CLOZEL MARTINE
WELLER THOMAS
KOBERSTEIN RALF
AISSAOUI HAMED
SIFFERLEN THIERRY
| 1. | l. |
| 2. | and optically pure enantiomers, mixtures of enantiomers racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixture of diastereoisomeric racemates, or meso forms and pharmaceutically acceptable salts thereof. |
| 3. | Compounds of the general formula (II) Formula (II) wherein: R'land R'2 independently represent hydrogen, hydroxy, lower alkoxy, lower alkenyloxy or halogen or may form with the phenyl ring a five, six or seven memberedring containing one or two oxygen atoms; R'3, R'4, R'5 independently represent aryl, aralkyl, lower alkyl, lower alkenyl, trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyllower alkyl ; <BR> <BR> <BR> XYindependently representsCH2CH2,OCH2,SCH2,S02CH2andNR'6CO ; R'6represents hydrogen, lower alkyl or aralkyl. and optically pure enantiomers, mixtures of enantiomers racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixture of diastereoisomeric racemates, or meso forms and pharmaceutically acceptable salts thereof. |
| 4. | 2 [1 (3, 4Dimethoxybenzyl)7, 8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]Nnaphthalen1ylmethylacetamide. |
| 5. | NBenzo [1, 3] dioxol5ylmethyl2 [l (3, 4dimethoxybenzyl)7, 8dimethoxy 1, 3,4,5tetrahydrobenzo [c] azepin2yl]acetamide 5. 2 [1 (3, 4Dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]Nindan2ylacetamide 6.2 [5 (3,4Dimethoxybenzyl)7,8dimethoxy2,3dihydro5Hbenzo [n [1, 4] oxazepin 4yl]Nindan2ylacetamide 7.2 [5 (3,4Dimethoxybenzyl)7,8dimethoxy2,3dihydro5Hbenzo [ig [1, 4] oxazepin 4yl]Nindan1ylacetamide 8.2 [1 (3, 4Dimethoxybenzyl)7, 8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]Nindan1ylacetamide 9.2 [9 (3,4Dimethoxybenzyl)2,3dimethoxy5,5dioxo5,6,7,9tetrahydro516thia 8azabenzocyclohepten8yl]Nindan2ylacetamide 10. 2[9(3,4Dimethoxybenzyl)2,3dimethoxy5,5dioxo5,6,7,9tetrahydro516thia 8azabenzocyclohepten8yl]Nindan1ylacetamide 11.2 [1 (3, 4Dimethoxybenzyl)7, 8dimethoxy1,3,4, 5tetrahydrobenzo [c] azepin2 yl]Nindan1ylacetamide 12.2 [l (3, 4Dimethoxybenzyl)7, 8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]Nindan2yl2phenylacetamide 13.2 [9 (3,4Dimethoxybenzyl)2,3dimethoxy6,7dihydro9H5thia8aza benzocyclohepten8yl]Nnaphthalen1ylmethylacetamide 14.2 [9 (3,4Dimethoxybenzyl)2,3dimethoxy6,7dihydro9H5thia8aza benzocyclohepten8yl]N(2ethoxybenzyl)acetamide 15.2 [9 (3, 4Dimethoxybenzyl)2, 3dimethoxy6, 7dihydro9H5thia8aza benzocyclohepten8yl]Nindan1ylacetamide 16.2 [5 (3,4Dimethoxybenzyl)7,8dimethoxy2,3dihydro5Hbenzo [f] [1, 4] oxazepin 4yl]N(1,2,3,4tetrahydronaphthalen1yl)acetamide 17. NBenzyl2 [9 (3, 4dimethoxybenzyl)2,3dimethoxy6,7dihydro9H5thia8aza benzocyclohepten8yl]acetamide 18. 2[5(3,4Dimethoxybenzyl)7,8dimethoxy2,3dihydro5Hbenzo[f][1, 4] oxazepi 4yl]Nindan1ylacetamide 19. NButyl2 [l (3, 4dimethoxybenzyl)7, 8dimethoxy1, 3,4,5tetrahydro benzo [c] azepin2yl]2phenylacetamide 20.2 [l (3,4Dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]Nindan1yl2phenylacetamide 21. NBenzo [l, 3] dioxol5ylmethyl2 [l (3, 4dimethoxybenzyl)7, 8dimethoxy 1, 3,4,5tetrahydrobenzo [c] azepin2yl]2phenylacetamide 22. NCyclopentyl2 [l (3, 4dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydro benzo [c] azepin2yl]2phenylacetamide 23. 2 [l (3, 4Dimethoxybcnzyl)7, 8dimethoxyl, 3,4,5tetrahydrobenzo [c] azepin2 yl]Nfuran2ylmethyl2phenylacetamide 2. |
| 6. | {2 [1 (3, 4Dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]2phenylacetylamino}acetic acid ethyl ester 25.2 [1 (3,4Dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]2phenylNpyridin4ylmethylacetamide 26.2 [I (3, 4Dimethoxybenzyl)7, 8dimethoxy1,3,4, 5tetrahydrobenzo [c] azepin2 yl]2phenylNpyridin3ylmethylacetamide 27. NCyclopropyl2 [1 (3, 4dimethoxybenzyl)7, 8dimethoxy1, 3,4,5tetrahydro benzo [c] azepin2yl]2phenylacetamide 28. 2[1(3, 4Dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]N (2oxotetrahydrofuran3yl)2phenylacetamide 29. 2[1(3, 4Dimethoxybenzyl)7, 8dimethoxy1, 3,4,5tetrahydrobenzo [c] azepin2 yl]N(4methoxyindan1yl)acetamide 30. 2 [1 (3, 4Dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]N(3phenylindan1yl)acetamide 31.2 [1 (3, 4Dimethoxybenzyl)7, 8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]N(4methylindan1yl)acetamide 32. 2{2[1(3, 4Dimethoxybenzyl)7, 8dimethoxy1, 3,4,5tetrahydrobenzo [c] azepin 2yl]2phenylacetylamino}3hydroxypropionic acid methyl ester 33.2 [l (3,4Dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]Nethylcarbamoylmethyl2phenylacetamide 34.2 [l (3,4Dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin2 yl]N[(ethylmethylcarbamoyl)methyl]2phenylacetamide 3. |
| 7. | 2[1(3,4Dimethoxybenzyl)8hydroxy7methoxy1, 3,4,5tetrahydro benzo [c] azepin2yl]Nindanlylacetamide 3. |
| 8. | 2[8Benzyloxy1(3,4dimethoxybenzyl)7methoxy1, 3,4,5tetrahydro benzo [c] azepin2yl]Nindan1ylacetamide 37. 3{2[1(3, 4Dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin 2yl]2phenylacetylamino}propionic acid methyl ester 38. NBenzo [1, 3] dioxol5ylmethyl2 [1 (3, 4dimethoxybenzyl)8hydroxy7methoxy 1, 3,4,5tetrahydrobenzo [c] azepin2yl]2phenylacetamide 39. N (IHBenzoimidazol2ylmethyl)2 [1 (3, 4dimethoxybenzyl)7, 8dimethoxy 1, 3,4,5tetrahydrobenzo [c]azepin2yl]2phenylacetamide 40.2 [8Allyloxyl (3,4dimethoxybenzyl)7methoxy1,3,4,5tetrahydro benzo [c] azepin2yl]Nindan1ylacetamide 41.2 [1 (3,4Dimethoxybenzyl)7methoxy8propoxy1,3,4,5tetrahydro benzo [c] azepin2yl]Nindan1ylacetamide 42.3 2 [l (3, 4Dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin 2yl]2phenylacetylamino}N, Ndimethylpropionamide 43.3 {2 [l (3,4Dimethoxybenzyl)7,8dimethoxy1,3,4,5tetrahydrobenzo [c] azepin 2yl]2phenylacetylamino}NethylNmethylpropionamide 44.2 [1 (3, 4Dimethoxybenzyl)8isopropoxy7methoxy1,3,4,5tetrahydro benzo [c] azepin2yl]Nindan1ylacetamide 45.2 [8 (2, 2Difluoroethoxy)1 (3, 4dimethoxybenzyl)7methoxy1,3,4,5 tetrahydrobenzo [c] azepin2yl]Nindan1ylacetamide 4. |
| 9. | Pharmaceutical compositions for the treatment of disorders which are associated with the role of orexin, especially disorders such as obesity and sleep disorders, comprising containing a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, and usual carrier materials and adjuvants. |
| 10. | 47 The compounds of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, for use as medicaments for the treatment of disorders which are associated with a role of orexin, especially obesity and sleep disorders. |
| 11. | 48 A method of treating or preventing diseases or disorders where an antagonist of a human orexin receptor is required, which comprises administering to a subject in need thereof an effective amount of a compound as claimed in any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof. |
| 12. | A process for the manufacture of pharmaceutical compositions for the treatment of disorders associated with the role of orexin, especially obesity and sleep disorders, containing one or more compounds as claimed in any one of claims 1 to 15, or a pharmaceutically acceptable salt or salts thereof, as active ingredients which process comprises mixing one or more active ingredient or ingredients with pharmaceutically acceptable excipients and adjuvants in a manner known per se. |
| 13. | A compound as described as endproduct in any one of examples 1 to 43. |
| 14. | The invention as hereinbefore described. |
The orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: the orexin A (OX-A) (a 33 aminoacid peptide) and the orexin B (OX-B) (a 28 aminoacid peptide) (Sakurai T. et al., Cell, 1998,92,573-585). Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92,573-585). On the other hand, it was also proposed that orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcoleptic patients (Chemelli R. M. et al., Cell, 1999,98,437-451). Two orexin receptors have been cloned and characterized in mammals. They belong to the superfamily of G-protein coupled receptor (Sakurai T. et al., Cell, 1998,92,573-585). The orexin-1 receptor (OXI) is selective for OX-A and the orexin-2 receptor (OX2) is capable to bind OX-A as well as OX-B.
