); 3.60 ppm (s, 3H, 10-OCH ₃ ); 5.00 ppm (d, 1H, J = 9.82 Hz, CH); 5.65 ppm (d, 1H, J = 9.82 Hz, CH); 5.75 ppm (s, 1, NH); 6.54 ppm (d, 1H, J = 9.07 Hz, aryl-H); 6.62 ppm (d, 1H, J = 10.58 Hz, aryl-H); 6.72 ppm (s, 1H, aryl-H);

6.89 ppm (s, 1H, aryl H); 7.00 ppm (s, 1H, aryl-H).

Connection 34)

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

Yield: 95% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 1.26 ppm (t, 3H, J = 7.56 Hz,

CH ₃ );

3.31 ppm (m, 1H, CH); 4.22 ppm (q, 2H, J = 6.80 Hz, OCH ₂ ); 5.23 ppm (d, 1H, J = 9.82 Hz, CH); 5.84 ppm (d, 1H, J = 9.82 Hz,

CH); 6.05 ppm (s, 1H, NH); 6.82 ppm (d, 1H, J = 8.31 Hz, aryl

H); 6.92 ppm (s, 1H, aryl-H); 7.01 ppm (s, 1H, aryl-H); 7.74 ppm

(d, 1H, J = 8.31 hz, aryl-H);

7.95 ppm (s, 1H, aryl-H). ESI-MS for Ci9H ₁₄ Cl ₂ NNaO ₅ , calculated: 408.24 g / mol; found

(negative mode): 407.0 (MH-Na), 365.0 (MH-Na-CO ₂ ).

Compound 35)

1, 3,10-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt Yield: 94% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.30 ppm (m, 1H, CH); 5.06 ppm (d, 1H, J = 9.82 Hz, CH); 5.73 ppm (d, 1H, J = 9.82 Hz, CH); 5.80 ppm (s, 1H, NH); 6.67 ppm (d, 1H, J = 8.31 Hz, aryl H); 6.75 ppm (s, 1H, aryl-H); 6.93 ppm (s, 1H, aryl H); 7.07 ppm (d, 1H, J =

8.31 Hz, aryl-H);

7.32 ppm (s, 1H, aryl-H).

GRA3182 Foreign countries de.doc ESI-MS for C ₁₆ H ₉ Cl ₃ NNaO ₃ , calculated: 392.62 g / mol; found (negative mode): 368.5 (MH-Na), 332.3 (MH-Na-CO ₂ ).

Compound 36) 10-Bromo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt Yield: 97% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 3.32 ppm (m, 1H, CH); 5.10 ppm (d, 1H, J = 9.83 Hz, CH); 5.74 ppm (d, 1H, J = 9.82 Hz, CH); 5.86 ppm (s, 1H, NH); 6.65 ppm (d, 1H, J = 8.31 Hz, aryl H); 6.78 ppm (s, 1H, aryl-H); 6.96 ppm (s, 1H, aryl-H); 7.20 ppm (d, 1H, J = 8.31 Hz, aryl-H); 7.43 ppm (s, 1H, aryl-H). ESI-MS for CI ₆ HgBrCl ₂ NNaO ₃ , calculated: 437.05 g / mol; found (positive mode): 416.0 (MH ⁺ -Na), 370.2 (MH ⁺ -Na-CO ₂ ); (negative mode): 413.9 (MH-Na), 376.0 (MH-Na-CO ₂ ).

Connection 37)

1,3-dichloro-8,10-dimethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza be ^'nzo [c] fluoren-6-carboxylic acid, sodium salt

Yield: 94% of theory

¹ H-NMR (de-DMSO / TMSext.): Δ = 2.01 ppm (s, 3H, CH ₃ ); 2.09 ppm

(s, 3H, CH _3); 3.33 ppm (m, 1H, CH); 4.98 ppm (d, 1H, J = 9.82

Hz, CH); 5.62 ppm (d, 1H, J = 9.82 Hz, CH); 5.74 ppm (s, 1H, NH); 6.66 ppm (s, 1H, aryl H); 6.72 ppm (s, 1H, aryl-H); 6.89 ppm (s, 1H,

Aryl-H); 7.02 ppm (s, 1H, aryl-H).

ESI-MS for C ₁₈ Hι ₄ Cl ₂ NNaO ₃ , calculated: 386.23 g / mol; found

(positive mode): 364.2 (MH ⁺ -Na), 318.2 (MH ⁺ -Na-CO ₂ ); (negative mode): 362.1 (MH-Na), 317.9 (MH-Na-CO ₂ ).

