MXPA97005883A - 2-aminoindanos as selective ligands of dopamine - Google Patents
2-aminoindanos as selective ligands of dopamineInfo
- Publication number
- MXPA97005883A MXPA97005883A MXPA/A/1997/005883A MX9705883A MXPA97005883A MX PA97005883 A MXPA97005883 A MX PA97005883A MX 9705883 A MX9705883 A MX 9705883A MX PA97005883 A MXPA97005883 A MX PA97005883A
- Authority
- MX
- Mexico
- Prior art keywords
- solid
- compound
- added
- water
- ether
- Prior art date
Links
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 title description 4
- 229960003638 dopamine Drugs 0.000 title description 2
- 239000003446 ligand Substances 0.000 title description 2
- 230000027455 binding Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 239000011780 sodium chloride Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 210000003169 Central Nervous System Anatomy 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 102000004073 Dopamine D3 Receptors Human genes 0.000 claims abstract description 5
- 108090000525 Dopamine D3 Receptors Proteins 0.000 claims abstract description 5
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 5
- 230000000694 effects Effects 0.000 claims abstract description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 201000000980 schizophrenia Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 206010057666 Anxiety disease Diseases 0.000 claims description 2
- 206010012289 Dementia Diseases 0.000 claims description 2
- 206010026749 Mania Diseases 0.000 claims description 2
- 206010061536 Parkinson's disease Diseases 0.000 claims description 2
- 230000027288 circadian rhythm Effects 0.000 claims description 2
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- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 2
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- 206010012335 Dependence Diseases 0.000 claims 1
- 230000036506 anxiety Effects 0.000 claims 1
- 125000005418 aryl aryl group Chemical group 0.000 claims 1
- 229940079593 drugs Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 1
- 150000002431 hydrogen Chemical group 0.000 abstract 1
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- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 150000003141 primary amines Chemical class 0.000 description 6
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
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- CSKNSYBAZOQPLR-UHFFFAOYSA-N Benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 5
- 101700067048 CDC13 Proteins 0.000 description 5
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
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- VTWMVSNABLUVLZ-UHFFFAOYSA-N methyl 2-prop-2-ynylpent-4-ynoate Chemical compound COC(=O)C(CC#C)CC#C VTWMVSNABLUVLZ-UHFFFAOYSA-N 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N methyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- JCDWETOKTFWTHA-UHFFFAOYSA-N methylsulfonylbenzene Chemical compound CS(=O)(=O)C1=CC=CC=C1 JCDWETOKTFWTHA-UHFFFAOYSA-N 0.000 description 1
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 1
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- JQJOGAGLBDBMLU-UHFFFAOYSA-N pyridine-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=N1 JQJOGAGLBDBMLU-UHFFFAOYSA-N 0.000 description 1
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to compounds and their pharmaceutically acceptable salts suitable for treating disorders of the central nervous system associated with the activity of the dopamine D3 receptor of Formula I: wherein R1 and R2 are independently H, C1-8 alkyl, or C1 alkylaryl -8; X is CH2R3 or NHSO2R4; Y is hydrogen, CH2R3, NHSO2R4, CONR1R2, SO2NR1R2, SO2CH3, halogen, OSO2CF3, SCH3 or OCH3, R3 is NHSO2R4, SO2R4, CONR1R2aril, and R4 is NR1R2, C1-C8alkyl, aryl or C1- alkylaryl
Description
2-AMINOINDANOS AS SELECTIVE LIGANDS OF DOPAMINE D3
BACKGROUND OF THE INVENTION The present invention relates to 2-aminoindane analogs that selectively bind to the dopa ina receptor D3 in vi tro. The dopamine D3 receptor has recently been cloned by Sekoloff et al., (Nature, 347,
146 (1990)). It was hypothesized that this receptor subtype is important for the action of antipsychotics. Interestingly, this receptor shows great abundance in regions of the brain that are associated with emotional and cognitive functions. Compounds with this profile may be useful for treating disorders of the central nervous system, for example schizophrenia, mania, depression, geriatric disorders, drug abuse and addiction, Parkinson's disease, anxiety disorders, sleep disorders, circadian rhythm disorders and dementia.
Statement of Information Exhibition; Arneric, S.P. et al., Neuropharmacol. , 2JL, 885
(1982) describes indane analogues compared to other dopamine agonists. The compounds with substitution 5,6 were found inactive in this model of food consumption.
P447 Arneric, S.P. et al., Arch. Int. Pharmocodyn. Ther. , 257, 263 (1982) describes analogs of 2-aminotetralin and 2-aminoindane wherein the substituted 5,6-dimetsxy compound is revealed once again as an inactive agent in an assay to evaluate contractions in vascular smooth muscle. Bhatnagar, R.K. et al., Pharmacol., Biochem. Behav. , 17. (Suppl 1), 11 (1982) discusses SAR studies of several structural entities that include aminoindans that interact with dopamine receptors. The 5,6-dimethoxy indanes are revealed as inactive compounds. Cannon, J.G. et al., J. Med. Chem., 25., 858 (1982) describes 4,7-dimethoxy-2-amino indanes and their dopaminergic and cardiovascular actions. Cannon, J.G. et al., J. Med. Chem., 25, 1442
(1982) reveals the synthesis of 5,6-dimethyoxy and di-hydroxy indanes and also certain biological characteristics that show that they are free of dopamine receptor activity. Cannon, J.G. et al., J. Med. Chem., 27, 186
(1984) describes the synthesis of N-alkylated derivatives of the 2-amino-4,6-dihydroxy indanes. Cannon, J.G. et al., J. Med. Chem., 2jB, 515
(1985) describes the resolution of 4-hydroxy aminoindanes. Cannon, J.G. et al., J. Med. Chem., 29, 2016 (1986) describes the ortho OH / methyl, hydroxymethyl, formyl or carboxy derivatives of 2-aminoindanes (substitution 4.5), aminotetralins and benz [f] quinolines. Hacksell, U. et al., J. Med. Chem., 24, 429 (1981) describes the synthesis of monophenolic 2-aminoindanes as stimulants of the central dopamine receptor. Ma, S. et al., J. Pharmacol. Exp. Ther., 256, 751 (1991) describes the relationships of the activity of the inertgic dopa structure of the 2-aminoindanes with di-substitution mainly at positions 4,5. Nichols, D.E. et al., J. Med. Chem., 3J3, 703 (1990) describes non-neurotoxic analogues tetralin and indane of 3,4- (ethylenedioxy) amphetamine. PCT Patent Publication No. O90 / 07490 describes 2-aminotetralins and 2-aminoindanes with aromatic substitution with an OCH3 or OH in conjunction with a Br group. European Patent 88302599.1 filed on March 24, 1988 discloses antiarrhythmic aminoindanes having a bicyclic structure and a methyl group in the amine, not disclosed in the subject invention. U.S. Patent No. 4,132,737 discloses trifluoromethyl-substituted 1-aminoindanes while the present invention refers to 2-aminoindanes; and United States Patent No.
,225,596 discloses substituted tetralins but not in the form in which they are substituted here.
