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    US6900236B1

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    US006900236B1 c2) United States Patent (10) Patent No: US 6,900,236 BL Makriyannis et al. 45) Date of Patent: May 31, 2005 (61) CANNABIMIMETIC INDOLE DERIVATIVES Wo wosnssin 2003 Wo Woda — am (75) Inventors: Alexandros Makeiyannis, Watertown, WO WOUSIRSIOS S28 MA(US) Honglete Deng acon MA WO WOURIASISS RN o WO WOU) ams (13) Assigaeo: University of Connecticut, Farmington, OTHER PUBLICATIONS cris) C-Attached Aminoalkylindoles; Potent Cannabinoid ‘Mimetes; Thomas E. D’amba etal; Biorganie & Medicinal (7) Notice: Subject o any disclaimer, the term of this Chemistry Letters, vo. 6, No.1 pp. 17-22, 1996 pateat is extended or adjusted under 35. Evaluation Of Binding ln A Transfected Cel Line Express- USC. 1540) by o cays ing A PergheralCanoainoi Receptor (CB2}:Indenticn tion OF Cannahioid expe Subtype Seestive Liguns G1) Appl No; 101,059 Vincent M. Showalter et a; The Joumal of Pharmacology. (2) PCT Fed: Oct. 18, 20 and. Experimental Therapeutics, vo 278, No. 3: pp. 589-599, XP OOI087918, 1994). (86) PCT No. PCT/US00/28832 Pharmacological Characterization Of Three Novel Cannab- rEoD iid Receptor Agonists In Tae Mouse fated Vas Defer G), cs; Roger G. Pertwee eta XP-OO1D41044; European @,@ Dae Oct 21, 2002 Journal of Pharmacology 284 (1995) pp. 241-247. (87) PCT Pub. Nos WOOL28557 Aminosislindles: Stuetr~Aciviy Relationships OF . Novel Canabined Mime Michael A. Essent tl ECL Pee Dab AP es 20M XP 000851090; J. Med. Chem 1995, 38, pp. 3094-3105. ‘Three-Dimensional Quantitative Structue—Actvity Rela- eta tionship Study Of The Camabimimetic(Aminealkylindoles (©) Provisional application No. 66/159.907, Hed on Oct. 18, le Using Comparative Molecular Field Analysis; ‘XP-002212407; JoongYoun Shim et al; J. Med. Chem (1) Ima? AIK 31/405; CO7D 209/12, 9S: $1 pp. 4521-4532, AMS30, A Competitive Cannabinoid Receptor Antagonist; CO7D 209/14; COTD 20911 : Pate, skater sagaga, XP OO06S3566; Roger Porte ea, Life Seienes, vol. 56, (2) US.cl st4is; 548/483; Sages XP.O006 3 os, 2924, pp. 1949-1955, 1995. (58) eld of Search S415) S883, fe Pamcoporie MeL For Cans A Ari 548484 goalkylindoles Derived From Molecular Superimposition 5 ences i OF CHI Cannabinod Receptor Agoniss. CPSS245. and Go od eo WINSS212-2, Joong—Youn Shim et al; American Chemical US. PATENT DOCUMENTS Society pp. 165-184, XP-001008771, (1999 Stucture~Actvity Relationships of Indle-And Pyeole-D- S03 A IDG Suet el crived Cannabinoids; XP 001097982; Jeany L. Wiley et als 3Hes]02t A 91969 Brown See emer ee The Joural of Pharmacology and Experimenial Therapeu- 3507458 A SA9TL Brenna tis; pp 995-1004; Vol 285; No.3 (1998) Zoseons A ior? Bullock International Publication WO 97100860, CB2 Receptor Ago- Species A S1915 Mateot tah sist Compounds; Murille Rinaldi etl, Published Jan. 9, 303m A TAVIS Nile 1997 3015086 A LQIYTS: Wieht Pacheco M, el al; “Aminotkyindles: Actions On Specific 3928598 A LAVTS cher -Proein-L inked Receptors"; J. Phammaol. Exp. Thets 3945673 A 311976 Archer vvol. 257, No. 1, pp. 170-183 and 172 Table (L991), (Continued) Tet, IV. etal “Volume Learaing Algor Avticiat . [Neural Networks For 3D QSAR Studies"; J. Med. Chem; POREIGN PATENT DOCUMENTS vol 4, No, 15 (201) pp. 2411-2420, 2413, 2414 Table L e ono sus98 ati EP 0737671 10/1996 ic a) S168 a2 'N1908 Primary Examiner Tug lala FR 22400483 5975 (14) Aitorney, Agent, or Firm—Alix, Yab istas, rR msi 12000 (74) Attorney, Agent, or Firm—Alix, Yale & Ristas, LLP oo mimi a diss 6 ABSTRACT ® ssosm2as 1982 ® Bows 121990, Novel cannabimimetis indole. derivatives ae presented Wo wososrim 11/1999 ‘which have preeremial high aft for one of the cane WO WoWweEIs) en abinid CL CHD recepir sites. The improved receptor « affinity makes these analogs therapeutically useful as medi Wo woovassy 42001 cations in individuals and animals for treatment of pain, ted eee oan ylaucoma, epile nausea associated with chemotherapy. WO WoOL25i%8 42001 shea, epilepsy, sted with chemotherapy Wo WooLamm 42001 WoO WoOL32I6) S200, 16 Claims, No Drawings US 6,900,236 BL Page 2 3953,608 44030857 44054589 40857545 40857546 4087547 4088777 402.902 44152450 i733 4170233 419517 fs 495 4208351 42785608 429,048 43096 4395.60 499787 assu2i¢ 47585597 4812457 4816276 4885.295 5053545 5.00824 756 5284867 5328737 51434295 54400052 5.462.960 89 580 521.215 5532237 5535998 505.906 507933 S89 5624941 535,530 5688895 5145459 S747524 5804001 5817651 S878 5874450 5925028 5925,168 210 5908777 sas 5028084 096,740 6127399 660/066 6.284.188 6 391,900 657.900 10.737 2020119972 2oso12a34 aaisr49082 2msn077689 oyn0778s1 2ns7590 US. PATENT DOCUMENTS a al Al Al al Al al 41976 a qT S198 S107, S97 raise uyavaL i192 21984 oven 71985 1098 rovi995 21986 51996 71996 71996 21997 31097 aor aor oer nji997 4198, S998 51198. 1q1998 21999 21999 1999 71999 819) 911000 1200 22000 S200 10720 12200 i201 sian 203 208 same ama 8208 420 2004 sian Aveber Razdan t Blanchard t ‘Avcher ea ‘Aber “Aber ‘here “Aber Day ea. Ryan Aches Mecho Ais eta ‘cher ‘Thar Mechoulam et Wintr ea Ryan Nelson Mehta Matin et Narumia etal Mechoolm ta Bell “Tanaka ot DAmbe ta Miauehi et Klbog etal DrAmbe ta Mecho ea Makriganis eta Mechoula allt eta Mechovln a Le DrAmbe ta Mechoulam ea Banh et a Mecho ta Makriganis etal Makzyennis eta Cullinan ea Kato et Drama ta Makes. Makrijanis el Lee etal Baa et Shoham et Bender Rial et Banh et Mechoolm ta Yuan Makeyeanis ct. Mitendot ea. Makeyenis ct Makes a. Garon etal Leathers a Makeyennis a. Makegemnis ct. Makes. Makeyeanis ta. Makesamnis a. OTHER PUBLICATIONS Abadji V,, Lin S., Taha G, Griffin G., Steverson LA, Pertwee RG, Makriyannis As “(R)-Methanadamie: chiral novel ansadamide, possessing higher poteney and metabolic stability”; J. Med. Chem; 37(12); 1889-1893; 1994 CODEN: JMCMAR; ISSN: 0022-2623; XPOI2040032 ‘Alo, BL; Kandi, A; Patil, PA; Sharp, M. J; Sidgu, M ‘As and Snieekus, V. Sequential Directed Ortho Metalation Boronic Acid Cross-Coupling. Reactions. A general Regiospecifie Roule to Oxygenerated —Dibenza{bal] pytan-t-ones Related to Ella Aci, J. Org. Chem, 1991, 56, 3763-3708, “Ammone M., Maruani J, Chaperon Petal, Selective Inibi- tion of suerose and ethanol intake by SR1AI716, an antago nist of eeneal cannabinoid (CB1) receptors, Psjehophar- geal, (1997) 132, 104-106 (absirct only). Barnett-Norris etal; “Exploration of biologically relevant conformations anandamide,...”:J.Med. Chem vol. 4, 4861-4872; 1998. Beak, Ps Brown, R.A The Teniany Amide as an Eifective Digecior of Oth Lithition, J Org. Chem. 1982, 47, 4-36. Belgaoakar etal; “synthesius of isocoumarins”; Indian J Chem vo. 13, No, 4, 336-338; 1975 (abstract onl). Beliramo M, Stella N.,Calignano A. Lin, ¥, Makriyannis A, Piomeli’D; “Functional Role Of Hih-Alfinity Anan amide Transport, a8 Revealed By Selective Inhibition”, Science; vol. 