Orexin receptors are found in the mammalian host and may be responsible for many biological functions such as pathologies including, but not limited to, depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis ; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction ; psychosexual dysfunction ; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; feeding disorders such as anorexia, bulimia, cachexia and obesity; diabetes; appetite/taste disorders; vomiting/nausea ; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease ; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma ; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcus; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; pituitary growth hormone; adrenohypophysis hypofunction; adrenohypophysis hyperfunction ; hypothalamic
hypogonadism ; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms ; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome ; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardinal infarction; ischaemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e. g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, migraine and angina; urinary bladder incontinence e. g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy ; insomnia; parasomnia ; jet-lag syndrome; and neurodegerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration epilepsy; seizure disorders and other diseases related to orexin.
The present invention provides benzazepines and related heterocyclic derivatives which are non-peptide antagonists of human orexin receptors, in particular OX1 and OX2 receptors. In particular, these compounds are of potential use in the treatment of obesity and/or sleep disorders.
So far not much is known about low molecular weight compounds which have a potential to antagonise either specifically OXI or OX2 or both receptors at the same time. Recently WO 99/09024, WO 99/58533, WO 00/47577 and WO 00/47580 have been published wherein phenyl urea and phenyl thiourea derivatives are described as being preferably OX1 receptor antagonists. Also quite recently WO 00/47576 described cinnamide derivatives as OXl receptor antagonists. The novel compounds of the present invention belong to an entirely different class of low molecular weight compounds as compared to all prior art orexin receptor antagonists so far published.
The present invention relates to novel benzazepines and related heterocyclic derivatives of the general formula (I).
Formula (I) wherein: R1, R2, R3, R4 independently represent cyano, nitro, halogen, hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, R"CO-, NR12R13CO-, R12R13N-, R11OOC-, R"S02NH-, or R14-CO-NH-, or R2 and R3 together as well as Rl and R2 together and R3 and R4 together may form with the phenyl ring a five, six or seven-membered saturated ring containing one or two oxygen atoms; R5, R6, R7, R8, R9, R10 independently represent hydrogen, aryl, aralkyl, lower alkyl, lower alkenyl, trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl ; R11 represents lower alkyl, lower alkenyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl ; R12 and R13 independently represent hydrogen, lower alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl ; R14 represents lower alkyl, aryl, cycloalkyl, heterocyclyl, R12R13N-, R11O-; -X-Y- independently represents -CH2-CH2-, -O-CH2-, -S-CH2-, -SO2-CH2- and -NHR15-CO-; Rls represents hydrogen, lower alkyl or aralkyl.
The compounds of formula (I) can contain one or more asymmetric centres and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates, or meso forms and pharmaceutically acceptable salts thereof.
In the present description the term"lower alkyl", alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 6 carbon atoms, preferably a straight or branched-chain alkyl group with 1-4 carbon atoms. Examples of straight-chain and branched Cl-C8 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl, ethyl, n- propyl, isopropyl, n-butyl, 2-butyl, tert-butyl and n-pentyl.
The term"lower alkenyl", alone or in combination, signifies a straight-chain or branched-chain alkenyl group with 2 to 5 carbon atoms, preferably allyl and vinyl.
The term"lower alkoxy", alone or in combination, signifies a group of the formula alkyl-O-in which the term"alkyl"has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert- butoxy, preferably methoxy and ethoxy.
Lower alkenyloxy groups are preferably vinyloxy and allyloxy.
The term"cycloalkyl", alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms.
Examples of C3-C8 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl, cyclohexyl and particularly cyclohexyl or lower alkyl substituted cycloalkyl which may preferably be substituted
with lower alkyl such as methyl-cyclopropyl, dimethyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, methyl-cyclohexyl, dimethyl-cyclohexyl.
The term"aryl", alone or in combination, signifies a phenyl or naphthyl group which optionally carries one or more substituents, preferably one or two substituents, each independently selected from cyano, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, nitro, trifluoromethyl, trifluoromethoxy, amino, carboxy and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-tert-butoxyphenyl, 4- fluorophenyl, 2-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl and 2-naphthyl. Preferred are carboxyphenyl, lower alkoxy-phenyl, hydroxyphenyl and particularly phenyl.
The term"aralkyl", alone or in combination, signifies an alkyl or cycloalkyl group as previously defined in which one hydrogen atom has been replaced by an aryl group as previously defined. Preferred are benzyl and benzyl substituted in the phenyl ring with hydroxy, lower alkyl, lower alkoxy or halogen preferably chlorine.
Particularly preferred is benzyl.
For the term"heterocyclyl"and"heterocyclyl-lower alkyl", the heterocyclyl group is preferably a 5-to 10-membered monocyclic or bicyclic ring, which may be saturated, partially unsaturated or aromatic containing for example 1,2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur which may be the same or different. Example of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, thiazolyl, isothiazolyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, indazolyl, indolyl, isoindolyl, isoxazolyl, oxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, dihydropyrrolyl, pyrrolidinyl, isobenzofuranyl, tetrahydrofuranyl,
dihydropyranyl. The heterocyclyl group may have up to 5, preferably 1,2 or 3 optional substituents. Examples of suitable substituents include halogen, lower alkyl, amino, nitro, cyano, hydroxy, lower alkoxy, carboxy and lower alkyloxy-carbonyls.
The term"halogen"signifies fluorine, chlorine, bromine or iodine and preferably chlorine and bromine and particularly chlorine.
The term"carboxy", alone or in combination, signifies a-COOH group.
A group of preferred compounds according to the present invention are compounds of formula (II)
General formula (II) wherein : R'land R'2 independently represent hydrogen, hydroxy, lower alkoxy, lower alkenyloxy or halogen or may form with the phenyl ring a five, six or seven membered-ring containing one or two oxygen atoms; R'3, R'4, R'5 independently represent aryl, aralkyl, lower alkyl, lower alkenyl, hydrogen trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl ; <BR> <BR> <BR> -X-Y-independently represents-CH2-CH2-,-O-CH2-,-S-CH2-,-SO2-CH2-and-NR'6-CO-; R represents hydrogen, lower alkyl or aralkyl.
The compounds of formula (II) can contain one or more asymmetric centres and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixture of diastereoisomeric racemates, or meso forms
and pharmaceutically acceptable salts thereof.
