EA023648B1 - NDANYL-SUBSTITUTED 4,5,6,7-TETRAHYDRO-1H-PYRAZOLO[4,3-c]PYRIDINES, THEIR USE AS MEDICAMENT, AND PHARMACEUTICAL PREPARATIONS COMPRISING THEM - Google Patents

Abstract

The invention relates to substituted 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridines of formula I, their use as medicament, and pharmaceutical preparations comprising them.The compounds of formula I act on the TASK-1 potassium channel. The compounds are suitable for the treatment or prevention of atrial arrhythmias, for example atrial fibrillation (AF) or atrial flutter.

Description

(57) The invention relates to substituted 4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridines of the formula I, their use as a medicine and pharmaceutical preparations containing them.

023 648 Β1

The compounds of formula I affect the potassium channel TA8K-1. The compounds are suitable for the treatment or prevention of atrial arrhythmias, for example atrial fibrillation or atrial flutter.

Claims (15)

wherein A represents phenyl or pyridyl optionally substituted with 1 or 2 substituents independently selected from F, C1, Br, _(C1-C6) alkyl, _(C1-C6) alkyloxy-, N0- or K ¹² K ¹³ N- C (O) -, where one or more hydrogen atoms of the alkyl radical may be substituted by fluorine atoms; K ¹ represents K ¹⁰ -C (O) -, K ^p - (C1-C ₆ ) alkyl-, (C ₃ -C ₆ ) cycloalkyl or (C1-C ₆ ) alkyl-8O ₂ -, where one or more hydrogen atoms of the alkyl radical may be substituted with fluorine atoms; K ² represents H, OH, _(C1-C6) alkyloxy or _(C1-C6) alkyl-C (O) O-; K ³ represents H or (C1- _C6 ) alkyl; K ⁴ represents H; K ⁵ represents H; each of K ⁶ -K ^{9 is} independently selected from H, P, C1, Br, ΝΟ, (C ₄ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₁ -C ₆ ) alkyloxy and (C ₁ -C ₆ ) alkyl-8- provided that the two groups of K ⁶ -K ⁹ are H, where one or more hydrogen atoms of the alkyl radical may be substituted with fluorine atoms; To ¹⁰ represents _(C1-C6) alkyl, (C ₃ -C ₆₎ cycloalkyl, _(C1-C6) alkyloxy-, _(C1-C6) alkyl-O- _(C1-C6) alkyl or Ρ . ^Ι2 Ρ. ^{Ι3 Ν-} , where one or more hydrogen atoms of the alkyl radical may be substituted with fluorine atoms; K ¹¹ represents H, (C3-C6) cycloalkyl or (C1-C6) alkyloxy, wherein one or more hydrogen atoms of the alkyl radical may be substituted with fluorine atoms; each of K ¹² and K ¹³ independently represents H or (C1-C6) alkyl, and / or its stereoisomeric forms and / or mixtures of these forms and / or physiologically tolerated salts of the compounds of formula I. 2. The compound according to claim 1, where A represents phenyl or pyridyl optionally substituted with 1 or 2 substituents independently selected from F, C1, _(C1-C4) alkyloxy, _(C1-C4) alkyl and ΝΟ, wherein one or more hydrogen atoms of the alkyl radical may be substituted by fluorine atoms; K ¹ represents K ¹⁰ -C (O) -, P ¹¹ - (C ₁ -C. ₁ ) alkyl- or (C1-C ₂ ) alkyl-8O ₂ -; K ² represents H, OH, _(C1-C4) alkyloxy or _(C1-C4) alkyl-C (O) O-; K ³ represents H or (C1- _C6 ) alkyl; K ⁴ represents H; K ⁵ represents H; each of K ⁶ -K ^{9 is} independently selected from H, P, C1, Br, ΝΟ, (C ₄ -C ₄ ) alkyl, cyclopropyl, (C ₄ -C ₄ ) alkyloxy and (C ₁ -C. ₁ ) alkyl -8- provided that the two groups of K ⁶ -K ⁹ are H, where one or more hydrogen atoms of the alkyl radical may be substituted with fluorine atoms; K ¹⁰ is (C ₄ -C ₄ ) alkyl, cyclopropyl, (C ₄ -C ₄ ) alkyloxy, (C1-C ₄ ) alkyl-O- (C1-C ₄ ) alkyl or K ¹² K ¹³ ^; K ¹¹ represents H, cyclopropyl or (C ₄ -C ₄ ) alkyloxy, wherein