277; 1094-1007; 1997. Berdyshev EV, Cannabinoid reeepors and the regulation of immune response, Chem Phys. Lipids. Nov. 200; 108(1-2):169-90. Berglund et al; *Steuctural requirements for arachidonyle- thanolamide interaction with CBL and CB2 cannabinoid receptors: ...”; Porstanglanins, kukotienes and essential fatty acids; 89(2); 111-118; (1998). abstract ony) Bocinar, VN., Loznski, MO. Perk, PS; “Synthesis fo 2,Sclissiuted 1,3 onadizoles and 14-dibydro-1.2.4, ‘SUeteaznes”, Ukrainskii Khimicheskit Zhurnal (Russian Edition); 48(12), 1308-1311; 1982 (abstract ony). Braces, M et al, Structural Adaptations in a Membrane Enzyme That Terminates Endocannabinoid Signaling. Sei- cence 2002, 298(5599}: 1793-176, Breaneisen R, Pali A, Ebobly MA, Henn V. Spies ¥: The elect of orally and rectally administered A9-ietahydeocan- rnabinol on spasticity, a pilot study with 2 patents, In. J. Pharmacol Ther (1996) 34:446-482 (abstract only). Brown et l; “Synthesis and lydeoboration of (-}-2-pheny- laporinene, Comparison of :mo00(2-phenylapoisopinocarmphey)borane with its 2-aetyl and 2-eyl analogues forthe chiral hydacarbo- ration of representative alkenes", J. Ong. Chem; $5(4), 1217-1223, (19%). Buckley NE, MeCoy Kl, Mpzey E eta, “Immunomodula- tion by cannabinoids is absent in mice deficient forthe cannabinoid CB2 receptor”; Eur, J. Pharmacol (2000) 396:L41-149, Burstein etal; “detection of cannabinoid receptors ««-"s Biochem. Biophys. Res. Commun. vol. 176(1);, 492-497, 1991 (abstract onl). Buseh-Petenon el al; “Unsaturated side chain beta-LI-hydroxyhexahydrocannabinol analogs"; J. Med ‘Chem; 39; 3790-3796, (1996), US 6,900,236 BL Page 3 CCalignano A, La Rana G. Diu A, Piomeli D;*Contol of pin inition by endogenous cannabinoids"; Nature (19) 394:277-291" (abstract only). CCalignano A. La Rana G., Beltamo, ML, Makriyannis A. Piomeli D; “Potemiaton of Anandamide Hypotension by the Transp Zinhibitor, ANMOM"; Eur J, Pharmacol; 1997, 337 RI-R2 Catigoano AL Rana G.,Malsiyanis A, Lin S., Beluamo M, DiomellD;“Inibition of latesinal Mott by Anan- dane, an Endogenous Cannashioi Eur J Pharmacol 1997; 340 RT-RS. Campbell FA eta; “Are canabioids an effective and safe treatment option inthe management of pai? A guaitative systematic review"; BMJ. Jul. 7, 2001;323(7308):13-6. Charalambous A. etal; “Savio ASTHC: A Novel Pho- toalnity Label fo the Cannabinoid Receptor”; J. Med Chem. 35, 3076-3079 (1992). Charalambous A. etal; “Pharmacological evaluation of talogenated .."; Pharmacol Biochem. Bebav; ol. 40; No. 3; 08-512; 1991, ‘Chong etal “Relationship Between the Inhibition Constant (Ki) ad the concentration of Inhibitor which causes 50% Inhibition (1C50) of an Enzymatic Reaction’, Biochem Pharmacol, 2, 3099-3103, (1973) (abst oi). CCherest M, Luscindi X; “The ation of aul chloride and of acetic anhydride on the lithium nitronate sat of 2-phe- ylniroethane.."; Tetabedeon 42(14); 3825-3840; 1986; in Freach with English absrac. 1° Charest M, Lasinchi XA novel electrophilic N-am dation via elecron deficient complexes: action of frie chloride on N-aetyloxyamides"; Tetabedron Lets KG), TISETIB; 189. Colombo G, Agaio R, Diaz G.t al “Appetite suppression and weight los. afler the canmabinid antagonist SRIAITIO"; Life Sei. (1998) 63-PL13-PLUIT. (abstract only) CConpon etal; “Syathess spd pharmacological evaluation of ether and rested analogues of dei deta and dell}, -tetahydrocanabino"; J. Med. Cem; vol; No. 11 3310-3816; 1991 CConsoe P, MastyR, Ren J, Tiery W, Pertwee R; petcived eflets of smoked cannabis om patents with tiple slersis"; Eur. New. (1997) 38-44-48. (abstract only, CConomet als Aust J. Chem ;23; 1069-1071; (1970 (abstract only Crawley etal; “Anandamide, an endogenous ligand of the cannabinoid receptor, induces hypomasliy and ypsher ta in vivo in eodenis"; Pharmacology Biochomisty and Behavior; vol. 46; 967-972; 190, *1* Demuyack L. et al; "Rearrangement of Indol(2.