Examples of preferred compounds of formula (II) are: 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- naphthalen-1-ylmethyl-acetamide N-Benzo [1, 3] dioxol-5-ylmethyl-2- [1- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5- tetrahydro-benzo [c] azepin-2-yl]-acetamide 2-[1-(3,4-Dimethoxy-benzyl)-7, 8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-2-yl-acetamide 2- [5- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-2,3-dihydro-5H-benzo [: [1, 4] oxazepin-4-yl]- N-indan-2-yl-acetamide 2- [5- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo [fl [1, 4] oxazepin-4-yl]- N-indan-1-yl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-1-yl-acetamide 2- [9- (3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetra hydro-5X-thia-8-aza- benzocyclohepten-8-yl]-N-indan-2-yl-acetamide 2- [9- (3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetra hydro-5X-thia-8-aza- benzocyclohepten-8-yl]-N-indan-l-yl-acetamide 2-[1-(3,4-Diethoxy-benzyl)-7,8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-1-yl-acetamide 2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-2-yl-2-phenyl-acetamide
2- [9- (3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8 -aza- benzocyclohepten-8-yl]-N-naphthalen-1-ylmethyl-acetamide 2- [9- (3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8 -aza- benzocyclohepten-8-yl]-N-(2-ethoxy-benzyl)-acetamide 2- [9- (3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8 -aza- benzocyclohepten-8-yl]-N-indan-1-yl-acetamide 2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-ben hzo[f][1, 4] oxazepin-4-yl]- N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide N-Benzyl-2- [9- (3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8 -aza- benzocyclohepten-8-yl]-acetamide 2- [5- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-2,3-dihydro-5H-benzo [f] [1, 4] oxazepin-4-yl]- N-indan-1-yl-acetamide N-Butyl-2- [l- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2- yl]-2-phenyl-acetamide 2- [1- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-1-yl-2-phenyl-acetamide N-Benzo [1, 3] dioxol-5-ylmethyl-2-[1-(3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5- tetrahydro-benzo [clazepin-2-yl]-2-phenyl-acetamide N-Cyclopentyl-2- [l- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-2-phenyl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- furan-2-ylmethyl-2-phenyl-acetamide
f2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2- phenyl-acetylamino}-acetic acid ethyl ester 2- [l- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2- phenyl-N-pyridin-4-ylmethyl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2- phenyl-N-pyridin-3-ylmethyl-acetamide N-Cyclopropyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-2-phenyl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N-(2- oxo-tetrahydro-furan-3-yl)-2-phenyl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N-(4- methoxy-indan-1-yl)-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N-(3- phenyl-indan-1-yl)-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N-(4- methyl-indan-1-yl)-acetamide 2-{2-[1-(3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2- phenyl-acetylamino}-3-hydroxy-propionic acid methyl ester 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- ethylcarbamoylmethyl-2-phenyl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- [(ethyl-methyl-carbamoyl)-methyl]-2-phenyl-acetamide
2- [l- (3, 4-Dimethoxy-benzyl)-8-hydroxy-7-methoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2- yl]-N-indan-1-yl-acetamide 2- [8-Benzyloxy-l- (3, 4-dimethoxy-benzyl)-7-methoxy-l, 3,4,5-tetrahydro-benzo [c] azepin-2 yl]-N-indan-1-yl-acetamide 3- {2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2- phenyl-acetylamino}-propionic acid methyl ester N-Benzo [1, 3] dioxol-5-ylmethyl-2- [1- (3, 4-dimethoxy-benzyl)-8-hydroxy-7-methoxy- 1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2-phenyl-acetamide N (lH-Benzoimidazol-2-ylmethyl)-2- [l- (3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5- tetrahydro-benzo [c] azepin-2-yl]-2-phenyl-acetamide 2-[8-Allyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2- yl]-N-indan-1-yl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7-methoxy-8-propoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2- yl]-N-indan-1-yl-acetamide 3- {2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2- phenyl-acetylamino}-N,N-dimethyl-propionamide 3- {2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2- phenyl-acetylamino}-N-ethyl-N-methyl-propionamide 2- [l- (3, 4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1, 3,4,5-tetrahydro-benzo [c] azepin- 2-yl]-N-indan-1-yl-acetamide 2-[8-(2,2-Difluoro-ethoxy)-1-(3,4-dimethoxy-benzyl)-7-methox y-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-N-indan-1-yl-acetamide
Examples of particularly preferred compounds of formula (II) are: 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-2-yl-acetamide 2- [5- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo [f] [1,4] oxazepin-4-yl]- N-indan-1-yl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-1-yl-acetamide 2- [1- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-1-yl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-2-yl-2-phenyl-acetamide N-Butyl-2- [l- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2- yl]-2-phenyl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-1-yl-2-phenyl-acetamide N-Benzo [1, 3] dioxol-5-ylmethyl-2- [l- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5- tetrahydro-benzo [c] azepin-2-yl]-2-phenyl-acetamide N-Cyclopentyl-2-[1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-2-phenyl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- furan-2-ylmethyl-2-phenyl-acetamide {2- [l- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2- phenyl-acetylamino}-acetic acid ethyl ester
2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2- phenyl-N-pyridin-3-yhnethyl-acetamide 3- {2- [l- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2- phenyl-acetylamino}-propionic acid methyl ester N (lH-Benzoimidazol-2-ylmethyl)-2- [1- (3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5- tetrahydro-benzo [c] azepin-2-yl]-2-phenyl-acetamide 2-[8-Allyloxy-1-(3,4-dimethoxy-benzyl)-7-methoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2- yl]-N-indan-1-yl-acetamide 2- [l- (3, 4-Dimethoxy-benzyl)-7-methoxy-8-propoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2- yl]-N-indan-1-yl-acetamide 2- [1- (3, 4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1,3,4,5-tetrahydr o-benzo [c] azepin- 2-yl]-N-indan-1-yl-acetamide 2- [8- (2, 2-Difluoro-ethoxy)-l- (3, 4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-N-indan-1-yl-acetamide Examples of physiologically usable or pharmaceutically acceptable salts of the compounds of formula (I) are salts with physiologically compatible mineral acids such as hydrochloric acid, sulphuric or phosphoric acid; or with organic acids such as methanesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The compounds of formula (I) with free carboxy groups can also form salts with physiologically compatible bases.
Examples of such salts are alkali metal, alkali earth metal, ammonium and alkylammoniumsalts such as Na, K, Ca or tetraalkylammonium salt. The compounds of formula (I) can also be present in the form of a zwitterion.
Preferred compounds as described above have IC50 values below 1000 nM;
especially preferred compounds have ICso values below 100 nM which have been determinated with the FLIPR (Fluorometric hnaging Plates Reader) method described in the beginning of the experimental section.
The compounds of the general formula (I) and their pharmaceutically usable salts can be used for the treatment of diseases or disorders where an antagonist of a human orexin receptor is required such as obesity, diabetes, prolactinoma, narcolepsy, insomnia, sleep apnea, parasomnia, depression, anxiety, addictions, schizophrenia and dementia.
The compounds of formula (I) and their pharmaceutically usable salts are particularly useful for the treatment of obesity and sleep disorders.
The compounds of formula (I) and their pharmaceutically usable salts can be used as medicament (e. g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e. g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e. g. in the form of nasal sprays) or rectally (e. g. in the form of suppositories). However, the administration can also be effected parenterally, such as intramuscularly or intravenously (e. g. in the form of injection solutions).
The compounds of formula (I) and their pharmaceutically usable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees, and hard gelatine capsules.
Suitable adjuvants for soft gelatine capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The invention also relates to processes for the preparation of compounds of Formula (I).
The compounds of general formula (I) of the present invention are prepared according to the general sequence of reactions outlined in the schemes below, wherein Rl, R2, R, R4, R5, R6, R, R8, R9, Rl° are as defined in formula (I) above. As the case may be any compound obtained with one or more optically active carbon atom may be resolved into pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates and the meso-forms in a manner known per se.
The compounds obtained may also be converted into a pharmaceutically acceptable salt thereof in a manner known per se.
The compounds of the general formula (I) may be prepared by standard procedures (procedure A wherein R and R8 are hydrogen) and (procedure B wherein R7 and R8 are other than hydrogen) shown in Scheme 1 using synthesized benzazepine and related heterocyclic derivatives.
Scheme 1
Benzazepine derivatives wherein X and Y are CH2 and R6 is hydrogen might be prepared from the corresponding phenylpropylamine by coupling with the desired carboxylic acid or acyl chloride followed by treatment with POC13 and finally NaBH4 (Bischler-Napieralski reaction) as shown in Scheme 2a. R R 1 R6C02H R I or R5COCI RZ I \ p R4 3 N'k RS o R4 R4. O ) CI''O Bischler-Napieralski 2) NH40H 25% reaction 3) LiAIH4 R R1 R1 R3ZJW OAOH R3X\NH R4 R4 Rs Scheme 2a Benzazepines with variable substituents on position 8 might be prepared by hydrogenolysis of the corresponding 8-benzyloxy-1, 3,4,5-tetrahydro-benzazepines followed by O-alkylation with the appropriate electrophile (Scheme 2b). The benzylethers can be obtained with the previous procedure (Scheme2a) applied to 3- (4-benzyloxy-phenyl)-propionic acid derivatives.
R5CO2H R1 KgUUrt or RSCOCI R2 I \ O I I I _, l 11 Bn NH2 BnO Ni'i RS Rq, Rq. 1) BnBr/K2CO3 Bischler-Napieralski 2) 2N NaOH reaction 0 R ci) 0 R2 4) NH40H25%) 5) LiAIH4 BnO<NH R4 Rs R R2 1) Procedure A or B 2) H21 Pd (C) HO H 3) R11Br/K2CO3 0 0 0 Ri /I' Rio o R4 Rs R7 Rs Rg Scheme 2b Benzothiazepine and benzoxazepine derivatives wherein X is O or S, Y is CH2 and R6 is hydrogen might be prepared from the corresponding arylamine by coupling with the desired carboxylic acid or acyl chloride followed by treatment with POC13 and finally NaBH4 (Bischler-Napieralski reaction) as shown in Scheme 3. R R or R5COC1 R2 I \ X O zu Ruz R4 4 1) CICN Bischler-Napieralski reaction Rl Pi R2 I XH R2 / 3 NU R4 R4 R5
Scheme 3 1, 3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives wherein X is Nuis, Y is Co, R6 is hydrogen might be prepared by Friedel-Crafts acylation of the correspond acetamido-aniline with the respective acyl chloride (Sternbach L. H. et al., J. Org. Che 1962,27,3781-3788), followed by N-deprotection, cyclisation by treatment with met esters of a-amino acids (Sternbach L. H. et al., J. Org. Chem., 1962,27, 3788-3796) finally hydrogenolysis of the dihydro compound (Fryer R. I. et al., J. Med. Chem., 19 386-389) (Scheme 4).