SUMMARY OF THE INVENTION In one aspect, the present invention is directed to compounds and pharmaceutically acceptable salts of Formula I:
where R! and R2 are independently H, C-8 alkyl or alkylaryl C ^ g; X is CH2R3 or NHS02R4; Y is hydrogen, CH2R3, NHS02R4, CONR ^, S02NR2R2, S02CH3; halogen, OS02CF3, SCH3 or OCH3; R3 is NHSO2R4, S02R, C0NR! R2 or aryl; and R 4 is NR? R2, C 1 Cg alkyl, aryl or C 1- C alkylaryl. In another aspect, the present invention is directed to compounds and pharmaceutically acceptable salts of Formula I, above, which include racemic mixtures and the two enantiomers. Preferred are structures of Formula I wherein Ri and R 2 are independently H and a lower alkyl (C 1 ß alkyl); and Y is CONR ^, S02NRÍR2, S02CH (wherein R 'and R are independently H and lower alkyl). In a further aspect of the present invention there is mentioned a method for treating schizophrenia, by administering a therapeutically effective amount of a compound of Formula I to a patient suffering from schizophrenia. In yet another aspect, this invention is directed to a method for treating disorders of the central nervous system associated with the activity of the dopamine D3 receptor in a patient in need of this treatment, which comprises administering to the subject an amount of a compound of the Formula I, therapeutically effective to mitigate said disorder. Typically, the compound of Formula I is administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier. In a further aspect, this invention is directed to a pharmaceutical composition for treating disorders of the central nervous system associated with the activity of the dopamine D3 receptor, which comprises an effective amount of a compound of the Formula I with a pharmaceutically acceptable diluent or carrier.
DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to pharmaceutically acceptable compounds or salts of Formula I, as illustrated above, either in racemic or pure enantiomer form. X, Y, Ri, R2, R3 and R4 are independently selected as already mentioned above. "Alkyl" ranges from one to eight carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomeric forms thereof. Halogen is a fluorine, chlorine, bromine or iodine atom. "Aryl" includes benzene and aromatic heterocycles with 5- and 6-membered ring, containing either one or two heteroatoms selected from N, O, S. These aryl groups may be substituted with groups such as H, one or more halogens, CN , CF3, N02, C (0) NR! R2, S02NR? R2, NHC (O) -alkyl C! _3, or S02CH3. The pharmaceutically acceptable salts include salts of both organic and inorganic acids. Preferred pharmaceutically acceptable salts include salts of the following acids: methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric or maleic. The compounds of Formula I are orally or parenterally active. The oral compounds of Formula I can be administered in solid dose forms, such as tablets or capsules, or they can be administered in liquid dosage forms, for example elixirs, syrups or suspensions as is known to those skilled in the art. It is preferred that the compounds of Formula I be administered in the form of solid doses and that it be in the form of tablets. Typically, the compounds of Formula I can be administered in an amount of between about 0.25 mg to about 100 mg / person, one to three times a day. Preferably from about 10 to about 50 mg / day in divided doses. The exact dose and the frequency of administration depend on the particular compound of Formula I that is used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the patient. particular patient, of other medications that the individual is taking, as will be known to those of skill in this field, and can be determined more accurately by measuring the blood level or concentration of the active compound in the patient's blood and / or the response from the patient to the particular condition that is being treated. In this way, the compounds of the invention, together with a pharmaceutically acceptable carrier, diluent or buffer, can be administered in effective therapeutic or pharmacological amounts to mitigate the disorders of the central nervous system in relation to the physiological condition diagnosed. The compounds can be administered intravenously, intramuscularly, topically, transdermally in the form of skin patches, orally or orally, to man or to other vertebrates. The composition of the present invention can be presented for administration to humans and other vertebrates in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, solutions or oral suspensions, oil-in-water emulsions and of water in oil, which contain adequate amounts of the compound, suppositories and in suspensions or fluid solutions. For oral administration, unit dose forms may be prepared either solid or fluid. To prepare solid compositions as tablets, the compound can be mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose and similarly functional diluents or pharmaceutical carriers. . The capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into hard gelatin capsules of the appropriate size. Soft gelatine capsules are prepared by machine encapsulation of a suspension of the compound with an acceptable vegetable oil, light liquid petrolatum or any other inert oil. Fluid unit dose forms for oral administration, such as syrups, elixirs and suspensions, can also be prepared. The forms can be dissolved in an aqueous carrier together with sugar, aromatic flavoring agents and preservatives to form a syrup. The suspensions can be prepared with an aqueous vehicle with the aid of a suspension agent such as acacia, tragacanth, methylcellulose and the like. For parenteral administration, fluid unit dose forms can be prepared using the compound and a sterile vehicle. When preparing solutions, the compound can be dissolved in water for injection and sterilized by filtration before filling in suitable vials or ampoules and sealed. Adjuvants, such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. The composition can be frozen after filling in the vials and the water can be removed by application of vacuum. The lyophilized powder can then be sealed in the vial and reconstituted before use.
Chemical Synthesis Commercially available 4-bromobenzylbromide 1 was alkylated with the lithium enolate of t-butyl acetate (Scheme 1) and subsequently deesterified with trifluoroacetic acid to give carboxylic acid 2. Conversion to acyl chloride using chloride of thionyl and the subsequent Friedel-Crafts cyclization with aluminum chloride gave indanone 3. 6-Bromo-l-indanone 3 was obtained in four steps in an overall yield of 89%. 6-Bromo-l-indanone 3 was carboxylated using sodium hydride and dimethylcarbonate to give β-keto-methyl ester 4. A high yield (97%) was obtained on a large scale (0.67 mol) using this method. The β-ketoester was reduced with sodium borohydride and methanol to give the hydroxy-ester 5. Dehydration of the β-hydroxy ester with polyphosphoric acid gave the unsaturated ester 6 in a high yield within a period of 60 minutes (Vebrel, J., Carrie, R. Synthese ethoxycarbonylindenes, dihydro-1,2 naphthalenes et benzocycloheptene, Bull. Soc. Chi. Fr., 1982, ptll, 116-24). Ester demethylation was achieved with aqueous ethanesulfonic acid and formic acid (Loev, B., Acid Catalysed Hydrolysis of Esters, Chem. And Ind. 1964, 193-94) to give 7 in high yield. They were obtained
P447 similar results using boron tribromide. Asymmetric hydrogenation with (S) -BINAP-ruthenium (II) diacetate (Ohta, T, et al., Asymmetric hydrogentation of unsaturated carboxylic acids, J. Org. Chem., 1987, 52, 3174-76, and Kitamura, M. Et al., Practical synthesis of BINAP-ruthenium dicarboxylate complexes, J. Org. Chem. 1992, 57 4053-54) gave rise to 8 in a high enantiomeric purity (ratio 95: 5). Recrystallization of the salt of (R) - (+) - '.- methylbenzylamine / indanoic acid from diethyl ether / ethanol gave the optically pure acid. The enantiomeric proportions were evaluated by chiral HPLC separation of the reduced acid (alcohol). At this point, the carboxylic acid 8 underwent a Curtius rearrangement with the help of diphenylphosphorylazide (Ninomiya, K et al., A new convenient reagent for a modified Curtius reaction, Tetrahed, 1974, 30, 2154-57) to give t-butyl carbamate 9 which was converted to the primary amine 10, by refluxing it with trifluoroacetic acid. Dialkylation with bromopropane gave the tertiary amine 11. The overall synthesis of (S) - (+) - 5-bromo-2-N, N-dipropylaminoindane takes ten steps and gives an overall yield of 9%. (S) - (+) - 5-bromo-2-N, N-dipropylaminoindane (11) was used as the