GRA3182 Foreign countries de.doc Connection 38)

1,3-dichloro-8,11-dimethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt. Yield: 38% of theory ¹ H- NMR (de-DMSO / TMSext.): Δ = 1.87 ppm (s, 3H, CH ₃ ); 2.01 ppm (s, 3H, CH ₃ ); 3.37 ppm (m, 1H, CH); 5.15 ppm (d, 1H, J = 10.57 Hz, CH); 5.59 ppm (s, 1H, NH); 5.64 ppm (d, 1H, J = 10.58 Hz, CH); 6.31 ppm (d, 1H, J = 7.55 Hz, aryl-H); 6.71 ppm (d, 1H, J = 7.55 Hz, aryl-H); 6.80 ppm (s, 1H, aryl-H); 6.97 ppm (s, 1H, aryl H).

ESI-MS for CI ₈ Hι ₄ CI ₂ NNaO ₃ , calculated: 386.23 g / mol; found (positive mode): 364.0 (MH ⁺ -Na), 318.2 (MH ⁺ -Na-CO ₂ ); (negative mode): 362.1 (MH-Na), 318.1 (MH-Na-CO ₂ ).

Connection 39)

1,3-dichloro-9,11-dimethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt

Yield: 35% of theory

¹ H-NMR (de-DMSO / TMS _e x _t .): Δ = 1.88 ppm (s, 3H, CH ₃ ); 2.12 ppm (s, 3H, CH ₃ ); 3.32 ppm (m, 1H, CH); 5.08 ppm (d, 1H, J = 9.82

Hz, CH);

5.53 ppm (s, 1H, NH); 5.61 ppm (d, 1H, J = 9.82 Hz, CH); 6.22 ppm (s, 1H, aryl-H); 6.25 ppm (s, 1H, aryl-H); 6.77 ppm (s, 1H,

Aryl-H); 6.94 ppm (s, 1H, aryl-H). ESI-MS for C ₁₈ Hι ₄ Cl ₂ NNaO ₃ , calculated: 386.23 g / mol; found

(negative mode): 362.3 (M-H-Na).

Connection 40)

1, 3,10-trichloro-9-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt Yield: 79% of theory

GRA3182 Foreign countries de.doc ¹ H-NMR (de-DMSO / TMSext.): Δ = 2.18 ppm (s, 3H, CH ₃ ); 3.31 ppm (m, 1H, CH); 5.01 ppm (d, 1H, J = 9.82 Hz, CH); 5.69 ppm (d, 1H, J = 9.82 Hz, CH); 5.81 ppm (s, 1H, NH); 6.65 ppm (s, 1H, aryl-H); 6.75 ppm (s, 1H, aryl-H); 6.94 ppm (s, 1H, aryl-H); 7.31 ppm (s, 1H, aryl-H).

ESI-MS for C ₁₇ H ₁₂ Cl ₄ NNaO 3, calculated: 406.65 g / mol; found (positive mode): 386.0 (MH ⁺ ), 340.2 (MH ⁺ -CO ₂ ); (negative mode): 384.2 (MH-Na), 340.1 (MH-Na-CO ₂ ).

Connection 41)

1,3-Dichloro-9-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt

Compound 42) 1, 3-dichloro-11-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid, sodium salt

pharmacology

Example 5)

Receptor binding studies (Glycine B binding site of the NMDA receptor channel)

The assays for determining the affinity of the compound of the invention for the glycine B binding site of the NMDA receptor channel were performed on brain membrane homogenates (homogenate of cortex and hippocampus area from the brain of male rats, strain Wistar) (BM Baron, BW Siegel, BL Harrison, RS Gross, C. Hawes and P. Towers, Journal of Pharmacology and Experimental Therapeutics, (1996), Vol.279, p.62).

For this purpose, the cortex and hippocampus were removed from freshly drawn rat brains and dissected in 5 mmol / l TRIS acetate buffer,

GRA3182 Foreign de doc 0.32 mol / l sucrose pH 7.4 (10 ml / g fresh weight) with a Potter homogenizer (Braun / Melsungen, 10 strokes of the flask at 500 rpm) with ice cooling and then homogenized for 10 minutes at 1, 000 g and Centrifuged at 4 ° C. The first supernatant was collected and the sediment resuspended with 5 mmol / l TRIS acetate buffer, 0.32 mol / l sucrose pH 7.4 (5 ml / g original fresh weight) with the Potter homogenizer (10 strokes at 500 rpm) Ice cooling homogenized and centrifuged for 10 minutes at 1, 000 g and 4 ° C. The resulting 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 taken up with 5 mmol / l TRIS acetate buffer pH 8.0 (20 ml / g original fresh weight) and homogenized with 10 strokes of the flask at 500 rpm.