Scheme 4 For the preparation of benzazepine derivatives with electron-withdrawing substituents on the phenyl ring, the previous procedures based on the Bischler-Napieralski reaction are incompatible. Therefore cyano groups might be introduced by reaction of a triflate with cyanide ions and palladium (0) (Austin N. E. et al., Bioorg. Med. Chem. Lett., 2000,10, 2553-2555; Ritter K. et al., Synthesis, 1993,735 ; Selnick H. G. et al., Synth. Commun.
1995,25,20,3255-3262) (Scheme 5). R1 R15 R1 R15 R1 R2XNAc R ACI R2 A H'R2), NHR15 3 Friedel-Crafts R RS 11 Rs 4 reaction R4 0 3 R4 0 ru !' OCHg HCI.HAN O, Ri R15 R R2zIPt02 R2 R7 R7 3 N H R3 N R4 Rs Ra R5
Scheme 5
Carboxylic groups might also be introduced by reaction of a triflate with carbon monoxide, an alcohol and palladium (0) (Roth G. P. et al., Tetrahedron Lett., 1992, 33,1959 ; Ma D. et al., Bioorg. Med. Chem. Lett., 1998,8,18,2447-2450; Fisher M. J. et al., J. Med. Chem., 1997,40,2085-2101 ; Kraus G. A. et al., Tetrahedron Lett., 1994,35,9189-9190). These carboxylic functions can subsequently be converted into amino functionalties by hydrolysis and Curtius reaction (Scheme 6). ROHICO (CF3S02) 2° I IPd (0) HO /NBoc TEA /NBoc 'NBoc C (D- NE 1) hydrolysis 2) Curtius reaction NBoc R'CON<NBoc
Scheme 6 Halogen containing 2-benzazepines may be prepared by treatment of halogenated tetralone oximes with POC13/DMF and the resulting 1, 3,4,5-tetrahydro-1-oxo-2H-2-benzazepine-2- carboxaldehydes can be subsequently deformylated and reduced (Majo V. J. et al., Synth.
Commun., 1995,25,23,3863-3868) (Scheme 7). 1)deformylation \ DMFIPOC13 \ 2) reduction I -I/r I halo halogen halogen N. o
Scheme 7
8-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine might be prepared by regioselective nitrate of 2,3,4,5-tetrahydro-lH-2-benzazepin-1-one using potassium nitrate and sulfuric ac (Grunewald G. L. et al., J. Heterocyclic Chem., 1994,31,1609-1617) (Scheme 8). Schmidt reaction I \ KN031HZS04 0 1 1 CH 02N NH Scheme 8
Experimental Section I. Niolo Determination of OX1 and OX2 receptor antagonist activities The OXI and OXz receptor antagonist activities of the compounds of formula (I) were determinated in accordance with the following experimental method.
Experimental method: Intracellular calcium measurements Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, were grown in culture medium (Ham F-12 with L- Glutamin) containing 300 jug/ml G418,100 U/ml penicillin, 100 llg/ml streptomycin and 10 % inactivated foetal calf serum (FCS).
The cells were seeded at 80'000 cells/well into 96-well black clear bottom sterile plates (Costar) which had been precoated with 1% gelatine in Hanks'Balanced Salt Solution (HBSS). All reagents were from Gibco BRL.
The seeded plates were incubated overnight at 37°C in 5% C02.
Human orexin-A as an agonist was prepared as 1 mM stock solution in methanol: water (1: 1), diluted in HBSS containing 0.1 % bovine serum albumin (BSA) and 2 mM HEPES for use in the assay at a final concentration of 10 nM.
Antagonists were prepared as 10 mM stock solution in DMSO, then diluted in 96-well plates, first in DMSO, then in HBSS containing 0.1 % bovine serum albumin (BSA) and 2 mM HEPES.
On the day of the assay, 100 lil of loading medium (HBSS containing 1 % ECS, 2 mM HEPES, 5 mM probenecid (Sigma) and 3 FM of the fluorescent calcium indicator fluo-3 AM (1 mM stock solution in DMSO with 10% pluronic acid) (Molecular Probes) was added to each well.
The 96-well plates were incubated for 60 min at 37° C in 5% C02. The loading solution was then aspirated and cells were washed 3 times with 200 p1 HBSS containing 2.5 mM probenecid, 0.1% BSA, 2 mM HEPES. 100 RI of that same buffer was left in each well.
Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), antagonists were added to the plate in a volume of 50 1, incubated for 20 min and finally 100 1ll of agonist was added. Fluorescence was measured for each well at 1 second intervals, and the height of each fluorescence peak was compared to the height of the fluorescence peak induced by 10 nM orexin-A with buffer in place of antagonist. For each antagonist, ICso values (the concentration of compound needed to inhibit 50 % of the agonistic response) were determined. Selected compounds are displayed in Table 1 IC50 (nM) OX1 OX2 Example 9 23 1239 Example 3 99 > 10000 Example 5 64 7900 Example 34 41 9192 Example 35 32 7041 Example 20 23 231 Example23 21 189 Example 25 41 241 Example 42 12 174 Example 43 9 349
Table 1 II. Chemistry The following examples illustrate the preparation of pharmacologically active compounds of the invention but do not at all limit the scope thereof. All compounds were prepared in racemic form. All temperatures are stated in °C.
All hydrochloride salts were prepared by dissolving the free-base in dichloromethane and treating with an excess of HC1 in propanol-2 (5-6M).
A. Starting materials: Synthesis of tetrahydrobenzazepine and related heterocyclic derivatives: 3- (3, 4-Dimethoxy-phenyl)-propionamide To a stirred solution of 3- (3, 4-dimethoxy-phenyl)-propionic acid (10.0 g, 47.56 mmol) in dry THF (175 ml), under nitrogen, was added TEA (7.3 ml, 52.44 mmol), and the resulting mixture was cooled to-10°C before ethyl chloroformate (5 ml, 52.47 mmol) was added dropwise. After stirring at-10°C (20 min), ammonium hydroxide (25% in water, 105 ml) in THF (105 ml) was added and the mixture was stirred at - 15°C for 30 min and then at RT for 1. 5h. The reaction mixture was concentrated in vacuo, extracted three times with CH2C12 and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous MgS04, filtered and concentrated to give the titled compound (9.73 g, 46.50 mmol, 97%) as a colorless solid. No further purification of the crude amide was necessary.
LC-MS: rt = 2.94 min., 210 (M+1, ES+).
3- (3, 4-Dimethoxy-phenyl)-propylamine A solution of 3- (3, 4-dimethoxy-phenyl)-propionamide (11.09 g, 53.00 mmol) in anhydrous THF (400 ml) was slowly added to a stirred, ice-cooled suspension of L1A1H4 (4.02 g, 106.00 mmol) in anhydrous THF (170 ml). Upon completion of the addition, the mixture was stirred at reflux for 2h. After cooling to 0°C, H20 (5 ml) and NaOH 1N (5 ml) were added dropwise to decompose the excess of hydride. The suspension was then filtered and the residue after evaporation was partitioned between H20 (40 ml) and CH2C12 (100 ml). The organic layer was washed with NaHCO3 and brine, dried over
anhydrous MgSO4, and concentrated under reduced pressure to give the crude amine (7.00 g, 35.84 mmol, 68%) as a yellow oil.
'H-NMR (300 MHz, CDC13) 8 : 6.9-6.6 (3H, m), 3.9-3.8 (6H, d), 2.9-2.7 (2H, m), 2.65- 2.55 (2H, m), 1.9-1.75 (2H, m).
2-(3, 4-Dimethoxy-phenyl)-N-[3-(3, 4-dimethoxy-phenyl)-propyl]-acetamide A solution of3- (3, 4-dimethoxy-phenyl)-propylamine (12. 51 g, 64.06 mmol) and TEA (10 ml, 71.84 mmol) in anhydrous THF (70 ml) was cooled to 0°C and (3,4-dimethoxy- phenyl)-acetyl chloride (13.75 g, 64.07 mmol) in T} IF (28 ml) was added dropwise. After stirring at RT for 13h under nitrogen, a saturated aqueous NaHC03 solution was added and the reaction mixture was extracted three times with AcOEt. The organic phase was dried over anhydrous MgS04, filtered and the solvent was removed in vacuo. A subsequent washing of the crude solid with toluene gave the titled compound (12.81 g, 34.30 mmol, 53%) as a beige solid.
LC-MS: rt = 4.00 min., 374 (M+1, ES+).
1- (3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-b enzo [c] azepine A mixture of 2- (3, 4-dimethoxy-phenyl)-N [3- (3, 4-dimethoxy-phenyl)-propyl]-acetamide (6.16 g, 16.49 mmol) and POC13 (4.95 ml, 54.07 mmol) in anhydrous acetonitrile (185 ml) was stirred at reflux for 4h under nitrogen. After cooling, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (125 ml). The solution was cooled to 0°C and NaBH4 (4.31 g, 113.93 mmol) was added portionwise. After stirring at 0°C for 2h under nitrogen, the reaction mixture was poured into H2O and extracted three times with CH2C12. The combined organic extracts were washed with brine, dried over anhydrous MgS04, filtered and concentrated to give a crude oil. Flash chromatography (CH2Cl2/MeOH : 9/1) gave the titled compound as a racemic mixture (2.29 g, 6.40 mmol, 39%, yellow oil).