P447 intermediate for the preparation of several enantiomerically pure analogues. An exchange of halogen and metal with tertiary butyl lithium gave the lithium anion, which was treated with tri-ethylsilylisocyanate to obtain the analogue 5-carboxamide 12. This was reduced to a primary amine 14 with borane methylsulfide. In a separate series of reactions, lithium anion 11 was treated with paraformaldehyde (Rec.Trav.Pays-Bays, 1965, 1200) to obtain the 5-hydroxymethyl analogue 13 which was converted to mesylate using methanesulfonyl chloride. This mesylate was converted to phenylsulfone 16 using sodium salt of benzenesulfinic acid. It was also converted to acetamide 17, by acetonitrile, obtained by treatment with mecyilate with sodium cyanide. The acetonitrile intermediate was hydrated using sodium hydroxide and hydrogen peroxide to obtain 17 (Cacchi, S. et al., Amides from nitrilee using basic hydrogen peroxide under phase-transfer catalyzed conditions, Synthesis 1980, 243-44). Scheme 3 illustrates the preparation of compounds 18-22, starting from the 5-hydroxymethyl analogue 13. This analog was prepared from 6-bromo-2-ind- (1-en) oico (7) and was asymmetrically hydrogenated using the diacetate of (R) -BINAP-ruthenium (II) to provide the acid (R) - (-) - 5-bromoindanoic acid (8). The carboxylic acid 8
P447 underwent a Curtis rearrangement with the help of diphenylphosphoryl azide to give the t-butyl carbamate 9 which was converted to the primary amine 10 by refluxing with trifluoroacetic acid. Dialkylation with bro-oropropane gave the tertiary amine 11. A metal-halogen exchange with tert-butyl lithium gave the lithium anion which was treated with paraformaldehyde to obtain the 5-hydroxymethyl analog 13. The (R) - (-) - 5-hydroxymethyl-2-N, N-dipropylaminoindan (13) was converted, in a yield of 96%, into the chloromethyl analogue 18 using thionyl chloride in tetrahydrofuran (Chem. Rev. 1963, 63, 557). Displacement of the chloride with 4-bromothiophenol in basic solution gave (R) - (-) - 5 - (4-bromobenzene) thiomethyl-2-N, N-dipropylaminoindan (19) in a yield of 93%. This sulfide was oxidized in a 79% yield using peracetic acid to provide sulfone 20. Palladium copolymerization of formamide with aryl bromide gave (R) - (-) - 5 - (4-carboxyimidobenzene) sulfonylmethyl-2- N, N-dipropylamino-indane (21). Dehydration of the carboxamide using titanium tetrachloride and triethyl amine (Tetrahed Lett, 1971, 1501) gave the cyano analog 22 in a yield of 78%. Scheme 4 illustrates the preparation of compounds 24-39 starting with (R) - (-) - 5-bromo-2-N, N-
P447 dipropylaminoindan (11) which was lithiated by metal / halogen exchange in position 5 and treated with diphenylphosphorylazide. The resulting azide was reduced in the same vessel with lithium aluminum hydride (Chem. Pharm. Bull 1986, 1524) to provide (R) - (-) - 5-amino-2-N, N-dipropylaminoindan (23) in 41% yield. This primary amine was sulfonylized with benzenesulfonyl chloride or 4-chlorobenzenesulfonyl chloride to give 24 and 25, respectively. The (R) - (-) - 5-bromo-2-N, N-dipropylaminoindane (11) was lithium by metal / halogen exchange with tert-butyl lithium and then treated with trimethylsilylisocyanate to obtain the 5-carboxamide analogue 12. This was reduced to the primary amine 14 with borane-methylsulfide. This primary amine 14 was sulfonylized with several sulfonyl chlorides to give analogs 26 to 39. Scheme 5 illustrates the preparation of compounds 53 to 56 starting with dimethyl malonate which is dialkylated with propargyl bromide under phase transfer conditions. to give diester 40, which was decarboxylated (AP Krapcho and AJ Lovey, Tetrahed, Lett 1973, 957, AP Krapcho, JF Wseimaster, JM Eldridge, EGE Jahngen, Jr., AJ Lovey, and WP Stephens, J. Org. Chem. 1978, 43, 138) to give the monoester (41). Hydrolysis of the ester with aqueous sodium hydride
P447 provided the acid (42) which was converted to the t-butylcarbamate (43) by a Curtis rearrangement modified with diphenyl phosphoryl azide (K. Ninomiya, T. Shioiri, and S. Yamada, Tetrahed, 1974, 30, 2151) . The t-butylcarbamate was hydrolysed in 4-amino-1,6-heptadiin (44) with trifluoroacetic acid and the amine was protected as the trifluoroacetamide (45) using trifluoroacetic anhydride and triethylamine in tetrahydrofuran. The diine (45) was cyclized with 2-butyne-1,4-diacetate 46 using ilkinson's catalyst (P. Magnus and D. itty, Tetrahed.Lett., 1993, 34, 23) in ethanol to give indane (47) . The trifluoroacetamide and acetate entities were hydrolysed with potassium hydroxide in aqueous methanol to give the crude amine (48), which was dialkyl with 1-bromopropane in acetonitrile to give the dipropylamine (49) in an overall yield of 81% from 46. The diol (49) was converted to 5,6-bis (chloromethyl) indan (50) with thionyl chloride. The 5,6-bis (chloromethyl) indane (50) was converted to the diazide (51) with sodium azide in dimethylformamide. The diazide was not isolated, but it was extracted with the methyl-t-butyl ether and reduced with lithium aluminum hydride. The reaction showed an incomplete reduction and, therefore, was subjected to reduction with magnesium in methanol (S.N. Maiti, P. Spevak, and A.V. Narender Reddy, Syn. Comm. 1988,
P447 18,1201) to give the crude diamine (52). The diamine was reacted with several sulfonyl chlorides in pyridine to give bis (sulfonamide) 53, 54 and 55. The 5,6-bis (chloromethyl) indane (56) was converted to bis (methylphenylsulfone) with sodium benzenesulfinate in dimethylformamide.
EXAMPLES The procedures are illustrated as chemical formulas in schemes 1 to 5, after this section of examples. The compounds are listed and represented in the schemes.
Procedure 1: 3- (4-bromophenyl) propionic acid. 2 t-Butyl acetate (159 mL, 1180 mmol) was added to lithium diisopropylamide (941 mmol) in tetrahydrofuran at -78 ° C followed by 4-bromobenzyl bromide (200 g, 784 mmol). The batch temperature was maintained at -15 ° C for 4 hours, at which time the reaction was quenched with ammonium chloride. The mixture was extracted with diethyl ether and the organic layer was washed with dilute hydrochloric acid, water and brine, drying with sodium sulfate to give a pale oil. This was refluxed with trifluoroacetic acid (150 mL, 1960 mmol) by
P447 1 hour. The trifluoroacetic acid was removed under vacuum and the residue was separated between diethyl ether phase and aqueous phase of sodium hydroxide. The aqueous layer was acidified with concentrated hydrochloric acid at 0 ° C and extracted with diethyl ether. This organic layer was washed with water and brine and dried over sodium sulfate to obtain a white solid, after removing the solvent in vacuo (167 g, 93%), mp 132-134 ° C.
Procedure 2 6-Bromo-l-indanone. 3 3- (4-Bromophenyl) propionic acid (162 g, 706 mmol) and thionyl chloride (155 mL, 2120 mmol) were refluxed for 90 minutes. The thionyl chloride was then removed in vacuo to give an amber oil. This oil, aluminum chloride (109 g, 816 mmol) and dichloromethane (1000 mL) were refluxed for 90 minutes and then poured onto ice. The dilute hydrochloric acid was added and the mixture was extracted with diethyl ether. The organic layer was washed with 2N hydrochloric acid, water, aqueous sodium bicarbonate solution, water and brine. The product was subjected to flash chromatography on a 25 x 7 cm silica gel column and eluted with ethyl acetate / dichloromethane (5:95) to obtain a pale brown solid after removing the
P447 vacuum solvent (142 g, 95%), mp 107-109 ° C.