-3] quinones to derivatives. with E-azaaspidespermane skeleton”; Tevahedron Later; 30() 710-722; 1989; in reach with English sac, DePetrocells L, Meck D, Palmisano A. et a, “The endos- nous cunnsbinid snandamideibibits human bess cancer cell proliferation; Pros. Nat, Acad. Sci, USA (ul. 1998) 95:8375-8380. Dessemaud F, Cadas H., Piomelli Ds “Anandamide ami- doydrolase tivity inet brain- microsomes"; J. Biol ‘Cham; 270, 6030-6035; (195), he Deutsch D.G. et al; “Fatty acid sulfonyl Muorides inhibit nandamide metabolism and bind to cannabinoid receptor’, Biochem. Biophys. Res. Commun. 231(I); 217-221; 1997; ‘CODEN: BBRCA9; ISSN:0006-291X; XPOO214093 Deutsch D.G., Chin S.A “Enzymati synthesis and degra dation of anandamide, 2 cannabinoid receptor agonist”, Biochemistry Pharmacology; 445); 791-796; 1993. Devane, W.A. otal; “Determination and Characterization of 4 Cannabinoid Receptor in a Rat Bran”; Mol. Pharmacol., 34, 605-613 (1988) (abstract onl). Di Marzo, V., Melek, D., Bisogno, T., DePetrocells, Ls “Endocanaabinoids: endogenous ‘caanabiaoid —roeptor ligands with neuromodulatory action"; Trends Neurosci (1998) 21:521-528. Domiaiam etal, “Syathesis of $-(teet-Alkyl)esorcinols"; J. Ong. Chem. 43(2); 44-46; (1977), Drake etal, “lassicalnonclasscal hybrid cannabinoids’ J ‘Med. Chem, vo. 41(19);, 3596-3008 (1998). Edery et al; “Activity of novel aminocannabinoids in baboons’; J. Med. Chem 275 1370-1373 (1984), Fahreaholtz, K. E,, Lurie, M. and Kierstead, AR, Ws “The ‘Tal Syitesis of dl-A9-Terahydrocannabinol and Four of Its somers" J. Amer. Chem. Soc. 1967, 89(23), 5934-5041 Fahrenholtz; “the syntbesis of 2 metabolites... ”5 J. Org, ‘Chem, vol. 37(13), 1972; XPOOZILI824. Fisera, L, Kovac, J Lesco, J, Smabovsky, V5 “Furan erivatives, Pat LVL 1,3-dipolar eycloaddtions of het- eracyeles. V. Reaction of C-acetyl-N-pheayintrilimine with furan derivatives”; Chemicke Zvest; 35(1); 93-104 1981 (abstract only), Fre, E. & Mechoulam, R.; “Pharmacological activity of the eannabinoidreceplor agonist, anandamide, a brain con- slituent”; European Joumal of ‘Pharmacology, vol. 231; 313-314; 1993, Galiegue $ et al. ; “Expression of central and peripheral ‘cannabinoid receptor in human immune tissues and leuko cyte subpopulation”; Eur J Biochem; Aug. 15, 1995,282(1)54-6. (absiract only), Gareau, Y; Duttesne, C; Gallant, M Rochetl, Cs Sawyer, IN; Slipetz,D.M.; Tremblay, N Weech, PK; Metters, K. (MG Labelle, M, “Structure activity relationships of ttrahy drocanabino! analogs on human cannabinoid receploss”, Bioorg, Med. Chem, Let, 1996, 6(2), 189-194 Gold et ak; “A comparison of the discriminative stimulus properties of delta?