Subsequently, the membrane homogenate was 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

Closed the centrifuge tube with the membrane sediment with parafilm and frozen for 24 hours at -20 ° C. The following day, the membrane sediment was thawed and taken up with ice cold 5 mmol / l TRIS acetate buffer, 0.1% saponin (w / v) pH 7.0 (10 ml / g original fresh weight) and homogenized with 10 strokes at 500 rpm then centrifuged for 20 minutes at 50,000 g and 4 ° C. The resulting supernatant was discarded and the sediment was taken up in a small volume with 5 mmol / l TRIS acetate buffer pH 7.0 (about 2 ml / g original fresh weight) and homogenized again with 10 strokes of the flask at 500 rpm. After determining the protein content, the membrane homogenate

GRA3182 Foreign countries de.doc adjusted to a protein concentration of 10 mg protein / ml with 5 mmol / l TRIS acetate buffer pH 7.0 and frozen in aliquots until testing.

For the receptor binding assay aliquots were thawed, 1:10 diluted with 5 mmol / l TRIS acetate buffer pH 7.0, homogenized with 10 strokes at 500 rpm with the Potter homogenizer (10 strokes at 500 rpm) with ice cooling and for 60 minutes at Centrifuged 55,000 g at 4 ° C. The supernatant was decanted and the membrane sediment was adjusted with ice-cold 50 mmol / l TRIS acetate buffer pH 7.0 to a protein concentration of 1 mg / ml and homogenized again with 10 strokes of the piston at 500 rpm and kept in suspension on a magnetic stirrer in an ice bath with stirring. From this membrane homogenate in each case 100 .mu.l were used per 1 ml batch in the receptor binding test (0.1 mg protein / ml in the final batch).

In the binding assay, the buffer used was 50 mmol / l TRIS acetate buffer pH 7.0 and the radioactive ligand 1 nmol / l ( ³ H) MDL 105.51 9 (B: M. Baron et al., 1996). Of the. Proportion of non-specific binding was determined in the presence of 1 mmol / l glycine B.

In further mixtures, the compounds according to the invention were added in concentration series and the displacement of the radioactive ligand from its specific binding to the glycine B binding site of the NMDA receptor channel was determined. The respective triplicate batches were incubated for 120 minutes at 4 ° C. and then harvested by filtration through glass fiber filter mats (GF / B) to determine the radioactive ligand bound to the membrane homogenate. The on the fiberglass filters

GRA3182 Foreign countries de.doc Retained radioactivity was measured after addition of scintillator in β-counter.

The affinity of the compounds of the invention for the glycine B binding site of the NMDA receptor channel was determined to be IC50

(Substance concentration with 50% displacement of the radioactive ligand from its specific binding) calculated according to the law of mass action by means of non-linear regression and is given in Table 5 after conversion (according to the Cheng-Prussoff relationship) as Ki value.

GRA3182 Foreign countries de.doc

Table 5: Glycine B binding data

GRA3182 Foreign de doc Example 6) Formalin Test (Mouse)

The investigations for the determination of the antinociceptive effect of the compounds according to the invention were published in

Formalin test on male albino mice (NMRI, 25-35 g, Iffa Credo, Belgium).

In the formalin test, a distinction is made between the first (early) phase (0-15 min after formalin injection) and the second (late) phase (15-60 min after formalin injection) (D. Dubuisson al, Pain, Vol. 4, pp. 161-174 (1977)). The early phase represents a model of acute pain as a direct response to formalin injection, while the late phase is considered a model of persistent (chronic) pain (TJ Coderre et al, Pain, Vol. 52, pp. 259). 285 (1993)).

The compounds according to the invention were investigated in the second phase of the formalin test in order to obtain statements about substance effects in chronic / inflammatory pain.

By a single subcutaneous formalin injection (20 .mu.l, 1% aqueous solution) in the dorsal side of the right hindpaw a nociceptive reaction was induced in freely moving test animals, which manifests itself in significant licking and biting of the affected paw.

For the study period in the second (late) phase of the formalin test, nociceptive behavior was continuously monitored by observation of the animals. The pain behavior was quantified by summing the seconds in which the animals showed licking and biting of the affected paw during the study period. After injection of substances,

GRA3182 Foreign de doc which are antinociceptively effective in the formalin test, the described behaviors of animals are reduced, possibly even repealed. According to the substance experiments in which the animals had been injected with test substance before formalin, the control animals were given vehicle, i. H. Solvent (eg

0.9% NaCl solution), injected prior to formalin application. The behavior of the animals after substance administration (n = 10 per substance dosage) was compared with a control group (n = 10). Based on the quantification of pain behavior, the substance effect in the formalin test was determined as a change in control in percent. The ED5Q calculations were performed by regression analysis. Depending on the mode of administration of the compounds according to the invention, the application time before the formalin injection was selected (intraperitoneal: 15 min, intravenous: 5 min).