one or more hydrogen atoms of the alkyl radical may be substituted with fluorine atoms; each of K ¹² and K ¹³ independently represents H or (C1-C4) alkyl, and / or its stereoisomeric forms and / or mixtures of these forms and / or physiologically tolerated salts of the compounds of formula I. 3. The compound according to claim 1 or 2, where A is phenyl or pyridyl optionally substituted with 1 or 2 substituents independently selected from P, C1, methoxy, ethoxy, methyl, ethyl, N6-, CP ₃ O- or CP ₃ ; K ¹ represents K ¹⁰ -C (O) -, K ¹¹ - (C ₁ -C ₄ ) alkyl- or CH ₃ -BO ₂ -; K ² represents OH, methoxy, ethoxy or methyl-C (O) O- or ethyl-C (O) O-; K ³ represents H or methyl; each of K ⁴ and K ⁵ represents H; each of K ⁶ -K ^{9 is} independently selected from H, P, C1, Br, ΝΓ-, methyl, ethyl, cyclopropyl, methoxy, ethoxy, methyl-B-, ethyl-B- and CP ₃ , provided that two groups of K ⁶ -K ⁹ are H; K ¹⁰ represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, methoxy, ethoxy, (C ₁ -C ₂ ) alkyl-O- (C ₁ -C ₂ ) alkyl or K ¹² K ¹³ ^; K ¹¹ represents H, cyclopropyl, methoxy, ethoxy or CP3, each of K ¹² and K ¹³ independently represents H, methyl or ethyl; and / or its stereoisomeric forms and / or mixtures of these forms and / or physiologically tolerated salts of the compounds of formula I. 4. The compound according to any one of claims 1 to 3, where A represents phenyl or pyridyl, optionally substituted with 1 or 2 substituents independently selected from P, C1, methoxy, methyl, Ν ^, CP ₃ O-, CP ₃ ; K ¹ represents K ¹⁰ —C (O) -, K ¹¹ - (C _and H _2i ) -, isopropyl, tert-butyl or CH ₃ —BO ₂ -, where and is 1, 2 or 3; K ² represents OH or methoxy; K ³ represents H or methyl; each of K ⁴ and K ⁵ represents H; K ⁶ represents H; K ⁷ and K ^{8 are} independently selected from H, P, C1, Br; K ⁹ represents H, P, C1, Br, Ν ^, methyl, ethyl, cyclopropyl, methoxy, ethoxy, methyl-B-, ethylB- or CP3; K ¹⁰ represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, methoxy or methoxymethyl-; K ¹¹ represents H, cyclopropyl, methoxy or CP ₃ , and / or its stereoisomeric forms and / or mixtures of these forms and / or physiologically tolerated salts of the compounds of formula I. 5. The compound according to any one of claims 1 to 4, selected from the group consisting of 3- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -5-propionyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3c] pyridine -3-yl] benzonitrile; 3- [5-cyclopropanecarbonyl-1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1Npyrazolo [4,3-c] pyridine -3-yl] benzonitrile; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (3-trifluoromethoxyphenyl) -1,4,6,7tetrahydropyrazolo [4,3-c] pyridine -5-yl] standard; 1- [3- (3-chlorophenyl) -1 - ((1B, 2B) -4,6-difluoro-2-hydroxyindan-1-yl) -1,4,6,7-tetrahydropyrazolo [4,3c] pyridine -5-yl] ethanone; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (2-fluoro-5-methoxyphenyl) -1,4,6,7tetrahydropyrazolo [4,3 -c] pyridin-5-yl] ethanone; 3- [5-acetyl-1 - ((1K, 2K) -4-bromo-6-fluoro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4.3s ] pyridin-3-yl] benzonitrile; 3- [5-acetyl-1 - ((1K, 2K) -6-fluoro-2-hydroxy-4-methylindan-1-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4.3s ] pyridin-3-yl] benzonitrile; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (6-trifluoromethylpyridin-2-yl) -1,4,6,7tetrahydropyrazolo [4,3 -c] pyridin-5-yl] ethanone; 3- [5-cyclopropanecarbonyl-1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1Npyrazolo [4,3-c] pyridine -3-yl] benzamide; 3- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -5-isobutyryl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3c] pyridine -3-yl] benzonitrile; 3- (3-cyanophenyl) -1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -1,4,6,7tetrahydropyrazolo [4,3-c] pyridine- methyl ester 5-carboxylic acid; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (4-fluoro-3-trifluoromethylphenyl) -1,4,6,7tetrahydropyrazolo [4,3 -c] pyridin-5-yl] ethanone; 3- [5-acetyl-1 - ((1K, 2K) -4,6-dichloro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3c] pyridine -3-yl] benzonitrile; 1- [1 - ((1B, 2B) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (3-trifluoromethylphenyl) -1,4,6,7tetrahydropyrazolo [4,3-c] pyridine -5-yl] ethanone; - 39,023,648 racemic 1- [1 - ((18,28) -4,6-difluoro-2-hydroxy-2-methylindan-1-yl) -3 - (4-fluoro-3 trifluoromethylphenyl) -1,4, 6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone; 3- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -5- (3,3,3-trifluoropropyl) -4,5,6,7-tetrahydro-1Npyrazolo [4,3-c] pyridin-3-yl] benzamide; 3- [5-acetyl-1 - ((1K, 2K) -4-chloro-6-fluoro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4.3s ] pyridin-3-yl] benzonitrile; 3- [5-acetyl-1 - ((1K, 2K) -6-chloro-4-fluoro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4.3s ] pyridin-3-yl] benzonitrile; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (3-methoxyphenyl) -1,4,6,7tetrahydropyrazolo [4,3-c] pyridine -5-yl] ethano on; 3- [5-acetyl-1 - ((1K, 2K) -4,6-difluoro-2-methoxyindan-1-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3c] pyridine -3-yl] benzonitrile; 1 - [(8) -3- (4-fluorophenyl) -1-indan-1-yl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (4-fluorophenyl) -1,4,6,7-tetrahydropyrazolo [4,3c] pyridine -5-yl] ethanone; 3- [5-acetyl-1 - ((1K, 2K) -4-cyclopropyl-6-fluoro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1Npyrazolo [4,3-s ] pyridin-3-yl] benzonitrile; (1K, 2K) -1- [5-cyclopropylmethyl-3- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] 4.6-difluorindan-2-ol ; ester (1K, 2K) -1- [3- (3-cyanophenyl) -5-propionyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] 4.6-difluorindan-2- ilpropionic acid; 1- [1 - ((1K, 2K) -4,6-dichloro-2-hydroxyindan-1-yl) -3 - (6-trifluoromethylpyridin-2-yl) -1,4,6,7tetrahydropyrazolo [4,3 -c] pyridin-5-yl] ethanone; (1K, 2K) -4,6-difluoro-1- [3- (4-fluorophenyl) -5- (2-methoxyethyl) -4,5,6,7-tetrahydropyrazolo [4,3c] pyridin-1-yl ] indan-2-o la; 1- [1 - ((1K, 2K) -6-chloro-4-fluoro-2-hydroxyindan-1-yl) -3 - (4-fluorophenyl) -1,4,6,7tetrahydropyrazolo [4,3-s ] pyridin-5-yl] ethanone; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (4-trifluoromethylphenyl) -1,4,6,7tetrahydropyrazolo [4,3-c] pyridine -5-yl] ethanone; (1K, 2K) -4,6-difluoro-1- [3- (4-fluorophenyl) -5-propyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1yl] indan-2 -ola; 3- [5-acetyl-1 - ((18,28) -4,6-difluoro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3c] pyridine -3-yl] benzonitrile; 3- [5-acetyl-1 - ((1K, 2K) -6-chloro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3c] pyridin-3 -yl] benzonitrile; 1 - [(K) -3- (4-fluorophenyl) -1-indan-1-yl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone; 3- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -5- (2-methoxyacetyl) -4,5,6,7-tetrahydro-1Npyrazolo [4,3 -c] pyridin-3-yl] benzonitrile; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3 - (3-trifluoromethylphenyl) -1,4,6,7tetrahydropyrazolo [4,3-c] pyridine -5-yl] ethanone; 1- [1 - ((18,28) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (3-trifluoromethoxyphenyl) -1,4,6,7tetrahydropyrazolo [4,3-c] pyridine -5-yl] ethanone; 1- [1 - ((1K, 2K) -6-chloro-2-hydroxyindan-1-yl) -3- (4-fluorophenyl) -1,4,6,7-tetrahydropyrazolo [4,3c] pyridin-5 -yl] ethanone; 3- [5-cyclopropylmethyl-1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1Npyrazolo [4,3-c] pyridine -3-yl] benzonitrile; 3- [5-acetyl-1 - ((1K, 2K) -4-ethyl-6-fluoro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4.3s ] pyridin-3-yl] benzonitrile; 3- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -5- (2-methoxyethyl) -4,5,6,7-tetrahydro-1Npyrazolo [4.3 -c] pyridin-3-yl] benzonitrile; 3- [5-acetyl-1 - ((1K, 2K) -6-fluoro-2-hydroxy-4-methylsulfanylindan-1-yl) -4,5,6,7-tetrahydro-1Npyrazolo [4,3-s ] pyridin-3-yl] benzonitrile; 3- [5-acetyl-1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3c] pyridine -3-yl] benzonitrile; 3- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -5- (3,3,3-trifluoropropyl) -4,5,6,7-tetrahydro-1Npyrazolo [4,3-c] pyridin-3-yl] benzamide; 3- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -5- (2,2-dimethylpropionyl) -4,5,6,7-tetrahydro-1Npyrazolo [4 3-c] pyridin-3-yl] benzonitrile; racemic 1- [1 - ((1K, 2K) -5,6-dichloro-2-hydroxyindan-1-yl) -3- (4-fluorophenyl) -1,4,6,7tetrahydropyrazolo [4,3-s] pyridin-5-yl] ethanone; 1- [1 - ((1K, 2K) -4,6-difluoro-2-methoxyindan-1-yl) -3- (4-fluorophenyl) -1,4,6,7-tetrahydropyrazolo [4,3c] pyridine -5-yl] ethanone; - 40 023648 1- [3- (3-chlorophenyl) -1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -1,4,6,7-tetrahydropyrazolo [4,3c] pyridine -5-yl] ethanone; racemic 3- [5-acetyl-1 - ((1K, 2K) -4,6-difluoro-2-hydroxy-2-methylindan-1-yl) -4,5,6,7tetrahydro-1H-pyrazolo [4, 3-c] pyridin-3-yl] benzonitrile; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3-p-tolyl-1,4,6,7-tetrahydropyrazolo [4,3c] pyridin-5 -yl] ethanone; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (4-fluoro-3-methoxyphenyl) -1,4,6,7tetrahydropyrazolo [4,3 -c] pyridin-5-yl] ethanone; 5- [5-acetyl-1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3c] pyridine -3-yl] -2-fluorobenzonitrile; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (3-fluorophenyl) -1,4,6,7-tetrahydropyrazolo [4,3c] pyridine -5-yl] ethanone; 1- [3- (4-chlorophenyl) -1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -1,4,6,7-tetrahydropyrazolo [4,3c] pyridine -5-yl] ethanone; racemic 1- [1 - ((1K, 2K) -5,7-dichloro-2-hydroxyindan-1-yl) -3- (4-fluorophenyl) -1,4,6,7tetrahydropyrazolo [4,3-s] pyridin-5-yl] ethano n; 1- [1 - ((1K, 2K) -4,6-difluoro-2-hydroxyindan-1-yl) -3- (4-methoxyphenyl) -1,4,6,7tetrahydropyrazolo [4,3-c] pyridine -5-yl] ethano on; (1K, 2K) -4,6-difluoro-1- [3- (4-fluorophenyl) -5-isopropyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1yl] indan-2 -ola; (1K, 2K) -1- [5-acetyl-3- (3-cyanophenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -6-fluoro-2hydroxyindan- 4-carbonitrile; 3- [1 - ((1K, 2K) -4,6-dichloro-2-hydroxyindan-1-yl) -5-methanesulfonyl-4,5,6,7-tetrahydro-1 N-pyrazolo [4,3-c] pyridine -3-yl] benzonitrile, their stereoisomeric forms and / or their physiologically tolerated salts. 6. A medicament for treating or preventing ΤΑδΤΑ-1 channel-mediated diseases, comprising a compound of formula I and / or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5. 