-letrubydrocannabinol and CP 55,940 in ‘als and rhesus monkeys"; J. Pharmacol. Exp. Thee vol 262(2); 479-486; 1992. ‘Hampson, A.., Grimaldi, M. Axpirod J. Wink D; “Canna bidiol and (-) 9 tetahydrocannabinol are neuroprotective antioxidants"; Proc. Nall Acad Sei, USA (Iul, 1998) 95; 8268-8273, Hargreaves, Ket al; “Anew sensitive method for measuring thermal nociception in cutaneous hyperalgesia; Plain; 32; 77-88; (1988) (abstract only), Herzberg U, Eli E, Beanett GJ, Kopin U; “The analgesic elfecs of R() WIN 55,212-2 mesylate, » high affinity ‘cannabinoid agonist in a'rat model of neuropathic pain", Neurosci. Letts. (1097) 221; 157-160, Uillacd C.1, Edgemond, W. S.,Jarrahian W., Campbell, W. B; “Accumulation N-Arachidonoylethanolamide (Ananda- ‘mide) into Cerebellar Granule Cells Occurs via Faellitated Diffusion”; Journal of Neurochemsry; 69; 631-638 (1997), US 6,900,236 BL Page 4 Horevoets AG et ab “Inactivation of Bsckerihia col cuter membrane phospholipase A bythe afnity label hexa- ecanesulfonyl fluoride”; Eu. Biochem, 198; 247-253, 1991, Horevoets ALG et ak; “Inactivation of reconstituted Escherichia col outer membrane phospholipase Aby mem brane-perturbing peptides results in an increased reactivity towards the affinity label hexadecanesulfonl forge”; Eur J. Biochem, 1983 255-261; 1991, Howlett et al; “Azido and isothicyanato substituted aryl pytaaokes bind covalently tothe CBI cannabinoid receptor and impair signal transduction”; Journal of Neurochemistry; vol, 745) (2000) 2174-2181; XPOOLI7395 oviett et a; “Streochomical effects of 11-Oll- 6- or T-pesition and i selected fromm nito; itso; amin; alkylamino: dialkylamino; aio (N,);eyano;isothioeyano and phenyl X is selected from halogen; hydrogen; hydroxy; lower atkanoate; formyl; amino; eyano; isothioeyano and auido i selected from saturated or unsaturated straight ‘carbon chains with a maximum length of seven carbon toms; saturated or unsaturated branched carbon chains ‘witha maximum length of seven carbon atoms; eyelic aliphati rings interconnected tothe indole-I postion with one orto carbon atoms; bieyeli aliphatic ings interconnected tote indole-t poston with one ot 180 carbo atoms; and beteroeyelic ings interconnected to the indole-1 positon with one or fwo carbon atoms, is selected fom Hand lower alk Y¥ is selected from earboayl and CH=CH (cis o trans) Ris selected from pheay;napthy; 9-antracenyl ada- ‘nant; pyreny; phenyl with no more than 1Wo Sb- stunts selected from halogen, nto, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, aide, eyano and isothioeyan;ngpibyl with no ‘more than two substituents selected from halogen, ito, nitroso, amino, alkylamino, dislkylamino, roxy, methoxy, lower alkyl, azido, cyano and ‘sothioeyan; and 9-anthraceny with ao more than two substituents selected. from halogen, nitro, nitroso, amino, alkylamino, dialkylmino, hydeoxs, methoxy, lower alkyl, ado, eyano and isoioeyano, ‘The analogs of this embodiment show high binding R, © afinities forthe CB and CB2 cannabinoid receptors. More Jmportantl, some of these compounds show aot only com- parable cannabimimetic sctvity with the compound WIN ‘5521-2 but also a surprisingly higher selectivity for one of the CBL or CB2 receptors. More specifically, the inventive analogs showed similar or higher receptor binding affinity than the well-knovin indole cannabinoid WIN 552122 ‘Another embodiment of the invention is shown as B, Ia this embodiment the functionalities of the novel eanaabimi- ‘lic indole analogs were modified inthe indole3 andior indole positions. ° va Z may be in the 4, 5-, 6 of 7-position and is selected from halogen; hydroxy; methoxy and lower alkyl X is selected from hydrogen; hydroxy; lower alkanoate; formyl; amino; eyano and