Process 3 6-bromo-2-carboxymethyl-1-indanone. 4 6-Bromo-l-indanone (142 g, 672 mmol) in tetrahydrofuran (1200 L) was added slowly to dimethyl carbonate under reflux (143 mL, 1680 mmol), sodium hydride (80.6 g, 2020 mmol, 60 % in oil, and washed with pentane after weighing) and tetrahydrofuran (1200 mL). After refluxing the mixture for 2.5 hours, the acetic acid (240 mL) was added dropwise at 0 ° C and then allowed to warm to room temperature. The mixture was separated between a diethyl ether / dichloromethane phase and an aqueous phase of dilute hydrochloric acid. The organic layer was washed with 2N hydrochloric acid, water, aqueous sodium bicarbonate and brine and then dried over sodium sulfate to obtain a brown solid after removal of the solvent in vacuo (176 g, 97% crude) and melting point. 124.5-127.5 ° C. 1 H-NMR (300 MHz, CDC13) (a ratio of about 3: 1 enol to ketone tautomers) 7.91 (d, 0.27H), 7.77 (d, 0.73H, J = 1.8), 7.73 (dd, 0.27H), 7.54 (dd, 0.73H, J = 8.1, 1.8), 7.93 (d, 0.27H), 7.34 (d, 0.73H, J = 7.9), 3.86 (s, 2.19H), 3.83 (m, 0.27H), 3.80 (?, 0.81H), 3.50 (m, 0.27H), 3.47 (s, 1.46H), 3.32 (m, 0.27H).
P447 Method 4. 6-Bromo-2-carboxymethyl-1-hydroxyindan. The 6-bromo-2-carboxymethyl-l-indanone (139 g, 650 mmol), methanol (1100 L) and tetrahydrofuran (200 L) were stirred at 0 ° C. Sodium borohydride (9.30 g, 245 mmol) was added in portions over 45 minutes and stirred another 45 minutes. More sodium borohydride (12.4 g, 326 mmol) was added in portions over 45 minutes and stirred for another 60 minutes. Water was added and the solvent was removed under vacuum at 35 ° C. The residue was partitioned between diethyl ether and water. The organic layer was washed with water and brine and then dried over sodium sulfate. A flash chromatography of the crude product was carried out on a 30 x 7 cm silica gel column, eluting with dichloromethane / ethyl acetate / hexane (1: 2: 5), obtaining an orange wax (99.6 g, 57%) 1H -NMR (300 MHz, CDC13) (a ratio of approximately 1: 1 of cis to trans diastereomers) 7.55 (s, 0.43H), 7.51 (s, 0.57), 7.39 (t, 0.57H, J = 8.1), 7.39 (t, 0.43H, J = 8.1,), 7.13 (d, 0.43H, J = 8.1), 7.08 (d, 0.57H, J = 8.1), 5.44 (d, 0.57H, J = 6.9), 5.30 ( d, 0.43H, J = 6.0), 3.79 (s, 1.71H), 3.77 (s, 1.29H), 3.45-2.95 (, 3H), 2.87 (s, 1H).
P447 Procedure 5 6-Bromo-2-carboxymethyl-1-indene. 6 The 6-bromo-2-carboxymethyl-1-hydroxyindane (99.4 g, 367 mmol) was heated with polyphosphoric acid (475 g) for 60 minutes (oil bath temperature 70 ° C, exotherm raising the reaction temperature to 80 ° C). The reaction was then added to water and extracted with diethyl ether and hexane. The organic layer was washed with water and dilute aqueous sodium bicarbonate and brine, and dried over sodium sulfate to obtain a brown solid after removal of the solvent in vacuo (81.Og, 87%), mp 93.5-95.0 ° C. 1 H-NMR (300 MHz, CDC13) 7.64 (m, 2H),
7. 45 (dd, 1H, J = 8.0, 1.8), 7.37 (d, 1H, J = 8.0), 3.85 (s,
3H), 3.64 (d, 2H, J = 1.7).
Process 6 6-bromo-2-ind- (1-en) oic acid. 7 The 6-bromo-2-carboxymethyl-l-indene (74.3 g, 293 mmol), the methanesulfonic acid (19.3 mL, 293 mmol), the formic acid (286 mL, 95%) and the water (15 mL) were added. they were shaken mechanically under reflux for 6 hours. Diethyl ether, tetrahydrofuran and water were added and the solution was extracted as a very dilute solution. The organic layer was washed with water and brine. It was mixed with activated carbon for 5 minutes and then filtered through soil of
P447 diatoms. It was dried over sodium sulfate and the solvent was removed in vacuo to obtain a pale yellow solid (62.7 g, 89%), mp 227.5-228.5 ° C. ""? -N R (300 MHz, d6 acetone) 7..81 (s, 1H), 7.71 (, 1H), 7.52 (s, 2H), 3.67 (d, 2H, J = 2.0).
Procedure 7 (S) - (+) - 5-Bromo-2-indanoic acid. 8 The crude 6-bromo-2-ind- (l-en) oic acid (29.4g, 123.0 mmol), the diacetate of [(S) -2, 2'-bis (diphenylphosphino) -1, 1'-hydrophyl ] Ruthenium (II) (0.67 mmol) crude, degassed methanol (350 mL) and tetrahydrofuran (35 mL) were stirred under a nitrogen atmosphere (48 PSI) for 63 hrs. The suspension was filtered through diatomaceous earth and the solvent was removed under vacuum. The residue was partitioned between diethyl ether and water. The organic layer was basified with 15% aqueous sodium hydroxide. This aqueous layer was acidified with concentrated hydrochloric acid (0 ° C) and extracted with diethyl ether / dichloromethane. This organic layer was washed with water and brine, dried over sodium sulfate. The solvent was removed in vacuo to obtain a green solid which was triturated with tetrahydrofuran and petroleum ether. The liquid was separated by decantation to give a green solid and the solvent was removed under vacuum to obtain a brown solid which was recrystallized from
P447 from toluene and petroleum ether to give the brown solid (23.2 g, 78%), melting point 110.0-111.5 ° C. [] 25589 = + 23 ° (c = 0.97 MeOH). 1 H-NMR (300 MHz, CDC13) 7.35 (s, 1H), 7.29 (d, 1H, J = 8.1), 7.08 (d, 1H, J = 8.0), 3.37 (m, 1H), 3.24 (m, 2H ), 3.19 (m, 2H). The optical purity was determined by reduction of the carboxylic acid in alcohol (borane-dimethylsulfide complex) by analyzing it with a Chiracel OD-H column eluted with isopropanol / hexane (1:20) at 1 mL / min. The non-recrystallized crude product indicated a ratio of enantiomers of 95: 5. The acid could be crystallized to an optical purity in the form of the (R) - (+) -a-methylbenzylamine salt, from methanol and diethyl ether, to obtain white crystals, melting point 155 ° C.
Procedure 8 (S) - (+) - 5-bromo-2-r (2-methyl- (2-propoxy) carbonylaminol indan 9 (S) - (+) - 5-bromo-2-indanoic acid (18.9 g, 78.4 mmol), diphenylphosphoryl azide (21.6 g, 78.4 mmol), t-butanol (80 mL), 1,4-dioxane (80 mL) and triethylamine (10.9 mL, 78.4 mmol) were refluxed for 12 hours The solvent was removed under vacuum and the residue was partitioned between diethyl ether and water The organic layer was washed with 2N hydrochloric acid, aqueous sodium bicarbonate and brine The solution was dried over sodium sulfate and the solvent was removed in vacuo get a clear solid.
P447 subjected to flash chromatography on a 29 x 5 silica gel column eluting with tetrahydrofuran / hexane (1:10). The solvent was removed in vacuo to obtain a white solid (8.3 g, 34%), melting point 125-126 ° C [a] 25589 = + 10 ° (c = 0.95 MeOH).