LC-MS: rt = 3.02 min., 358 (M+l, ES+).
[1- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1,3,4,5-tetrahydro-benzolc] azepin-2yl]- phenyl-acetic acid methyl ester
A mixture of 1- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH- benzo [c] azepine (1.10 g, 3.08 mmol), TEA (1.3 ml, 9.33 mmol), methyl a- bromophenylacetate (487 p1, 3.09 mmol) in anhydrous toluene (13 ml) was stirred at reflux for 17h under nitrogen. After cooling, the reaction mixture was dissolved in CH2C12 (40 ml), washed with Ha0 (15 ml) and the aqueous phase was extracted two times with CH2C12. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt/hexane : 1/1) gave the titled compound as a mixture of stereoisomers (1.34 g, 2.65 mmol, 86%, yellow oil).
LC-MS: rt = 3.99 min. and rt = 4.24 min., 506 (M+1, ES+).
[1- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [clazepin-2yl]- phenyl-acetic acid To a solution of [1- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid methyl ester (1.17 g, 2.31 mmol), in MeOH (9 ml) and dioxane (12 ml), was added dropwise aqueous NaOH 2N (11 ml, 22 mmol). The resulting yellow homogeneous mixture was then stirred at 45°C for 8h. The reaction mixture was then concentrated in vacuo and washed with Et2O (5 ml). The aqueous phase was acidified (pH = 1) with HC1 2N and extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous MgS04, filtered and concentrated to give the titled carboxylic acid (1.14 g, 2.31 mmol, 100%) as a beige solid.
LC-MS: rt = 3.58 min., 492 (M+l, ES+).
3- (4-Benzyloxy-3-methoxy-phenyl)-propionic acid benzyl ester A mixture of 3- (4-hydroxy-3-methoxy-phenyl)-propionic acid (5. 1 g, 25.99 mmol), anhydrous K2CO3 (25 g, 180.88 mmol) and benzyl bromide (7. 5 ml, 63.14 mmol) in anhydrous acetone (100 ml) was stirred at reflux for 7.5h under nitrogen. After cooling, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (CH2C12) gave the titled compound (8.83 g, 23.45 mmol, 90%).
LC-MS: rt = 5.65 min., 377 (M+1, ES+).
3- (4-Benzyloxy-3-methoxy-phenyl)-propionic acid To a solution of 3- (4-benzyloxy-3-methoxy-phenyl)-propionic acid benzyl ester (11.03 g, 29.30 mmol), in MeOH (110 ml) and dioxane (145 ml), was added dropwise aqueous NaOH 2N (139 ml, 278 mmol). The resulting yellow homogeneous mixture was then stirred at 50°C for 17h. The reaction mixture was then concentrated in vacuo and washed with Et20 (100 ml). The aqueous phase was acidified (pH = I) with HCI 2N and extracted three times with CH2C12. The combined organic phases were dried over anhydrous MgS04, filtered and concentrated to give the titled carboxylic acid (8. 4 g, 29.30 mmol, 100%) as a colorless solid.
LC-MS: rt = 4.53 min., 285 (M-1, ES-).
3- (4-Benzyloxy-3-methoxy-phenyl)-propionamide To a stirred solution of 3- (4-benzyloxy-3-methoxy-phenyl)-propionic acid (8.38 g, 29.30 mmol) in dry THF (110 ml), under nitrogen, was added TEA (4.5 ml, 32.33 mmol), and the resulting mixture was cooled to-10°C before ethyl chloroformate (3.1 ml, 32.53 mmol) was added dropwise. After stirring at-10°C (20 min), ammonium hydroxide (25% in water, 65 ml) in THF (65 ml) was added and the mixture was stirred at-15°C for 30 min and then at RT for 1. 5h. The reaction mixture was concentrated in vacuo, extracted three times with CH2C12 and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous MgSO4, filtered and concentrated to give the titled compound (8.40 g, 29.30 mmol, 100%) as a colorless solid. No further purification of the crude amide was necessary.
LC-MS: rt = 4.08 min., 286 (M+1, ES+).
3- (4-Benzyloxy-3-methoxy-phenyl)-propylamine A solution of 3- (4-benzyloxy-3-methoxy-phenyl)-propionamide (7.85 g, 27.53 mmol) in anhydrous THF (210 ml) was slowly added to a stirred-ice-cooled suspension of LiAlH4 (2.09 g, 55.07 mmol) in anhydrous THF (90 ml). Upon completion of the addition, the mixture was stirred at reflux for lh. After cooling to 0°C, H20 (15 ml) was added
dropwise to decompose the excess of hydride and the suspension was then filtered. The residue after evaporation was partitioned between H20 (50 ml) and CHUCK (100 ml). The organic layer was washed with NaHCO3 and brine, dried over anhydrous MgS04, and concentrated under reduced pressure to give the crude amine (6.03 g, 22.22 mmol, 81%) as a yellow oil.
LC-MS: rt = 3.20 min., 272 (M+1, ES+). <BR> <BR> <BR> <BR> <BR> <BR> <P>N [3- (4-Benzyloxy-3-methoxy-phenyl)-propyl]-2- (3, 4-dimethoxy-phenyl)-acetamide A solution of 3- (4-benzyloxy-3-methoxy-phenyl)-propylamine (6.06 g, 22.36 mmol) and TEA (3.5 ml, 25.14 mmol) in anhydrous THF (25 ml) was cooled to 0°C and (3,4- dimethoxy-phenyl)-acetyl chloride (4.80 g, 22.36 mmol) in THF (10 ml) was added dropwise. After stirring at RT for 28h under nitrogen, a saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted three times with AcOEt. The organic phase was dried over anhydrous MgS04, filtered and the solvent was removed in vacuo. A subsequent washing of the crude solid with toluene gave the titled compound (6.57 g, 14.61 mmol, 65%) as a beige solid.
LC-MS : rt = 4.90 min., 450 (M+1, ES+).
8-Benzyloxy-1- (3, 4-dimethoxy-benzyl)-7-methoxy-2, 3,4,5-tetrahydro-lH- benzo [clazepine A mixture of N [3- (4-benzyloxy-3-methoxy-phenyl)-propyl]-2- (3, 4-dimethoxy-phenyl)- acetamide (6.04 g, 13.43 mmol) and POC13 (4.1 ml, 44.78 mmol) in anhydrous acetonitrile (350 ml) was stirred at reflux for 5h under nitrogen. After cooling, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (120 ml). The solution was cooled to 0°C and NaBH4 (3.50 g, 92.70 mmol) was added portionwise. After stirring at 0°C for 2h under nitrogen, the reaction mixture was poured into H20 and extracted three times with CH2C12. The combined organic extracts were washed with brine, dried over anhydrous MgS04, filtered and concentrated to give a crude oil. Flash chromatography (CH2Ck/MeOH : 9/1) gave the titled compound as a racemic mixture (2.44 g, 5.62 mmol, 42%, yellow oil).
LC-MS: rt = 3.52 min., 434 (M+l, ES+).
(3,4-Dimethoxy-phenoxy)-acetonitrile To a solution of 3, 4-dimethoxyphenol (5.0 g, 0.0324 mol) in dry acetone (160 ml), were added chloroacetonitrile (2.05 ml, 0.0324 mol) and anhydrous K2CO3 (6.72 g, 0.0486 mol). The reaction mixture was stirred at reflux for 20h under nitrogen. After cooling, the mixture was filtered and concentrated in vacuo. The residue was combined with H20, extracted with CH2C12, the combined organic phases were dried over anhydrous MgS04, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt/hexane : 3/7) gave the titled product (4,5 g, 68%) 'H-NMR (300MHz, CDC13) 8 : 6.8 (lH, d), 6.6 (lH, d), 6.5 (lH, dd), 4.75 (2H, s), 3.85 (6H, d).
2- (3, 4-Dimethoxy-phenoxy)-ethylamine To a cold (0°C) suspension of LiAlH4 (1.73 g, 0.0456 mol) in anhydrous THF (72 ml), was added dropwise a solution of (3,4-dimethoxy-phenoxy)-acetonitrile (5.88 g, 0.0304 mol) in anhydrous THF (42 ml). The resulting mixture was allowed to warm-up and stirred at RT for 20h under nitrogen. The mixture was combined with a mixture of H20/2N NaOH (aq) (4/1) to destroy the excess of LiAlH4. The white suspension was filtered and the solid was washed with CH2C12. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2C12/MeOH : 9/1) gave the titled product (4,65 g, 77%) 'H-NMR (300MHz, CDC13) 8 : 6.78 (lH, d), 6.55 (lH, d), 6.4 (lH, dd), 3.95 (2H, t), 3.80 (6H, d), 3.05 (2H, t), 1.92 (2H, br. s.).