7. The use of a compound of formula I and / or its pharmaceutically acceptable salt according to any one of claims 1 to 5 for the treatment or prevention of ΤΑδΚ-1 channel-mediated diseases. 8. The use of a compound of formula I and / or its pharmaceutically acceptable salt according to any one of claims 1 to 5 for the treatment or prevention of arrhythmias, atrial tachyarrhythmias, atrial fibrillation and atrial flutter. 9. The use of a compound of formula I and / or its pharmaceutically acceptable salt according to any one of claims 1-5 for the treatment or prevention of respiratory disorders during sleep, attacks of central and obstructive sleep apnea, syndrome of increased resistance of the upper respiratory tract, chain-Stokes breathing , snoring, disorders of central regulation of breathing, sudden infant death syndrome, postoperative hypoxia and apnea, respiratory muscle disorders, respiratory disorders after prolonged mechanical ventilation (weaned Ie), respiratory disorders during adaptation in high mountains, acute respiratory disorders, chronic pulmonary disorders with hypoxia and hypercapnia, chronic obstructive pulmonary disease and hypoventilation syndrome due to obesity. 10. The use of a compound of formula I and / or its pharmaceutically acceptable salt according to any one of claims 1 to 5 as a respiratory stimulant for the treatment or prevention of respiratory depression associated with anesthesia or procedural sedation for minor interventions or for diagnostic purposes. 11. The use of a compound of formula I and / or its pharmaceutically acceptable salt according to any one of claims 1 to 5 as a respiratory stimulant for the treatment or prevention of respiratory depression with opioids in the treatment of chronic pain, for example, with a malignant tumor or palliative therapy or procedural sedation and / or weaning from prolonged mechanical ventilation. 12. The use of a compound of formula I and / or its pharmaceutically acceptable salt according to any one of claims 1 to 5 for the treatment or prevention of multiple sclerosis and inflammatory or degenerative disorders of the central nervous system. 13. The use of a compound of formula I and / or its pharmaceutically acceptable salt according to any one of claims 1 to 5 for intravenous administration, oral administration, nasal administration, intramuscular administration, subcutaneous administration, inhalation administration, topical administration or pharyngeal administration. 14. The method of obtaining the compounds of formula I according to any one of claims 1 to 5, comprising reacting 4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridines 3 with epoxides 6 or 10 to obtain 2-hydroxyindane -1-yl-substituted 4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridines 11 by heating a mixture of compound 3 and epoxide 6 in the presence of an excess of base in an inert solvent or by deprotonation of compound 3 with a base and its alkylation with epoxide 6: - 41 023648 where the residues A, K ³ , K ⁶ , K ⁷ , K ⁸ , K ⁹ have the same meanings as indicated in claims 1-5. 15. The method of obtaining the compounds of formula I according to any one of claims 1 to 5, comprising the interaction 4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine 3 with aminoindan-1-oles 4 ′ or 8 ′ by heating a mixture of compound 3 and aminoindan-1-ol 4 ′ or 8 ′ in the presence of phosphine and compound 1,1 '- (azodicarbonyl) to obtain compound 12 where the residues A, K ³ , K ⁶ , K ⁷ , K ⁸ , K ⁹ have the same meanings as indicated in claims 1-5, and where K ²