Procedure 9 (S) - (+) - 5-bromo-2-aminoindan. 10 (S) - (+) - 5-Bromo-2- [(2-methyl- (2-propoxy) carbonylamino] -indane (7.3 g, 23.4 mmol) and trifluoroacetic acid (9 mL, 117 mmol) were subjected to reflux for 60 minutes The trifluoroacetic acid was removed in vacuo and the residue was separated between diethyl ether / tetrahydrofuran and dilute sodium hydroxide The organic layer was washed with water and brine, dried over sodium sulfate The solvent was removed under vacuum to obtain a clear oil (4.9 g, 98%). [] 255? 9 = + 17 ° (c = 1.15 MeOH). 1 H-NMR (300 MHz, CDC13) 7.37 (s, 1 H), 7.27 (d, 1 H) , J = 8.2), 7.0 (d, 1H, J = 7.9), 3.84 (m, 1H), 3.13 (m, 2H), 2.64 (m, 2H), 1.40 (s, 2H).
Procedure 10 (S) - (+) - 5-bromo-2-N, N-di-l-propylaminoindane. 11 The (S) - (+) - 5-bromo-2-aminoindane (4.8 g, 22.6 mmol), the 1-bromopropane (10.4 L, 113 mmol), the carbonate
P447 of potassium (6.3 g, 45.3 mmol) and acetonitrile (50 mL) were refluxed for 22 hours. The solvent was removed in vacuo and the residue was partitioned between diethyl ether and water. The organic layer was washed with water and brine and dried over sodium sulfate. The dark oil was subjected to flash chromatography on a 24 x 2 cm silica gel column eluting with ethyl acetate / hexane (3:20). The solvent was removed in vacuo to give a clear oil (5.9 g, 88%). [a] 25589 = + 7 ° (c = 1.06 MeOH). The hydrochloride salt was crystallized from methanol and diethyl ether. Melting point 220.5 - 221.5 ° C.
Procedure 11 (S) - (+) - 5-carboxamido-2-N, N-dipropylaminoindane. 12 Tert-butyl lithium (12.4 mL of a 1.7 M solution in pentane, 21.06 mmol) was added (S) - (+) - 5-bromo-2-N, N-dipropylaminoindane (3.1 g, 10.53 mmol) in tetrahydrofuran ( 20 mL) at -78 ° C. After 7 minutes, trimethylsilyl isocyanate was added and the cold bath was removed. After 55 minutes, water was added and the mixture was extracted with diethyl ether and aqueous sodium hydroxide. The ether layer was washed with water and brine and dried over sodium sulfate. The solvent was removed in vacuo to obtain a pale yellow solid, melting point 97-99 ° C [a] 25599 = + 8 ° (c = 1.00 Me OH). The hydrochloride salt was crystallized from methanol and diethyl ether to give a pale yellow solid. { 2.19 g, 80%), melting point 283-285 ° C.
Procedure 12 (S) - (+) - 5-Hydroxymethyl-2-N, N-dipropylaminoindan. 13 The tert-butyl lithium (8.9 mL of 1.7 M solution in pentane 15.18 mmol) was added to (S) - (+) - 5-bromo-2-N, N-dipropylaminate (2.25 g, 7.59 mmol) in tetrahydrofuran (12 mL) at -78 ° C. After 5 minutes, the reaction was added to parafor aldehyde (0.27 g, 8.36 mmol) and tetrahydrofuran (12 mL) at -78 ° C. After 60 minutes, water was added and the mixture was extracted with diethyl ether and water. The ether layer was washed with water and brine and dried over sodium sulfate. The solvent was removed in vacuo to obtain a dark brown solid which was subjected to flash chromatography on a 27 x 2 cm silica gel column, eluting with dichloromethane / ethyl acetate / hexane (1: 4: 5) and (1) : 6: 3) to obtain 13 as an amber solid (1.12 g, 60%) melting point 52-54 ° C.
Procedure 13 (S) - (+) - 5-Aminomethyl-2-N, N-di-l-propylaminoindan. 14 Amide 13 (1.8 g, 6.9 mmol) was dissolved in THF
(20 ml) and borane-methylsulfide (2.7 ml of a 10M solution) was added. This solution was heated to reflux for 1
P447 hour and then cooled. Careful addition (20 mL) of 2N aqueous hydrochloric acid was added and the solution was stirred for 2 h. After neutralization with 2N sodium hydroxide the solution was extracted with ether. The ether layer was washed with water and brine and dried over eodium eulfate. Solvent removal provided the amine as an oil. '
Method 14 (S) - (+) - 5-Methylsulfoxymethyl-2-N, N-dipropylaminoindan. 15 Methanesulfonyl chloride (0.37 mL, 4.67 mmol), 13 (1.05 g, 4.24 mmol) triethylamine (0.71 mL, 5.09 mmol) and dichloromethane (10 mL) were stirred at 0 ° C. After 2 hours, the mixture was extracted with diethyl ether and aqueous sodium bicarbonate. The ether layer was washed with brine and dried over sodium sulfate. The solvent was removed under vacuum to obtain an amber oil (1.2 g, 87% crude).
Process 15 (S) - (+) - 5-phenylsulfonylmethyl-2-N, N-dipropylaminoindan. 16 Benzenesulfinic acid, sodium salt (0.54 g, 3.23 mmol) 15, (0.35 g, 1.08 mmol) and dimethylformamide (5 mL) were stirred at 50 ° C. After 24 hours, the mixture was extracted with diethyl ether and aqueous sodium bicarbonate. The ether layer was washed with water and brine and dried over sodium sulfate.
P447 sodium. The solvent was removed under vacuum to obtain a dark oil which was subjected to chromatography on a 22 x 1 cm silica gel column, eluting with dichloromethane / ethyl acetate / hexane (1: 6: 13). Sulfone 16 was obtained as a pale oil (0.12 g, 30%).
Process 16 (S) - (+) - 5-carboxamidomethyl-2-N, N-dipropylaminoindan. Sodium cyanide (0.51 g, 9.83 mmol), compound 15 (0.80 g, 2.46 mmol) and dimethylformamide (5 L) were stirred at 50 ° C. After 24 hours, the mixture was extracted with diethyl ether, dichloromethane and acidic sodium bicarbonate. The ether layer was washed with water and brine and dried over sodium sulfate. The solvent was removed in vacuo to obtain a dark oil which was subjected to flash chromatography on a 21 x 2 cm silica gel column, eluting with dichloromethane / ethyl acetate / hexane (1: 3: 16), (1: 6:15) and after (1: 10: 9). The solvent was removed in vacuo to give the cyanomethyl adduct as a dark oil (0.35g, 55%). This oil was combined with 15% aqueous sodium hydroxide (2.1 mL), tetrahydrofuran (12 mL) and 30% hydrogen peroxide (13.7 mL). After 54 hours the diethyl ether and water were added and the product was extracted. The ether layer was washed with water and brine and dried over sodium sulfate.
P447 The solvent was removed in vacuo to obtain a white wax (0.19 g, 59%).
Process 17 (R) - (-) - 5-chloromethyl-2-N, N-dipropylaminoindan. 18 Thionyl chloride (2.3 mL) was added slowly to (R) - (-) - 5-hydroxymethyl-2-N, N-dirpopilaminoindane (7.5 g in 60 mL dry THF) in an ice bath. After 60 minutes at room temperature ethanol (5 mL) was added and heated to reflux. The solvent was removed under vacuum and aqueous sodium hydroxide was added to the residue. It was extracted with ether. The ether layer was washed with water and brine and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was washed with flash chromatography. The elution was done with ethyl acetate / dichloromethane / hexane to give an oil.