The compounds of the invention showed a moderate to strong inhibition of formalin-induced nociception.

The corresponding results in the formalin test on the mouse or rat are summarized in Table 6 below.

Example 7) Formlin Test (Rat)

The investigations for the determination of the antinociceptive effect of the compounds according to the invention were published in

Formalin test on male rats (Sprague-Dawley, 1 50-170 g).

GRA3182 Foreign countries de.doc In the formalin test, the first (early) phase (0-15 min after formalin injection) and the second (late) phase (15-60 min after formalin injection) are differentiated (D. Dubuisson, SG Dennis, Pain 4, 161-174 (1977)). The early phase represents a model of acute pain as a direct response to formalin injection, while the late phase is considered a model of persistent (chronic) pain (TJ Coderre, J. Katz, AL Vaccarino, R. Melzack, Pain 52, 259-285 (1 993)).

The compounds according to the invention were investigated in the second phase of the formalin test in order to obtain statements about substance effects in chronic / inflammatory pain.

A single subcutaneous injection of formalin (50 μl, 5%) into the dorsal side of the right hindpaw induced a nociceptive reaction in freely moving test animals, which is reflected in the following behavioral parameters: lifting and holding the affected paw (score 1), shaking or twitching (score 2), licking and biting (score 3). The differing behaviors due to formalin injection were continuously recorded by observation of the animals in the late phase of the formalin test and weighted differently in a score. Normal behavior, in which the animal evenly loaded all four paws, was registered as score 0. Depending on the mode of administration of the compounds according to the invention, the application time before the formalin injection was selected (intraperitoneal: 15 min, intravenous: 5 min). After injection of substances which are antinociceptively effective in the formalin test, the described behaviors (score 1 - 3) of the animals are

GRA3182 Foreign countries de.doc reduced, possibly even picked up. The comparison was made with control animals that had received vehicle (solvent) before formalin application. The nociceptive behavior was determined as the so-called Pain Rate (PR). The various behavioral parameters were given a numerical weighting (factor 0, 1, 2, 3). The pain rate was calculated for 3-min intervals according to the following formula:

PR = [(To × 0) + (Ti × 1) + (T ₂ × 2) + (T ₃ × 3)] / 1 80,

where To, Ti, T ₂ , and T ₃ each correspond to the time in seconds in which the animal showed the behaviors 0, 1, 2, or 3. According to the mathematical formula, there was a value between 0 and 3 per 3 minute time interval. For the calculation period in the second (late) phase of the

Formalin tests, the area over the trapezium formula was calculated as AU D (area under the data). Based on the AUD calculations, the substance effect in the formalin test was determined as a change from control in percent. The ED ₅₀ calculations were performed by regression analysis. Substance and vehicle groups each comprise n = 10 animals.

The results of selected studies in the rat formalin test are summarized in Table 6 below.

GRA3182 Foreign countries de.doc

Table 6:. Formalin test (mouse and rat)

GRA3182 Foreign countries de.doc Example 8: Parenteral administration form.

38.5 g of compound 1 are dissolved in 1 l of water for injection at room temperature and then adjusted to isotonic conditions by adding anhydrous glucose for injection.

GRA3182 Foreign de doc

Claims

claims 1. A process for the preparation of tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid of general formula I,