N [2- (3, 4-Dimethoxy-phenoxy)-ethyl]-2-(3,4-dimethoxy-phenyl)-acetami de To a cold (0°C) solution of 2- (3, 4-dimethoxy-phenoxy)-ethylamine (2.3 g, 0.0118 mol) in anhydrous THF (21 ml), were added TEA (1.4 ml, 0.0192 mol) and portionwise 3,4- dimethoxyphenylacetylchloride (2.49 g, 0.0116 mol). The resulting mixture was stirred al RT for 20h under nitrogen. The mixture was combined with H20 and extracted three times with CH2C12. The combined organic phases were dried over anhydrous MgS04, filtered
and concentrated to give a crude solid. Recrystallisation over diethylether gave the titled product (3.59 g, 80%) as a white solid.
IH-NMR (300MHz, CDC13) 8 : 6.8 (3H, m), 6.4 (lH, d), 6.35 (lH, dd), 5.95 (lH, br. s) 3.95 (2H, t), 3.80 (12H, q), 3.6 (2H, m), 3.55 (2H, s).
LC-MS: rt = 3.84 min., 376 (M+1, ES+).
5- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-2,3,4,5-tetrahydro-benzot 1,4] oxazepine To a stirred solution of N [2- (3, 4-dimethoxy-phenoxy)-ethyl]-2- (3, 4-dimethoxy-phenyl)- acetamid (3.6 g, 9.56 mmol) in dry CH3CN (20 ml), was added POC13 (2.62 ml, 0.0286 mol). The resulting mixture was stirred at reflux for 3h under nitrogen. After cooling, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (80 ml). The solution was cooled to 0°C and NaBH4 (2.53 g, 0.067 mol) was added portionwise. The resulting pale yellow suspension was stirred at RT for 16h under nitrogen. The reaction mixture was poured into Ha0 and extracted three times with CH2Ck. The combined organic phases were dried over anhydrous MgS04, filtered and concentrated to give a crude oil. Flash chromatography (CH2C12/MeOH : 9/1) gave the titled product (1.14 g, 33%) as a viscous brown oil.
'H-NMR (300MHz, CDC13) 8 : 6.8-6.6 (5H, m), 6.45 (lH, s), 4.15 (lH, m), 3.80 (12H, q), 3.55-2.95 (6H, m).
LC-MS: rt = 2.99 min., 360 (M+1, ES+).
(3,4-Dimethoxy-phenylsulfanyl)-acetonitrile To a solution of 3, 4-dimethoxythiophenol (5.0 g, 0.0294 mol) in dry DMF (150 ml), were added chloroacetonitrile (1.85ml, 0.0294 mol), anhydrous K2CO3 (6.09 g, 0.0441 mol) and DMAP (358 mg, 2.9 mmol). The reaction mixture was stirred at 80°C for 20h under nitrogen. After cooling, the mixture was filtered and concentrated in vacuo. The residue was combined with H20, extracted with CH2C12, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt) gave the titled product (5.16 g, 84%).
IH-NMR (300MHz, CDC13) 8 : 7.2 (lH, d), 7.15 (lH, d), 6.9 (lH, d), 3.85 (6H, d), 3.5 (2H, s).
2- (3, 4-Dimethoxy-phenylsulfanyl)-ethylamine To a cold (0°C) solution of (3,4-dimethoxy-phenoxy)-acetonitrile (7.53 g, 0.036 mol) in anhydrous THF (41 ml), was added portionwise NaBH4 (1.22 g, 0.032 mol) and dropwise a solution of BF3. OEt2 (5.37 ml, 0.02 mol) in anhydrous THF (13.4 ml) over 30 min.. The resulting mixture was stirred at RT for 3h under nitrogen. The mixture was concentrated in vacuo, the residue was dissolved in CHUCK and washed with HC1 37%. The aqueous phase was neutralized with NaOH 30% and extracted with CH2Ck. The combined organic phases were dried over anhydrous MgS04, filtered and concentrated to give a crude oil.
Flash chromatography (CH2Cl2/MeOH : 9/1) gave the titled product (3.6 g, 46%).
IH-NMR (300MHz, CDC13) 6 : 7.05 (2H, m), 6.85 (lH, d), 3.80 (6H, d), 2.95 (2H, m), 1.7 (2H, br. s.).
2-(3, 4-Dimethoxy-phenyl)-N-[2-(3, 4-dimethoxy-phenylsulfanyl)-ethyl]-acetamide To a cold (0°C) solution of 2- (3, 4-dimethoxy-phenylsulfanyl)-ethylamine (3.97g, 0.0186 mol) in anhydrous THF (49 ml), were added TEA (3.11 ml, 0.0186 mol) and portionwise 3,4-dimethoxyphenylacetylchloride (4.0 g, 0.0186 mol). The resulting mixture was stirred at RT for 20h under nitrogen. The mixture was combined with H20 and extracted three times with CH2C12. The combined organic phases were dried over anhydrous MgS04, filtered and concentrated to give a crude solid. Flash chromatography (AcOEt) gave the titled product (7.08 g, 97%).
'H-NMR (300MHz, CDC13) 8 : 6.95-6.7 (6H, m), 5.95 (lH, br. s), 3.95 (12H, q), 3.5 (2H, s), 3.55 (2H, q), 2.95 (2H, t).
LC-MS: rt = 3.87 min., 392 (M+1, ES+).
9- (3, 4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia- 8-aza- benzocycloheptene To a stirred solution of 2- (3, 4-dimethoxy-phenyl)-N [2- (3, 4-dimethoxy-phenylsulfanyl)- ethyl]-acetamide (4.0 g, O. Olmol) in dry CH3CN (21 ml), was added POC13 (2.80 ml, 0.03 mol). The resulting mixture was stirred at reflux for 3h under nitrogen. After cooling, the
reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (85ml). The solution was cooled to 0°C and NaBH4 (2.7 g, 0.069 mol) was added portionwise, the resulting pale yellow suspension was stirred at RT for 16h under nitrogen. The reaction mixture was poured into H20 and extracted three times with CH2C12. The combined organic phases were dried over anhydrous MgS04, filtered and concentrated to give a crude oil. Flash chromatography (CH2C12/MeOH : 9/1) gave the titled product (1.14 g, 27%) as a viscous brown oil.
IH-NMR (300MHz, CDC13) 8 : 7.1 (1H, s), 6.8 (4H, s), 4.6 (lH, m), 4.15,3.80 (12H, q), 3.45-2.75 (6H, m).
LC-MS: rt = 4.39 min., 376 (M+1, ES+).
9- (3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8 -aza- benzycloheptene-8-carboxylic acid tert-butyl ester To a cold (0°C) stirred solution of 9- (3, 4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9- tetrahydro-5-thia-8-aza-bencycloheptene (417 mg, 1.11 mmol) in 5 mi of dry CH2C12, were added TEA (168 gL, 1.2 mmol) and di-tert.-butyl-dicarbonate (262 mg, 1.2 mmol).
The resulting mixture was allowed to warm-up and stirred at RT for 20h under nitrogen.
The reaction mixture was combined with water, extracted twice with CH2Ck, the combined organic phases were dried over anhydrous MgS04, filtered and concentrated to give a crude yellow oil. Flash chromatography (AcOEt) gave the title compound as a pale yellow oil (486 mg, 91%).
IH-NMR (300 MHz, CDC13) 8 : 7.15 (1H, d); 6.6-6.8 (4H, m) ; 5.05 (1H, m); 3.85 (12H, d); 3.65 (2H, m); 3.45 (2H, m); 2.75 (2H, m); 1.45 (9H, d).
9- (3, 4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahyd ro-5X6-thia-8- aza-benzycloheptene-8-carboxylic acid tert-butyl ester To a cold (0°C) stirred solution of 9- (3, 4-dimethoxy-benzyl)-2, 3-dimethoxy-6, 7-dihydro- 9H-5-thia-8-aza-benzocycloheptene-8-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol) in 1 ml of dry CH2C12, was added 3-chloroperbenzoic acid (106 mg, 0.614 mmol).
The resulting mixture was stirred at 0°C for 2h and allowed to warm-up and stirred at RT
overnight. The reaction mixture was combined with water, extracted twice with CH2Ck, the combined organic phases were dried over anhydrous MgS04, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt/hexane : 1/1) gave the title compound as a pale yellow solid (76 mg, 71%).
IH-NMR (300 MHz, CDC13) 8 : 7.15 (1H, d); 6.6-6.8 (4H, m) ; 5.25 (1H, m) ; 3.85 (12H, d); 3.65 (2H, m) ; 3.35 (2H, m) ; 2.75 (2H, m) ; 1.35 (9H, d).
9- (3, 4-Dimethoxy-benzyl)-2, 3-dimethoxy-6,7,8,9--tetrahydro-5-thia-8-aza- benzycloheptene 5,5-dioxide.