Method 18 (R) - (-) - (4-bromobenzene) iomethyl-2-N, N-dipropylaminoindan. 19 (R) - (-) -5-chloromethyl-2-N, N-dipropylaminoindane
(3.0 g), 4-bromothiophenol (2.4 g), sodium hydroxide (28 mL of 2N aqueous solution), tetrahydrofuran (28 mL) and a catalytic amount of tetrabutyl ammonium chloride were heated at 50 ° C for 60 minutes. Water was added and the mixture was extracted with ether. The ether layer was washed with
P447 water and 2N hydrochloric acid. The acid layer was basified with aqueous sodium hydroxide and extracted with ether / dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was subjected to flash chromatography, the eluent was ethyl acetate / dichloromethane / hexane to give a solid, mp 80-82 ° C. The hydrochloride salt was recrystallized from methanol / ether to give a solid of melting point 142-144 ° C.
Process 19 (R) - (-) - 5 - (4-bromobenzene) sulfonylmethyl-2-N, N-dipropylaminoindan. 20 Peracetic acid (1.7 mL, 32% acetic acid / water) was added to (R) - (-) - 5 - (4-bromobenzene) thiomethyl-2-N, N-dipropylmayinindane (1.5 g) in acetic acid glacial (7.5 L) in a cold water bath. After 4 hours, methyl sulfide (1 mL) was added; after another 30 minutes, ammonium hydroxide (3M) was added and the mixture was extracted with ether. The ether layer was washed with water and brine and then dried over sodium sulfate. The solvent was removed in vacuo to give a solid of melting point 132-134 ° C. The maleate salt, recrystallized from methanol / ether, gave a solid of
P447 melting point 130-131 ° C.
Process 20 (R) - (-) - 5 - (4-carboxamidobenzene) sulfonylmethyl-2-N, N-dipropylaminoindan. 21 The (R) - (-) -5- (4-bromobenzene) sulfonylmethyl-2-N, N-dipropylaminoindane (0.94 g), palladium acetate (0.05 g), 1,3-bis (diphenylphosphino) propane (0.21 g) g), diisopropylethylamine (0.75 mL), dimethylformamide (5 mL) and formamide (0.42 mL) were heated to 120 ° C under carbon monoxide. After seven hours, it was cooled to room temperature and sodium hydroxide (5 mL, 2N) was added. The water was added and the mixture was extracted with ether / tetrahydrofuran. The layer of. ether was washed with water and brine and then dried over sodium sulfate. The solvent was removed in vacuo and the residue subjected to flash chromatography; the elution was done with methanol / dichloromethane to give a solid, melting point 164-165 ° C. The fumarate salt, recrystallized from methanol / ether gave a solid of melting point 159-163 ° C.
Process 21 (R) - (-) - 5 - (4-cyanobenzene) sulfonylmethyl-2-N, N-dipropylaminoindan. 22 Titanium tetrachloride (0.15 mL in
P447 carbon tetrachloride, 3 mL) was added to (R) - (-) - 5 - (4-carboxamidobenzene) sulfonylmethyl-2-N, N-dipropylaminoindane (0.23 g), triethylamine (0.46 L) and tetrahydrofuran (5 mL ) in an ice bath. After 16.5 hours, aqueous sodium carbonate was added and the mixture was extracted with ether. It was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue subjected to flash chromatography; the elution was done with ethyl acetate / dichloroethane / hexane to give a solid. A recrystallized analytical sample of ethyl acetate / hexane gave a solid of melting point 90-91 ° C. The hydrochloride salt, recrystallized from methanol / ether, gave a solid of melting point 175 ° C (decomposition).
Process 22 (R) - (-) - 5-amino-2-N, N-dipropylaminoindan. 23 t-butyl lithium (9.9 mL, 1.7 M in pentane) was added to (R) - (-) - 5-bromo-2-N, N-dipropylaminoindane (11) (2.5 g) in tetrahydrofuran (15 mL) at -78 ° C. After 5 minutes, diphenylphosphoryl azide (2.0 mL) was added and the light was excluded from the reaction vessel. The cold bath was removed and after 45 minutes it was reapplied. The lithium aluminum hydride (42 mL, 1.0 N in tetrahydrofuran) was added and the reaction was allowed to warm to room temperature. Acid was added
P447 aqueous hydrochloric acid and the mixture was extracted with ether / tetrahydrofuran. The acid layer was basified with 15% sodium hydroxide and extracted with ether / tetrahydrofuran. The organic layer was washed with brine, filtered through diatomaceous earth and dried over sodium sulfate. The solvent was removed in vacuo and the residue was subjected to flash chromatography, the elution was carried out with methanol / dichloromethane to give an oil.
Process 23 (R) - (-) - 5-Benzenesulfonamido-2-N, N-dipropylaminoindan. 24 Benzenesulfonyl chloride (0.45 mL) was added to (R) - (-) - 5-amino-2-N, N-dipropylaminoindane (0.4 g), triethylamine (0.48 L) and dichloromethane (5 mL). After 19 hours, ammonium hydroxide (3M aqueous) was added and the mixture was extracted with ether. The ether layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was subjected to flash chromatography, elution was done with ethyl acetate / dichloromethane / hexane to give 0.51 g of the diphenylsulfonamido adduct. Potassium hydroxide (0.19 g) in methanol (5 L) and water (0.5 mL) were added. After 17 hours, the solvent was removed in vacuo and hydrochloric acid (2N) was added and then basified with
P447 sodium bircabonate accuse. The mixture was extracted with ether / dichloromethane and washed with brine. Then it was dried over sodium sulfate. The solvents were removed in vacuo to give an oil. The hydrochloride salt was recrystallized from methanol / ether, as a solid of melting point 214-215 ° C. (R) - (-) -5- (4-Chlorobenzene) sulfonamido-2-N, N-dipropylaminoindane. Substitution of 4-chlorobenzenesulfonyl chloride by benzenesulfonyl chloride (R) - (-) - 5-amino-2-N, N-dipropylmainoindane was treated according to procedure 23 to provide the title compound as an oil. The maleic acid salt recrystallized from methanol / ether gave a solid of melting point 167-169 ° C.