isothiocyano. R, is selected from saturated of unsaturated staght ‘arbon chains with a maximam length of seven carbon atoms saturated or unsaturated branched carbon chains ‘with « maximum length of seven carbon atoms; cyclic aliphatic rings interconnected tothe indole-L position with one or two carbon atoms; and bicyclic aliphatic rings interconnected o the indole-t position with one orto earhon atoms. RR is selected from H and lower alkyl Y is selected from carbonyl and CH=CH (cis or tran) R, is selected from phenyl; napthyl; nantracenyl;ada- ‘maniyl; pyrenyl phenyl with no mere than 10 sub- stituents selected ftom halogen, nit, nitroso, amino, alkylamino, dalkylamino, bycoxy, methoxy, lower alkyl, azide, cyano and iscthioeyano; napibyl with a0 8 US 6,900,236 BI 3 ‘more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hhydroxy, methoxy, lower alkyl, azido, cyano and isothioeyano, and 9-anthracenyl with no more than two substituents ‘selected from halogen, nitro, nitroso, _¢ amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, eyano and isothiocyano. ‘The analogs of this embodiment are surprisingly potent caansbizinetic compounds wih high CB1 sade Ct selectivity. ‘Since CB2 selective cannabinoids are able to activate the (CB? receptor and thereby modulate the immune system with Title psyshoactivity or other CNS eifects, these analogs are possible therapeutic agents. Additionally, Some of the iodide and fluoride containing, analogs are potential radioactive probes for imaging in Vivo the distribution of eannabinoid receptors. The azido modified analogs are excellent affinity probes for characterizing binding pockets of cannabinoid receptors. ‘The analogs disclosed herein are relatively easy to manu- facture. Additionally these analogs have better physiocher cal properties than naturally occurring cannabinoids. Thus, 29 the novel cannabimimetic indole derivatives. deseribed herein, and physiologically acceptable salis thereof, repre- sent potentially useful materials for providing 4 physiologi- cal elfect to teat paia, peripheral pain, glaucoma, epilepsy, nausea such as associated with cancer chemotherapy, AIDS ‘Wasting Syndrome, cancer, neurodegenerative diseases including Multiple Sclerosis, Parkinson's Disease, Hunting- ton’s Chotea and Alzheimer’s Disease, mental disorders such as Schizophrenia and depression; t prevent or reduce cesdotoxie shock and hypotensive shock; 10 modulate appe- tite; to reduce fertility, to prevent or reduce diseases asso- ciated with motor function such as Tourette's syndrome; to prevent or educe inflammation; to provide neuroprotection ‘and to eflect memory enhancement. ‘The novel cannabimimetic indole derivatives: described herein also provide useful materials for testing the eannab- ‘noid system. Thus, another aspect of the invention is the * administration of a therapeutically effective amount of an inventive compound, or a physiologically acceptable salt thereof, to an individual o¢ animal to provide a physiological effet DESCRIPTION OF SOME PREFERRED EMBODIMENTS As used herein, a“tberapeutially effective amount” of a compound, is the quantity of a compound which, when admiaistered to an individual or animsl, results in a suli- cieatly high level of that compound in the individual of animal to cause a discernible inrease or decrease in stimu lation of cannabinoid receptors. Physiological effects that result from cannabigoid receptor stimulation