To a stirred solution of 9- (3, 4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9- tetrahydro-5#6-thia-8-aza-benzycloheptene-8-carboxylic acid tert-butyl ester (310 mg, 0.61 mmol) in 3 ml of dry CH2Cl2, was added trifluoroacetic acid (372 1L, 4.86 mmol).
The resulting mixture was stirred at RT for 20h under nitrogen. The reaction mixture combined with water/NaOH 2N, extracted twice with CH2Cl2, the combined organic phases were dried over anhydrous MgS04, filtered and concentrated to give a crude oil.
Flash chromatography (CH2C12/MeOH : 1/1) gave the title compound as a pale yellow oil (118 mg, 47%).
IH-NMR (300 MHz, CDC13) 8 : 7.6 (1H, d) ; 6.85 (4H, m) ; 4.95 (1H, m) ; 3.95-3.81 (12H, m) ; 3.45 (4H, m) ; 3.25 (2H, m).
B. General procedure A: At-15°C a solution of the respective amine (1 equivalent) in THF (0.40 M) was added dropwise to a solution of 2-bromoacetyl bromide (1 equivalent) in THF (0.20 M). The reaction mixture was treated dropwise with a solution of diisopropylethylamine (4 equivalents) in THF (2.0 M), allowed to warm up slowly to RT and stirred at RT for 30 min. A solution of the respective benzazepine (1 equivalent) in THF (0.20 M) was added and the mixture was heated to 75°C for 15h. After cooling, AcOEt and H20 were added, and the aqueous phase was extracted two times with AcOEt. The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo.
Flash chromatography gave the benzazepine derivative.
Example 1 2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yll-N- naphthalen-1-ylmethyl-acetamide : prepared by reaction of 2-bromoacetyl bromide with 1-naphtalenemethylamine and 1- (3, 4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo [c] azepine.
LC-MS: rt = 3.95 min, 555 (M+1, ES+).
Example 2 N-Benzo[1, 3] dioxol-5-ylmethyl-2- [1- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5- tetrahydro-benzo [c] azepin-2-yl]-acetamide : prepared by reaction of 2-bromoacetyl bromide with piperonylamine and 1- (3, 4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4, 5-tetrahydro-1H-benzo[c] azepine.
LC-MS: rt = 3.67 min, 549 (M+1, ES+).
Example 3 2-[1-(3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-2-yl-acetamide : prepared by reaction of 2-bromoacetyl bromide with 2-aminoindane hydrochloride and 1- (3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-b enzo [c] azepine.
LC-MS: rt = 3.83 min, 531 (M+1, ES+).
Example 4: 2- [5- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo [fl [1, 4] oxazepin-4- yl]-N-indan-2-yl-acetamide :
prepared by reaction of 2-bromoacetyl bromide with 2-aminoindane hydrochloride and 5- (3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro- benzo [f] [1,4] oxazepine.
LC-MS: rt = 4.34 min, 533 (M+1, ES+).
Example 5 2- [5- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-2, 3-dihydro-SH-benzo [f] [1, 4] oxazepin-4- yl]-N-indan-1-yl-acetamide : prepared by reaction of 2-bromoacetyl bromide with 1-aminoindane and 5- (3, 4- dimethoxy-benzyl)-7, 8-dimethoxy-2,3,4,5-tetrahydro-benzo [f] [1, 4] oxazepine.
LC-MS: rt = 4.62 min, 533 (M+1, ES+).
Example 6 2- [1- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-1-yl-acetamide : prepared by reaction of 2-bromoacetyl bromide with l-aminoindane and 1- (3, 4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo [c] azepine.
LC-MS: rt = 3.90 min, 531 (M+1, ES+).
Example 7 2- [9- (3, 4-Dimethoxy-benzyl)-2, 3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-5X6-thia-8- aza-benzocyclohepten-8-yl]-N-indan-2-yl-acetamide : prepared by reaction of 2-bromoacetyl bromide with 2-aminoindane hydrochloride and 9- (3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-th ia-8-aza- benzocycloheptene-5,5-dioxide.
LC-MS: rt = 3.81 min, 581 (M+1, ES+).
Example 8 2- [9- (3, 4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7, 9-tetrahydro-5#6-thia-8- aza-benzocyclohepten-8-yl]-N-indan-l-yl-acetamide : prepared by reaction of 2-bromoacetyl bromide with 1-aminoindane and 9- (3, 4- dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8- aza-benzycloheptene- 5,5-dioxide LC-MS: rt = 4.49 min, 581 (M+1, ES+).
Example 9 2- [1- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N indan-1-yl-acetamide : prepared by reaction of 2-bromoacetyl bromide with S (+)-l-aminoindane and 1- (3, 4- dimethoxy-benzyl)-7, 8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo [c] azepine.
LC-MS: rt = 3.80 min, 531 (M+1, ES+).
Example 10 2- [5- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-2, 3-dihydro-5H-benzo[f][1,4] oxazepin-4- yl]-N-naphthalen-l-ylmethyl-acetamide : prepared by reaction of 2-bromoacetyl bromide with 1-naphtalenemethylamine and 5- (3, 4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo [F] [1, 4] oxazepine.
LC-MS: rt = 4.39 min, 557 (M+1, ES+).
Example 11 2- [5- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-2,3-dihydro-5H-benzo [f][1, 4] oxazepin-4- yl]-N-(2-ethoxy-benzyl)-acetamide:
prepared by reaction of 2-bromoacetyl bromide with 2-ethoxy-benzylamine and 5- (3, 4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo [fl [1, 4] oxazepine.
LC-MS: rt = 4.34 min, 551 (M+1, ES+).
Example 12 2- [5- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-2,3-dihydro-5H-benzo [f] [1, 4] oxazepin-4- yl]-N-indan-l-yl-acetamide : prepared by reaction of 2-bromoacetyl bromide with S (+)-l-aminoindane and 5- (3, 4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo [f] [1, 4] oxazepine.
LC-MS: rt = 4.32 min, 533 (M+1, ES+).
Example 13 2- [9- (3, 4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-az a- benzocyclohepten-8-yl]-N (1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide: prepared by reaction of 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-naphthalen-1- ylamine and 9- (3, 4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia- 8-aza- benzocycloheptene..
LC-MS: rt = 5.01 min, 563 (M+l, ES+).
Example 14 N-Benzyl-2- [5- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H- benzo[f][1, 4] oxazepin-4-yl]-acetamide : prepared by reaction of 2-bromoacetyl bromide with benzylamine and 5- (3, 4-dimethoxy- benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo [3 [1,4] oxazepine.
LC-MS: rt = 4.05 min, 507 (M+1, ES+).
Example 15 2- [9- (3, 4-Dimethoxy-benzyl)-2, 3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza- benzocyclohepten-8-yl]-N-indan-1-yl-acetamide : prepared by reaction of 2-bromoacetyl bromide with S (+)-l-aminoindane and 9- (3, 4- dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8- aza-benzocycloheptene.
LC-MS: rt = 4.85 min, 549 (M+1, ES+).
Example 16 2- [1- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-IN (4-methoxy-indan-1-yl)-acetamide : prepared by reaction of 2-bromoacetyl bromide with 4-methoxy-indan-1-ylamine and 1- (3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4, 5-tetrahydro-1H-benzo [c] azepine.
LC-MS: rt = 3.83 min, 561 (M+1, ES+).
Example 17 2- [l- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-1s (3-phenyl-indan-1-yl)-acetamide : prepared by reaction of 2-bromoacetyl bromide with 3-phenyl-indan-1-ylamine and 1- (3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-b enzo [c] azepine.
LC-MS: rt = 4.42 min, 607 (M+I, ES+).
Example 18 2- 1- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c]azepin-2-yl]-@ (4-methyl-indan-1-yl)-acetamide :
prepared by reaction of 2-bromoacetyl bromide with 4-methyl-indan-1-ylamine and 1- (3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-b enzo [c] azepine.
LC-MS: rt = 4.02 min, 545 (M+1, ES+).
Example 19 2- [8-Benzyloxy-1- (3, 4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-N-indan-l-yl-acetamide : prepared by reaction of 2-bromoacetyl bromide with S (+)-l-aminoindane and 1- (3, 4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo [c] azepine.
LC-MS: rt = 4.39 min, 607 (M+1, ES+).
C. General procedure B: To a solution of the respective [1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-phenyl-acetic acid (1 equivalent) in anhydrous DMF (0.04 M) was added PyBOP (1.1 equivalents), the respective amine (1 equivalent) and N-diisopropylethylamine (2.3 equivalents). The resulting mixture was stirred at RT for 15h under nitrogen. After reaction, AcOEt was added, and the organic phase was washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. Flash chromatography provided the benzazepine derivative.
Example 20 2- [1- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-2-yl-2-phenyl-acetamide : prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with 2-aminoindane hydrochloride.
LC-MS: rt = 4.26 min, 607 (M+1, ES+).
Example 21
N-Butyl-2-[1-(3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c]azepin- 2-yl]-2-phenyl-acetamide : prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with n-butylamine.