Process 24 (R) - (-) - 5-Ethanesulfonamidomethyl-2-N, N-dipropylaminoindan. 26 Ethane sulfonyl chloride (0.2 mL) was added to (R) - (-) - 5-aminomethyl-2-N, N-dipropylaminoindane (14) (0.5 g), pyridine (0.3 L) and tetrahydrofuran (5 L) ). After 2.5 hours, ammonium hydroxide was added and the mixture was extracted with ether. The ether layer was washed with water and brine and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was subjected to
P447, rapid chromatography. Elution with ethyl acetate / dichloromethane / hexane yielded an oil. The fumarate salt recrystallized from methanol / ether gave a solid, melting point 129-130 ° C. (R) - (-) - 5-benzenesulfonamidomethyl-2-N, N-dipropylaminoindan. 27 Substitution of the benzenesulfonyl chloride by ethanesulfonyl chloride, the (R) - (-) - 5-aminomethyl-2-N, N-dipropylaminoindane was treated according to procedure 24 to provide the title compound as an oil. The recrystallized maleate salt of methanol / ether gave a solid with melting point 144-145 ° C. (R) - (-) - 5 - (4-chlorobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindan. 28 Substitution of 4-benzenesulfonyl chloride by ethanesulfonyl chloride, (R) - (-) - 5-aminomethyl-2-N, N-dipropylanyninone was treated according to procedure 24 to afford the title compound as a solid of melting point 84-87 ° C. (R) - (-) - 5 - (3,4-dichlorobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindan. 29 Substitution of 3,4-dichlorobenzenesulfonyl chloride by ethanesulfonyl chloride, (R) - (-) - 5-aminomethyl-2-N, N-dipropylaminoindane was treated according to procedure 24 to provide the compound
P447 of the title as a solid. Recrystallization from toluene / hexane gave the solid of melting point 87-90 ° C. (R) - (-) - 5 - (4-iodobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindan. Substitution of the 4-iodobenzenesulfonyl chloride by ethanesulfonyl chloride, the (R) - (-) - 5-aminomethyl-2-N, N-dipropylaminoindane was treated according to procedure 24 to provide the title compound as a solid. Recrystallization from ether / hexane provided a solid of melting point 77-78 ° C. (R) - (-) - 5 - (4-acetamidobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindan. Substitution of the 4-acetamidobenzenesulfonyl chloride by ethanesulfonyl chloride, the (R) - (-) - 5-aminomethyl-2-N, N-diprop laminoindane was treated according to procedure 24 to afford the title compound as a solid . The hydrochloride salt, recrystallized from propanol, gave a solid of melting point 217-218 ° C. (R) - (-) - 5 - (4-Acetamido-3-chlorobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindan. 32 Substitution of 4-acetamido-3-chlorobenzenesulfonyl chloride by ethanesulfonyl chloride, (R) - (-) - 5-aminomethyl-2-N, N-diisopropylaminoindane was
P447 according to procedure 24 to provide the title compound as a solid, melting point 58-60 ° C. (R) - (-) - 5 - (4-trifluoromethylbenzene) sulfonamidomethyl-2-N, N-dipropylaminoindan. 33 Substitution of 4-trifluorobenzenesulfonyl chloride by ethanesulfonyl chloride, (R) - (-) - 5-aminomethyl-2-N, N-diisoprpilaminoindane was treated according to procedure 24 to provide the title compound as a solid, melting point 66-70 ° C. (R) - (-) - 5 - (4-nitrobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindan. The substitution of 4-nitrobenzenesulfonyl chloride with ethanesulfonyl chloride, (R) - (-) - 5-aminomethyl-2-N, N-dipropylmayinindane was treated according to procedure 24 to give the title compound as a melting point 94-97 ° C. The hydrochloride salt was triturated with ether and gave a solid. (R) - (-) - 5 - (4-cyanobenzene) sulfonamidomethyl-2-N, N-dipropylaminoindan. The substitution of 4-cyanobenzenesulfonyl chloride with ethanesulfonyl chloride, the (R) - (-) - 5-aminomethyl-2-N, N-dipropylaminoindane was treated according to procedure 24 to afford the title compound as a solid , melting point 104-106 ° C. The
P447 fumarate salt, recrystallized from methanol / ether gave a solid of melting point 174-177 ° C. (R) - (-) - 5 - (3-cyanobenzene) sulfonamidomethyl-2-N, N-dipropyl-aminoindane. Substitution of 3-cyanobenzenesulfonyl chloride by ethylsulfonyl chloride, the (R) - (-) - 5-aminomethyl-2-N, N-dipropylaminoindan was treated according to procedure 24 to provide the title compound as an oil. The hydrochloride salt, triturated with ether, provided a solid of melting point 110 ° C. (decomposition). (R) - (-) - 5 - (2-cyanobenzene) sulfonamidomethyl-2-N, N-dipropyl-aminoindane. 37 Substitution of 2-cyanobenzenesulfonyl chloride by ethanesulfonyl chloride, (R) - (-) - 5-aminomethyl-2-N, N-dipropylaminoindane was treated according to procedure 24 to provide the title compound as a solid. The hydrochloride salt, recrystallized from methanol / ether, gave a solid of melting point 185 ° C (decomposition). (R) - (-) - 5-f2- (5-trifluoro) pyridine sulfonamidomethyl-2-N, N-dipropyl-aminoindane. 38 Substitution of 2- (5-trifluoro) pyridinesulfonyl chloride by ethanesulfonyl chloride, (R) - (-) - 5-aminomethyl-2-N, N-dipropylaminoindane was treated
P447 according to procedure 24 to provide the title compound as a solid, melting point 125-127 ° C. The hydrochloride salt, recrystallized from methanol / ether gave a solid of melting point 207-209 ° C. (R) - (-) - 5-f3- (2,5-dichloro) iofeni1] sulfonamidomethyl-2-N, -dipropyl-aminoindan. Substitution of 2, 5-dichlorothiophen-3-sulfonyl chloride by ethanesulfonyl chloride, the (R) - (-) - 5-aminomethyl-2-N, N-dipropylaminoinano was treated according to procedure 24 to provide the title as a clear oil. Crystallization from ether / hexane provided a solid, melting point 79-80 ° C. The hydrochloride salt, recrystallized from methanol / ether gave a solid, melting point 106 ° C (decomposition).
Procedure: dimethyl 2, 2-di (2-propynyl) malonate. 40 Aqueous sodium hydroxide (1500 ml of a 12 N solution) was placed in a flask fitted with a stirrer on top. The benzyltriethylammonium chloride (54 g) was added and the solution was cooled to 0 ° C. With vigorous stirring, a solution of dimethylolonate (79.3 g) and
P447 propargyl (3 equivalents, 214 g) with an addition funnel over 25 minutes, keeping the temperature below 25 ° C (R.K. Singh, Synthesis 1985, 54) the suspension was allowed to stir for 3 hours at 25 ° C. The suspension was cooled in an ice bath and then carefully added to an ice / water mixture. This was extracted with t-butylmethylether, washing the organic layer with water (2X) and then with brine. It was dried over sodium sulfate and the solvent was removed to give the title compound as a crystalline solid (92% yield).
Method 26 2- (2-propynyl) -4-pentynoate methyl. 41 Dimethyl 2,2-di (2-propynyl) malonate (71 g) was treated with a Krapcho decarboxylation by heating at 170 ° C with sodium chloride (25 g) and water (23 ml) in di-ethyl sulfoxide ( 341 mi). After 15 hours, the solution was cooled and diluted with water and t-butylmethyl ether and extracted. The organic layer was washed with water (4X), brine and then dried over sodium sulfate. Removal of solvent gave a liquid that was distilled, the title compound was collected at 109 ° C (28 mm Hg).
P447 Procedure 27 2- (2-propynyl) -4-pentynoic acid. Methyl 2- (2-propynyl) -4-pentynoate (27.5 g) was saponified with sodium hydroxide (22 g) in refluxing water (250 ml). The solution was cooled and acidified with 12 N HCl to pH 3 and then extracted with t-butyl methyl ether. The organic layer was washed with brine and dried over sodium sulfate. Solvent removal gave the title compound.
Procedure 28 4- (t-Butyloxycarbonamylamino) hepta-1,6-diin. 43 To a solution of 2- (2-propynyl) -4-pentynoic acid 42 (25.0 g, 184 mol) in toluene (200 ml) was added triethylamine (19.5 g, 0.193 mol) with cooling. Diphenylphosphyrid azide (50.5 g, 0.193 mol) was added and the mixture was stirred at room temperature for 15 minutes. The mixture was heated in the steam bath until the reaction became exothermic. When the reaction was over, heating continued for 10 more minutes, during which time the gas evolution ceased. Dry t-butanol (150 ml) was added and the mixture was heated to reflux on a steam bath for 24 hours. The solvent was removed in vacuo and the residue was diluted with water and extracted twice with diethyl ether. The combined aqueous extracts were washed with
P447 water (2X), 10% sodium carbonate solution and brine. The solution was dried (MgSO4) and the solvent was removed in vacuo to leave a reddish-brown crude solid (35.35 g). A sample (3.2 g) was purified by flash chromatography (230-400 mesh silica gel, 10% ethyl acetate in hexane) to give a colorless solid (2.69 g). Crystallization from hexane gave the title compound (43) as colorless crystals (melting point 64-67 ° C).