include analgesia, decreased nausea resulting from chemotherapy, Sedation and increased appetite. Other physiological fu tions include relieving intraocular pressure in glaucoma patients and suppression of the immune system. Typically, about 10 mgiday 10 abou 1,000 mgiday is 3 possible “therapeutically elective amount” forthe inventive com- pounds ‘As used herein, an “individual” refers to a human. An “animal” refers to, for example, veterinary animals, such as, dogs, cats, horses and the like, and Farm animals, such as ‘cows, pigs andthe like ‘The compound of the present invention can be adminis- tered by a varity of known methods, including orally, rectally, or by parenteral routes (e.,_ intramuscular, intravenous, subcutaneous, nasal or topical). The form in which the compounds are administered will be determined by the route of administration, Such forms include, but are ‘not limited to, capsular and tablet formulations (For oral and rectal administration), liguid formulations (lor oral, 0 4 intravenous, intramuscular or subcutancous administration) and slow releasing microcariers (fr rectal, intramuscular or intravenous administration). The formulations ean also con- tin a physiologically acceptable vehicle and optional adjuvants, Ravorngs, coloranis and preservatives, Suitable physiologically to” acceptable vehicles may include, for example, saline, sterile water, Ringers solution, and iso- tonic sodium chloride solutions. The specific dosage level of active ingredient will depend upon a aumber of faciors, including, for example, biological activity ofthe particular preparation, age, body weight, sex and general heath of the Individual being treated, The inventive cannabinoid analogs are generally eseribed by the strctural formulas previously disclosed The following examples ace given for purposes of illustra tion only in order that the present invention may be more Tully understood, These examples are not Intended to limit in aay way the practice of the invention The prepared cannahimimetic indole derivatives. can generally be eseribed with reference to structural formulas 1 and 2 bolew and include physiologically acceptable salts thereof. ‘The inventive cannabimimetc indole derivatives of stuc- ‘wa Tamu neti oth aemiss nd vo enstiome sin the indole-6 postion and is selected from the group ‘consisting of Hy NOs; NHN, and NCS. R, is a heterocyclic ring intereoonected to the indole-1 ‘positon with one carbon atom, X is hydrogen. RR is selected from the group consisting of Hand methyl Y is carbonyl R, is selected from the group consisting of phenyl ‘napthyl;adamantanyl; pyrenyl and substituted versions of any ofthe above ‘The inventive materials of structural formal 1 are listed in TABLE 1. It should be noted that R, for all of the materials of TABLE 1 was. 1-(N-Methyl-2-piperidinyl) ‘methyl, All ofthe materials TABLE I have a chiral center andthe binding affinities ofthe materials of TABLE 1 were ‘obtained by evalusting their racemic samples, TABLE 1 {odopea! iodo hem Pet doe! oop! ‘Sate? dopey ‘Soneanno ‘odopel asp aay apy aap Taunt taps Minis US 6,900,236 BI 5 ‘TABLE L-coatinued Ken voleg ZR co cm A217 NCS HM tapht 35 as M00 HH tos nas AMI296 HH aphiyt 75388 AME HH Tape aad Hind rnapeyt S020 Hl Hsuoewadosanhiyl 288 96 Hemant man Ho 2pyesy a1 ™ 6 isin the indole-6 postion and is selected from the group consisting of hydrogen; NOs; NH, and hslogen X is selected from the group