wherein R ¹ , R ² , R ³ and R ^{4 are} independently selected from H, F, Cl, Br, I; C -C ₁₈ -alkyl, C ₂ -C ₁₈ -alkenyl or C ₂ -C ₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by N, S or O; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; OR ¹¹ , OC (O) R ¹¹ , C (O) R ¹¹ , C (O) OR ¹¹ , C (O) NR ¹¹ R ^{11 '} , NR ¹¹ R ^11' S (O ₂ ) R ¹¹ or SR ¹¹ , wherein R ¹¹ and R ^{11 'are} independently selected from GRA3182 Foreign countries de.doc H; d-ds-alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₁₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by N, S or O; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together are -CR ²³ = CH-CH-, -CR ²³ -CH = CH-, = CR ²³ -CH = CH-CH =, -CR ²³ = CH- CH = CH-, -CH = CR ²³ -CH = CH- or = CH-CR ²³ = CH-CH = form, with R ²³ selected from H, F, Cl, Br, I, OH or CrC ^ -alkyl, C ₂ -C ₁₀ alkenyl or C ₂ - C-io-alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently selected from H, F, Cl, Br, I; C-rC-io alkyl, C ₂ alkenyl or C ₂ -Cι _{0 0} -Cι alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; OR ¹⁸ , OC (O) R ¹⁸ , OC (S) R ¹⁸ , C (O) R ¹⁸ , C (O) OR ¹⁸ , C (S) R ¹⁸ , C (S) OR ¹⁸ , SR ¹⁸ , S ( O) R ¹⁸ or S (O ₂ ) R ¹⁸ , wherein R ^{18 is} selected from H; CiC-io-alkyl, C ₂ -C- | ₀ -Alkenyl or C -C ₀ alkynyl, in each case branched or unbranched, single or multiple GRA3182 Foreign countries de.doc substituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; NR ¹⁹ R ²⁰ , NR ¹⁹ C (O) R ²⁰ , C (NR ¹⁹ ) NR ²⁰ R ²¹ NR ¹⁹ C (S) R ²⁰ , C (S) NR ¹⁹ R ²⁰ or C (S) NR ¹⁹ NR ²⁰ R ²¹ or S (O ₂ ) NR ¹⁹ R ²⁰ , wherein R ¹⁹ , R ²⁰ and R ^{21 are} independently selected from H, O; C ₁ -C ₁₈ -alkyl, C ₂ -C ₁₈ -alkenyl or C ₂ -C ₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case simply or polysubstituted or unsubstituted; Aryl or Heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or R ¹⁹ and R ²⁰ or R ²⁰ and R ²¹ together form a C ₃ -C ₈ - Cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted, form or a corresponding heterocycle, in which at least one carbon atom in the ring is replaced by S, O or N; or R ⁷ and R ⁸ , R ⁸ and R ⁹ or R ⁹ and R ¹⁰ together GRA3182 Foreign de doc -CR ²² = CH-CH-, -CR ²² -CH = CH-, = CR ²² -CH = CH-CH =, -CR ²² = CH-CH = CH-, -CH = CR ²² -CH = CH- or = CH-CR ²² = CH-CH = form, with R ²² selected from H, F, Cl, Br, I, OH or d-do-alkyl, C ₂ -C ₁₀ alkenyl or C ₂ - C-io-alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted, characterized in that an optionally substituted aniline of the formula II in which R ⁷ , R ⁸ , R ⁹ and R ^{10 have} the abovementioned meaning,

Glyoxylic acid or glyoxylic acid hydrate and a benzofuran of the formula III in which R ¹ , R ² , R ³ and R ^{4 have} the abovementioned meaning, GRA3182 Foreign de doc