LC-MS: rt = 3.91 min, 547 (M+1, ES+).
Example 22 2- [1- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- indan-1-yl-2-phenyl-acetamide : prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with S (+)-1-aminoindane.
LC-MS: rt = 4.09 min and rt = 4.39 min (diastereoisomers), 607 (M+1, ES+).
Example 23 N-Benzo[1, 3] dioxol-5-ylmethyl-2-11- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5- tetrahydro-benzo [c] azepin-2-yl]-2-phenyl-acetamide : prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with piperonylamine.
LC-MS: rt = 3.88 min and rt = 3.98 min (diastereoisomers), 625 (M+1, ES+).
Example 24 N-Cyclopentyl-2-[1-(3,4-dimethoxy-benzyl-7,8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-2-phenyl-acetamide : prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with cyclopentylamine.
LC-MS: rt = 3.79 min and rt = 3.92 min (diastereoisomers), 559 (M+1, ES+).
Example 25 2- [1-(3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yll-N- furan-2-ylmethyl-2-phenyl-acetamide: prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with furfurylamine.
LC-MS: rt = 3.72 min and rt = 3.85 min (diastereoisomers), 571 (M+1, ES+).
Example 26 {2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydr o-benzolcjazepin-2yl]-2- phenyl-acetylamino}-acetic acid ethyl ester: prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with glycine ethyl ester hydrochloride.
LC-MS: rt = 3.72 min, 577 (M+l, ES+).
Example 27 2- [l- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2- phenyl-N-pyridin-4-ylmethyl-acetamide : prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with 4-picolylamine.
LC-MS: rt = 3.09 min, 582 (M+1, ES+).
Example 28 2- (1- (3, 4-Dimethoxy-benzyI)-7, 8-dimethoxy-1, 3,4, 5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyl-N-pyridin-3-ylmethyl-acetamide :
prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with 3-picolylamine.
LC-MS: rt = 3.20 min, 582 (M+1, ES+).
Example 29 N-Cyclopropyl-2- [l- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-2-phenyl-acetamide : prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with cyclopropylamine.
LC-MS : rt = 3.59 min, 531 (M+1, ES+).
Example 30 2- [1- (3, 4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N- (2-oxo-tetrahydro-furan-3-yl)-2-phenyl-acetamide : prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with 2-amino-4-butyrolactone hydrobromide.
LC-MS: rt = 3.46 min, 575 (M+1, ES+).
Example 31 2-12- [l- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]- 2-phenyl-acetylamino}-3-hydroxy-propionic acid methyl ester: prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with L-serine methyl ester hydrochloride.
LC-MS: rt = 3.40 min, 593 (M+1, ES+).
Example 32
2- [1- (3,4-Dimethoxy-benzyl)-7, 8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N ethylcarbamoylmethyl-2-phenyl-acetamide: prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with 2-amino-N-ethyl-acetamide.
LC-MS: rt = 3.37 min, 576 (M+1, ES+).
Example 33 2- (1- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N [(ethyl-methyl-carbamoyl)-methyl]-2-phenyl-acetamide : prepared by reaction of [l- (3, 4-dimethoxy-bcnzyl)-7, 8-dimethoxy-l, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with 2-amino-N-ethyl-N-methyl-acetamide.
LC-MS: rt = 3.42 min, 590 (M+l, ES+).
Example 34 3-f 2- [1- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl] 2-phenyl-acetylamino}-propionic acid methyl ester: prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with 3-amino-propionic acid methyl ester.
LC-MS: rt = 3.52 min, 577 (M+1, ES+).
Example 35 N (lH-Benzoimidazol-2-ylmethyl)-2- [l- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1,3,4,5- tetrahydro-benzo [c] azepin-2-yl]-2-phenyl-acetamide : prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with 2-aminomethyl-benzimidazole dihydrochloride hydrate.
LC-MS: rt = 3.36 min, 621 (M+1, ES+).
Example 36 3- {2- [l- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]- 2-phenyl-acetylamino}-N, N-dimethyl-propionamide : prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with 3-amino-N,N-dimethyl-propionamide.
LC-MS: rt = 3.42 min, 590 (M+l, ES+).
Example 37 3- {2- [1- (3, 4-Dimethoxy-benzyl)-7, 8-dimethoxy-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl]- 2-phenyl-acetylamino}-N-ethyl-N-methyl-propionamide : prepared by reaction of [1- (3, 4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-phenyl-acetic acid with 3-amino-N-ethyl-N-methyl-propionamide.
LC-MS: rt = 3.40 min, 604 (M+1, ES+).
D. Variation of substituents on position 8: General procedure : To a solution of the respective 8-benzyloxy-1, 3,4,5-tetrahydro-benzazepine in methanol (0.07 M) was added palladium (10 wt. % on activated carbon ; 10 % of the benzylether weight) and the resulting heterogeneous mixture was vigorously stirred under an hydrogen atmosphere at RT until disappearance of benzylether (TLC). After reaction the mixture was filtered through celite and concentrated in vacuo. Flash chromatography yielded the pure phenol derivative. To a solution of this phenol derivative (1 equivalent) in anhydrous DMF (0.04 M) was added successively anhydrous potassium carbonate (5 equivalents) and the respective electrophile (1.2 equivalents). The resulting heterogeneous mixture was stirred at
50°C for 15h. After reaction the mixture was dissolved in AcOEt and washed with a saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Flash chromatography provided the pure benzazepine derivative.
Example 38 2- [1- (3, 4-Dimethoxy-benzyl)-8-hydroxy-7-methoxy-1, 3,4,5-tetrahydro-benzo [c] azepin- 2-yl]-N-indan-1-yl-acetamide : prepared by hydrogenolysis of 2- [8-benzyloxy-l- (3, 4-dimethoxy-benzyl)-7-methoxy- 1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-N-indan-l-yl-acetamide.
LC-MS: rt = 3.64 min, 517 (M+1, ES+).
Example 39 N-Benzo [1, 3] dioxol-5-ylmethyl-2- [l- (3, 4-dimethoxy-benzyl)-8-hydroxy-7-methoxy- 1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2-phenyl-acetamide : prepared by hydrogenolysis of N-benzo [1, 3] dioxol-5-ylmethyl-2- [8-benzyloxy-l- (3, 4- dimethoxy-benzyl)-7-methoxy-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl]-2-phenyl-acetamide.
LC-MS: rt = 3.77 min, 611 (M+1, ES+).
Example 40 2- [8-Allyloxy-l- (3, 4-dimethoxy-benzyl)-7-methoxy-1, 3,4,5-tetrahydro-benzo [c] azepin- 2-yl]-N-indan-1-yl-acetamide : prepared by reaction of 2- [l- (3, 4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1, 3,4,5- tetrahydro-benzo [c] azepin-2-yl]-N-indan-l-yl-acetamide with allylbromide.
LC-MS: rt = 4.05 min, 557 (M+1, ES+).
Example 41
2-[1-(3,4-Dimethoxy-benzyl)-7-methoxy-8-propoxy-1, 3,4,5-tetrahydro-benzo [c] azepin- 2-yl]-N-indan-l-yl-acetamide : prepared by reaction of 2- [1- (3, 4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1, 3,4,5- tetrahydro-benzo [c] azepin-2-yl]-N-indan-I-yl-acetamide with 1-bromopropane.
LC-MS: rt = 4.13 min, 559 (M+1, ES+).
Example 42 2- [l- (3, 4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy-1, 3,4,5-tetrahydro- benzo [c]azepin-2-yl]-N-indan-1-yl-acetamide : prepared by reaction of 2- [1- (3, 4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1, 3,4,5- tetrahydro-benzo [c] azepin-2-yl]-N-indan-l-yl-acetamide with 2-bromopropane.
LC-MS: rt = 4.07 min, 559 (M+1, ES+).
Example 43 2- [8- (2, 2-Difluoro-ethoxy)-1- (3, 4-dimethoxy-benzyl)-7-methoxy-1,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-N-indan-l-yl-acetamide : prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1, 3,4,5- tetrahydro-benzo [c] azepin-2-yl]-N-indan-1-yl-acetamide with 2-bromo-1,1-difluoroethane.
LC-MS: rt = 4.14 min, 581 (M+1, ES+).
Abbreviations : AcOEt Ethyl acetate BSA Bovine serum albumine CHO Chinese hamster ovary DMF Dimethylformamide DMSO Dimethylsulfoxide ES Electron spray FCS Foetal calf serum FLIPR Fluorescent imaging plate reader HBSS Hank's balanced salt solution HEPES 4- (2-Hydroxyethyl)-piperazine-l-ethanesulfonic acid MeOH Methanol MS Mass spectroscopy LC Liquid chromatography PyBOP Benzotriazole-1-yl-oxy-tris-pyrrolidino-<BR> Phosphoniumhexafluorophosphate Rf Retention front Rt retention time RT Room temperature TEA Triethylamine Tf CFsSOz- THF Tetrahydrofuran TLC Thin layer chromatography
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