consisting of halogen; i; OH; OCOCH; OTS; NCS; OAc and CN, R, is saturated lower alkane with a maximum leogth of seven eathon atoms Ris selected from the group consisting of H and methyl Y is carbonyl R, is selected from the group consisting of phenyl; ‘napthyl; and substituted versions of any of te above, ‘The inventive materials of structural formula 1 are listed in TABLE 2 R, lists the number of carbon atoms in the chain at that position. TABLE, a ‘iodo! atopy! odo! iodo! 2 adopeyl iadopeayl odo! 2aodopeyl dopey! 2 odepeayl ante! odopeayl Siatopey! atopy! sodopey| Peto atopy! Bale Slopes Bale aminphey Dos ‘oneyanapenyl Bade Seaiepeay dingy Faapat Paap apy Fa tery asp sp aap spy test apy spy test 8 $ 5998 69 1857 168 ma 10 13 aos tos “as 49 230 US 6,900,236 BI 7 8 TABLE coil a eee oe ee ‘an in — ‘he above mats were arly pepe flaws ‘Gon! Peron precinct I Mc mtr Ute in Tbe 2 canbe ppd by nein Shoat — : . 1. EMgBr RS m3 ieee xO, — = I a I | | I A bu, be [rennecn 18 rs : I J “= I : we y ve y oe i bs ka exes He fe : ‘ = : | | US 6,900,236 BI 9 ‘When Z=NOs, the structures can be transformed t0 the ilferent substituents as Hse in Table 2 using methods outlined in Scheme 2. stone? 5 RS | Rasy Ni o Sr FOS” | hy H % aw y ‘ (any H s “The commercially unavsilable R3-COCL used in Scheme 1 an be prepared according fo Scheme 3 10 coon 1 tivo, S00, NOs oct No: ENOHH.D 2 ACOWL OAS uc t “ oe After these acid chlorides were connected indole 3-positon, the nitro group in them can be further trans- Tormed into amino, iodo, azido, and isothioeyanate groups according tothe methods outliged ia Scheme 4. a Q Amn Ce ae io, i I | | : fo, du. k ‘ k +R ae Arne US 6,900,236 BI i B. General Preparation Procedures for Materials Listed in ible 1 ‘These materials canbe prepare in similsely manners as those compounds listed in Table 2 by using N-methyl-2 Pipetnemey cre insead of acetyl halds forthe alkylation of indole L-position in Scheme 1 Examples of specific analogs were prepared as follows: 3.Aeyl-IH-indole. 17.5 ml of a 3M solution of methyl magnesium bromide in ethyl ether was added dropwise with Slirting toa solution of indole (5:85 g, 80 maa)) in 50 mk. of ethyl ether at O° C, Alter addition, the reaction mixture ‘was waemed up to room temperature and sited for 2hours (8). Then the rection mixture was cooled down agai to (C-and to it was added slowly with violent stirring a solution cof acyl chloride (50 mmol) in 50 mL of ethyl ether. The resillng rection mixture was warmed up to room tempera ture and stirred for another Uh followed by the slow addition of 375 mi of ammonium chloride aqueous solution, After violently stirring for 30 min, a white solid was fomed and flrated. The Hate was washed successively wit ethyl ether and reerystallized ftom ethyl scetateshexane to afford the produc. ‘Dimethyl 3-acyl-1H-indole. The foregoing procedure was ‘repeated Using 2-metbyl indole in plae of indole. TFAlkyl2-methyl-3-acy/-1H-indole, To a 1.2 mmol sus- pension of sodium hydride (48 mg, 604 in mineral ol) in 2 rm of dimethylformamide (DMF) was added 2-methy- seyl-IH-indole (06 mmol). After string at room tempera ture for 30 mia, alkyl bromie (06 mmol) was added Gropwise, The resting mixture was heated to 65° C, and slired for 3 followed by removal of solvent under vacuum. ‘The residue was separated by flash column chromatography (Gilica gel, petroleum ether-

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