under microwave irradiation, preferably throughout the reaction time, in a suitable solvent in the presence of a Bronsted acid or Lewis acid simultaneously, the olefin of the formula III and the glyoxylic acid or the Glyoxylic acid are used in excess. 2. The method according to claim 1, characterized in that as optionally substituted aniline is a compound of formula II, wherein R ^7, R ⁸ , R ⁹ and R ^{10 are} independently H, F, Cl, Br, I; dC ₆ -alkyl, branched or unbranched, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Benzyl or phenyl, in each case monosubstituted or polysubstituted or unsubstituted; OR ¹⁸ or C (O) OR ¹⁸ , wherein R ^{18 is} selected from H; d-Ce-alkyl, branched or unbranched, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or R ⁷ and R ⁸ , R ⁸ and R ⁹ or R ⁹ and R ¹⁰ together -CH = CH-CH = CH- or -CH = CH-CH = CH- forms used. 3. The method according to claim 2, characterized in that as optionally substituted aniline, a compound of formula II, wherein GRA3182 Foreign de doc R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently selected from H, F, Cl, Br, l, CH _3, C ₂ H _5, C ₃ H _7, C ₄ H _9, CF _3, CHF _2, CH ₂ F, OH, OCH _3, i OC ₂ H _5, C (0) OH, C (O) OCH ₃ or C (O) OC ₂ H ₅ , preferably off H, F, Cl, Br, I, CF ₃ , CHF ₂ , CH ₂ F or CH ₃ , in particular R ⁸ and R ^{10 are} independently of each other, preferably both the same, selected from Cl or CF 3 and R ⁹ and R ^{7 are} independently selected from H, F, Cl, Br, I, CF ₃ , CHF ₂ or CH ₂ F; preferably H, F, Cl, Br, I; especially H, inserts. 4. The method according to any one of claims 1 to 3, characterized in that the benzofuran is a compound of formula III, wherein R, R ² , R ³ and R are independently selected from H, F, Cl, Br, I; C 1 -C ₆ -alkyl, branched or unbranched, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle, in which at least one carbon atom in the GRA3182 Foreign countries de.doc Ring is replaced by N, S or O; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; OR ¹¹ , OC (O) R ¹¹ , C (O) R ¹¹ , C (O) OR ¹¹ , C (O) NR ¹¹ R ^{11 '} or SR ¹¹ , wherein R ¹¹ and R ^{11 are} independently selected H; C ₁ -C ₆ -alkyl, branched or unbranched, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together -CR ²³ = CH-CH-, -CR ²³ -CH = CH-, -CR ²³ = CH-CH = CH- or - CH = CR ²³ -CH = CH-, with R ²³ selected from H, F, Cl, Br, I, OH or C 1 -C ₄ -alkyl, branched or unbranched, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; starts. 5. The method according to claim 4, characterized in that the benzofuran is a compound of formula III, wherein R ¹ , R ² , R ³ and R ^{4 are} independently selected from H, F, Cl, Br, I; CF ₃ , CHF ₂ , CH ₂ F, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ ; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, single or multiple GRA3182 Foreign countries de.doc substituted or unsubstituted; Benzyl or phenyl, in each case monosubstituted or polysubstituted or unsubstituted; OH, OCH ₃ , OC ₂ H ₅₎ OC ₃ H ₅ , C (6) OH, C (O) OCH ₃ , C (O) OC ₂ H ₅ , C (O) OC ₃ H ₇ or R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together are -CH = CH-CH-, -CH-CH = CH-, -CH = CH-CH = CH- or -CH = CH- Form CH = CH-, starts. 6. The method according to any one of claims 1 to 5, characterized in that the optionally substituted aniline of the formula II, the glyoxylic acid or the Glyoxylsäurehydrat and the benzofuran of the formula III in a molar ratio of 1: 1, 5-3: 1, 5- 3 implements. 7. The method according to any one of claims 1 to 6, characterized in that the process in the presence of a Lewis acid, preferably a triflate (a trifluoromethanesulfonic acid salt), in particular a lanthanum, (for example scandium) or indium triflate, particularly preferably an indium triflate, or GRA3182 Foreign countries de.doc in the presence of a polymer-bound Lewis acids or clay minerals, preferably montmorillonite. 8. The method any one of claims 1 to 7, characterized in that the solvent used is acetonitrile invention. 9. The method according to any one of claims 1 to 8, characterized in that one carries out the reaction at a temperature in the range of 40-80 ° C, preferably from 50-60 ° C. 10. The method according to any one of claims 1 to 9, characterized in that one removes the solvent for isolating the compound of the general formula I or the sparingly soluble compound of the general formula I is filtered off. 11. The method according to any one of claims 1 to 10, characterized in that to purify the compound of general formula I with a suitable solvent, preferably with a non-polar organic solvent, the isolated compound washes and / or recrystallized the compound. 12. The method according to claim 11, characterized in that one uses as solvent for washing hexane or acetonitrile. 13. The method according to any one of claims 1 to 12, characterized in that by adding a base, preferably sodium hydroxide, potassium hydroxide or lithium hydroxide, in particular sodium hydroxide, to the isolated and optionally purified compound of the general formula I forms the corresponding salt. 14. Process for the preparation of 1, 3-dichloro-5,6,6a, 1 1 -b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-one GRA3182 Foreign countries de.doc carboxylic acid according to one or more of claims 1 to 13, characterized in that one converts 3,5-dichloroaniline, glyoxylic acid or Glyoxylsäurehydrat and benzofuran. 15. tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of general formula VI,

VI wherein R ¹ , R ² , R ³ and R ^{4 are} independently selected from H, F, Cl, Br, I; C ₁ -C ₁₈ -alkyl, C ₂ -C ₈ -alkenyl or C ₂ -C ₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by N, S or O; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; GRA3182 Foreign de doc OR ¹¹ , OC (O) R ¹¹ , C (O) R ¹¹ , C (O) OR ¹¹ , C (O) NR ¹¹ R ^{11 '} , NR ¹¹ R ^11' SS ((OO ₂₂ )) RR ¹ " ¹ oderde SSRR ¹ " ¹ ,, \ where R ¹¹ and R ^{11 'are} independently selected from H; Ct-Ci _δ -alkyl, C _{2 8} alkenyl or C ₂ -Cι -Cι ₈ -alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by N, S or O; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together -CR ²³ = CH-CH-, -CR ²³ -CH = CH-, = CR ²³ -CH = CH-CH =, -CR ²³ = CH-CH = CH-, -CH = CR ²³ -CH = CH- or = CH-CR ²³ = CH-CH = form, with R selected from -C ₁₀ alkenyl or C ₂ H, F, Cl, Br, I, OH or d-Cι ₀ alkyl, C ₂ - do-alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; R ⁵ is H; R ⁷ and R ^{9 are} independently selected from H, F, Cl, Br, I; C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl or C ₂ -C ₁₀ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; GRA3182 Foreign countries de.doc OR ¹⁸ , OC (O) R ¹⁸ , OC (S) R ¹⁸ , C (O) R ¹⁸ , C (O) OR ¹⁸ , C (S) R ¹⁸ , C (S) OR ¹⁸ , SR ¹⁸ , S ( O) R ¹⁸ or S (O ₂ ) R ¹⁸ , wherein R ^{18 is} selected from H; d-Cio-alkyl, C ₂ -Cι ₀ alkenyl or C ₂ -C ₁₀ alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N; Alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; NR ¹⁹ R ²⁰ , NR ¹⁹ C (O) R ²⁰ , C (NR ¹⁹ ) NR ²⁰ R ²¹ NR ¹⁹ C (S) R ²⁰ , C (S) NR ¹⁹ R ²⁰ or C (S) NR ¹⁹ NR ²⁰ R ²¹ or S (O ₂ ) NR ¹⁹ R ²⁰ , wherein R ¹⁹ , R ²⁰ and R ^{21 are} independently selected from H, O; C ₁ -C ₈ -alkyl, C ₂ -C ₁₈ -alkenyl or C ₂ -C ₁₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; QrCs-cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or a corresponding heterocycle in which at least one carbon atom in the ring is replaced by S, O or N, alkylaryl or alkylheteroaryl, in each case monosubstituted or polysubstituted or unsubstituted ; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; • or GRA3182 Foreign countries de.doc R ¹⁹ and R ²⁰ or R ²⁰ and R ²¹ together form a C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or form a corresponding heterocycle in which at least one C atom in the ring by S , O or N is replaced; or optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, in particular of the physiologically tolerated salts, or in the form of their solvates, in particular the hydrates. 16. Tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to claim 15, characterized in that R ¹ , R ² , R ³ or R ^{4 are} independently selected from H, F, Cl, Br, I; C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; OR ¹¹ , OC (O) R ¹¹ , C (O) R ¹¹ , C (O) OR ¹¹ , C (O) NR ¹¹ R ^{11 '} , NR ¹¹ R ^11' SS ((OO ₂₂ )) RR ¹¹¹¹ ooddeerr SSRR ¹¹¹¹ , wherein R ¹¹ and R ^{11 are} independently selected from H; C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; GRA3182 Foreign countries de.doc preferably R ¹ , R ² , R ³ or R ^{4 are} independently selected from H, F, Cl, Br, I; dd-alkyl, C ₂ -C ₄ -alkenyl or C ₂ -C ₄ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; OR ¹¹ , C (O) OR ¹¹ or SR ¹¹ , wherein R ^{11 is} selected from H; dd-alkyl, C ₂ -C ₄ -alkenyl or C ₂ -C ₄ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; in particular R ¹ , R ² , R ³ or R ⁴ are selected independently of one another H, F, Cl, Br, I; dd-alkyl, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; SH; OR ¹¹ or C (O) OR ¹¹ , wherein R ^{11 is} selected from H; Ci-d-alkyl, branched or unbranched, mono- or polysubstituted or unsubstituted; or more preferably R ¹ , R ² , R ³ or R ^{4 are} independently selected from H, F, Cl, Br, I, CH ₃ , C ₂ H ₅ , n-propyl, i-propyl, i-butyl, sec-butyl, n-butyl, t-butyl, CF ₃ , CHF ₂ , SH OH, OCH ₃ , OC ₂ H ₅ , C (O) OH C (O) OCH ₃ or C (O) OC ₂ H ₅ , R ^ö is H; GRA3182 Foreign countries de.doc R ⁷ and R ^{9 are} independently selected from H, F, Cl, Br, I; C 1 -C ₄ -alkyl, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; I OR ¹⁸ or SR ¹⁸ , with R ¹⁸ selected from H, -CC-alkyl, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; Phenyl, monosubstituted or polysubstituted or unsubstituted, preferably R ⁷ and R ^{9 are} independently selected from H, F, Cl, Br, I, CH _3, CF _3, OH, -OCH _3, in particular R ⁷ and R ^{9 are} selected from H. 17. Tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid of the general formula I. wherein R ¹ , R ² , R ³ and R ^{4 are} independently selected from H or phenyl, monosubstituted or polysubstituted or unsubstituted; or R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together -CR ²³ = CH-CH-, -CR ²³ -CH = CH-, = CR ²³ -CH = CH-CH =, -CR ²³ = CH-CH = CH-, -CH = CR ²³ -CH = CH- or = CH-CR ²³ = CH-CH = form, GRA3182 Foreign de doc with R ²³ selected from H, F, Cl, Br, I, OH or C 1 -C ₄ -alkyl, branched or unbranched, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; R ⁷ , R ⁸ , R ⁹ and R ^{i0 are} independently selected from H, F, Cl, Br, I; dC ₁₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₂ -Cι ₀ alkynyl, in each case branched or unbranched, mono- or polysubstituted or unsubstituted; OR ¹⁸ , OC (O) R ¹⁸ , OC (S) R ¹⁸ , C (O) R ¹⁸ , C (O) OR ¹⁸ , C (S) R ¹⁸ , C (S) OR ¹⁸ , SR ¹⁸ , S ( O) R ¹⁸ or S (O ₂ ) R ¹⁸ , wherein R ^{18 is} selected from H; C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl or C ₂ -C ₁₀ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; d-Cs-cycloalkyl, saturated or unsaturated, monosubstituted 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 monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; NR ¹⁹ R ²⁰ , NR ¹⁹ C (O) R ²⁰ , C (NR ¹⁹ ) NR ²⁰ R ²¹ NR ¹⁹ C (S) R ²⁰ , C (S) NR ¹⁹ R ²⁰ or C (S) NR ¹⁹ NR ²⁰ R ²¹ or S (O ₂ ) NR ¹⁹ R ²⁰ , wherein R ¹⁹ , R ²⁰ and R ^{21 are} independently selected from H, O; C ₁ -C ₁₈ -alkyl, C ₂ -C ₁₈ -alkenyl or C ₂ -d ₈ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C ₃ -C ₈ cycloalkyl, saturated GRA3182 Foreign countries de.doc or unsaturated, monosubstituted 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 monosubstituted or polysubstituted or unsubstituted; Aryl or Heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or R ¹⁹ and R ²⁰ or R ²⁰ and R ²¹ together form a C ₃ -C ₈ -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted, or form a corresponding heterocycle in which at least one C atom in the ring by S , O or N is replaced; or optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, in particular of the physiologically tolerated salts, or in the form of their solvates, in particular the hydrates. 18. Tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to claim 17, characterized in that R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently selected from H, F, Cl, Br, I; CC ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted or unsubstituted; GRA3182 Foreign de doc OR ¹⁸ , C (O) R ¹⁸ , C (O) OR ¹⁸ or SR ¹⁸ , wherein R ^{18 is} selected from H; C 1 -C ₄ -alkyl, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; Aryl, monosubstituted or polysubstituted or unsubstituted, preferably R ⁷ , R ⁸ , R ⁹ and R ^{10 are} independently selected from H, F, Cl, Br, I; C 1 -C ₄ -alkyl, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; OR ¹⁸ or SR ¹⁸ , with R ¹⁸ selected from H, C 1 -C ₄ -alkyl, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; Phenyl, monosubstituted or polysubstituted or unsubstituted, in particular R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are selected independently of one another H, F, Cl, Br, I; CH ₃ , CF ₃ , t-butyl, i-butyl, OH, -OCH ₃ , -OCF ₃ , SCH ₃ , -O-phenyl, particularly preferred R ⁷ and R ^{9 are} H and R ⁸ and R ^{10 are} Cl. 19. Tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to one of claims 15 to 18, characterized in that the compound in the form of their alkali salts, preferably the Potassium or sodium salts present. GRA3182 Foreign countries de.doc 0. Medicament containing as active ingredient at least one tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid derivative according to any one of claims 15 to 19 in the form shown or in the form of the acid or base or in the form of its Salts, in particular the physiologically acceptable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the Enantiomers or diastereomers, in any mixing ratio; and optionally containing suitable additives and / or adjuvants and / or optionally further active ingredients. 21. Use of at least one tetra-hydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to any one of claims 15 to 19 in the form shown or in the form of the acid or base or in the form of its salts, in particular the physiologically tolerated salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the Enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment of pain, in particular neuropathic and / or chronic pain and / or for the treatment of migraine. GRA3182 Foreign de doc 2. Use of at least one tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to one of claims 15 to 19 or in the form of the acid or base or in the form of its salts, in particular the physiologically acceptable salts, or in the form of its solvates, especially the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea. 23. Use of at least one tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to any one of claims 15 to 19 in the form shown or in the form of the acid or base or in the form of its salts, in particular the physiologically acceptable salts, or in the form of its solvates, especially the hydrates; especially in the form of its physiologically acceptable Salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, 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 manufacture of a medicament for the treatment / prophylaxis of epilepsy, Parkinson's disease, Huntington's disease, glaucoma, osteoporosis, ototoxicity, withdrawal symptoms in alcohol and / or drug abuse, stroke, cerebral ischemia, cerebral infarctions, cerebral edema, Hypoxia, anoxia and / or anxiolysis and / or anesthesia. GRA3182 Foreign countries de.doc 4. Use of at least one tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to any one of claims 15 to 19 in the form shown or in the form of the acid or base or in the form of its salts, in particular the physiologically acceptable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the Enantiomers or diastereomers, in any mixing ratio; for the preparation of a medicament for the treatment / prophylaxis 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, cough and / or mental illness. GRA3182 Foreign countries de.doc