Process 29 4-amino-epta-l, 6-diino. 44 The 4- (t-butyloxycarbonylamino) hepta-1,6-diino 43 (30.28 g, 0.146 mol) was cooled in ice and trifluoroacetic acid (90 ml) was added with stirring. The mixture was stirred for 20 minutes and the excess trifluoroacetic acid was removed in vacuo. The mixture was partitioned between water and diethyl ether and the ether solution was extracted twice with 5% hydrochloric acid solution. The combined aqueous extracts were washed with diethyl ether, cooled with ice and basified with solid sodium hydroxide. The mixture was saturated with sodium chloride and extracted three times with diethyl ether. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed in vacuo to give the title compound (44) as a
P447 amber oil (13.2 g, 84%). One sample (0.526 g) was combined with fumaric acid (0.570 g) and the mixture was recrystallized from methanol / diethylether to give a fumaric acid salt of 44 as light yellow crystals (0.694 g, melting point 178-179 ° C).
Procedure 30 4- (Trifluoroacetylamino) epta-1,6-diino. 45 A solution of 4-aminohepta-l, 6-diino 44 (14.63g, 0.137 mol) and triethylamine (20.8 g, 0.206 mol) in dry tetrahydrofuran (100 ml) was cooled in ice and trifluoroacetic anhydride (37.5 g, 0.178 mol ) which was added with a syringe pump within 30 minutes, the mixture was stirred at 0 ° C for 1 hour and allowed to stand at -15 ° C overnight. The mixture was cooled on ice and water (100 ml) was added dropwise. The mixture was extracted twice with diethyl ether. The combined organic extracts were washed with 10% hydrochloric acid, saturated sodium bicarbonate solution (2X) and brine. The solution was dried (MgSO) and the solvent removed in vacuo to leave a solid (29.6 g). Crystallization from hexane containing little ethyl acetate gave compound 45 in the form of slightly yellow crystals (21.5g, mp 55-57 ° C).
P447 Procedure 31 2- (Trifluoroacetylamino) -5,6-bis (acetoxymethyl) indane. 47 A solution of 2-butyne-1,4-diacetate 46 (34-03 g, 0.200 mol) and tris (triphenylphosphine) rhodium chloride (2.78 g, 3.00 mmol, 3 mol%) in ethanol gassed with argon (100 ml) ) was heated to 80 ° C and a solution of 4-trifluoroacetylamino) hepta-1,6-diino (20.32 g, 0.100 mol) in ethanol gassed with argon (70 ml) was added via a syringe pump in a period of 2.5 hours . The mixture was stirred at 75-80 ° C for 8 hours and at room temperature for 10 hours. The solvent was removed in vacuo to leave a dark oil. Purification by flash chromatography (silica gel 230-400 mesh, 25-30% ethyl acetate / hexane) gave an amber solid (24.5 g). Crystallization from ethyl acetate / hexane gave the title compound (47) as tan crystals (22.0 g, 59%, mp 98-100 ° C).
Method 32 and 33 2- (N, N-dipropylamino) -5,6-bis (hydroxymethyl) indan. 49 A solution of potassium hydroxide (10.10 g,
0. 180 mol) in water (35 ml) was added to a solution of 2- (trifluoroacetylamino) -5,6-bis (acetoxymethyl) indane 47 (20.1 g, 53.8 mmol) in methanol (200 ml) at room temperature and the mixture it was heated to reflux for 2.5 hours. The solvent was removed under vacuum to leave 2-amino-5,6-bis (hydroxymethylindane) (48) as a semi-solid. The crude product was mixed with 1-bromopropane (27.1 g, 0.220 mol) and potassium carbonate (22.32 g, 0.162 mol) in acetonitrile (100 ml) and the mixture was mechanically stirred under reflux on a steam bath for 17 hours . 1-Bromopropane (6.8 g, 0.055 mol) was added and the reflux continued for 4 hours. The mixture was diluted with water and extracted twice with ethyl acetate. The extracts were washed with brine and dried (MgSO). The solvent was removed under vacuum to leave a brown oil (15.75 g). Purification by flash chromatography (230-400 mesh silica gel, 30% ethyl acetate in tetrahydrofuran in ethyl acetate) gave the title compound (49) as a solid (12.1 g, 81%). A sample (0.50 g) was crystallized from ethyl acetate / hexane to give white crystals (0.48 g).
Procedure 34 2- (N, N-dipropylamino) -5,6-bis (chloromethyl) indan. 50 2- (N, N-dipropylamino) -5,6-bis (hydroxymethyl) indane
49 (2.78 g, 10.0 mmol) was cooled in ice and thionyl chloride (8.0 ml) was slowly added. The mixture was heated to reflux in a steam bath for 1.25 hours. The excess thionyl chloride was removed in vacuo. The residue was dissolved in chloroform and the solvent removed in vacuo. This was repeated providing an amber solid. The compound was stirred with a mixture of 10% sodium carbonate solution and tetrahydrofuran until the solid had dissolved. The mixture was extracted twice with diethyl ether and the combined extracts were washed with brine and dried (MgSO4). The solvent was removed in vacuo to give the title compound (50) as an oil (3.46 g).
Method 35 and 36 2- (N, N-dipropylamino) -5,6-bis (aminomethyl) indane. 52 Sodium azide (3.30 g, 50.8 mmol) was added to a solution of 2- (N, N-dipropylamino) -5,6-bis (chloromethyl) indane 50 (2.85 g, 9.07 mmol) in dimethylformamide (35 ml) at room temperature, and the mixture it was stirred at 80 ° C throughout the night. The mixture was diluted with water and extracted three times with methyl-t-butyl ether. The combined extracts were washed twice with water and once with brine. The solution was dried (MgSO4) and filtered. The solution containing 2- (N, N-dipropylamino) -5,6-bis (azidomethyl) indane 51 was cooled on ice and lithium aluminum hydride (1.0 M in tetrahydrofuran, 13 ml, 13 mmol) was added slowly and The resulting reaction was stirred at room temperature for 2 hours. Water (0.5 ml), 15% sodium hydroxide (0.5 ml) and water (1.5 ml) were added in succession. The mixture was stirred for 30 minutes and filtered. The aluminum eal was washed with tetrahydrofuran and the combined filtrate was evaporated giving an amber oil (2.27 g). The compound was dissolved in methanol (100 mL) and metallic magnesium (2.5 g) was added. The mixture was heated in a steam bath until the reaction became exothermic. The magnesium was exhausted, the solvent was removed in vacuo, to provide a solid. The mixture was suspended in water and extracted several times with 1: 1 tetrahydrofuran / diethylether emulsion. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed in vacuo to obtain the title compound (52) as a brown oil (0.92 g).
Method 37 2- (N, N-dipropylamino) -5,6-bis (4-chlorophenylsulphonylaminomethyl) indane. 53 A solution of 2- (N, N-dipropylamino) -5,6-bis (aminomethyl) indane 52 (0.276 g, 1.00 mmol) in pyridine (4.0 ml) was cooled in ice and 4-chlorobenzenesulfonyl chloride was added ( 0.53 g, 2.51 mmol). The mixture was stirred at 0 ° C for 40 minutes and at room temperature for 18 hours. Water was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with 10% sodium carbonate solution and extracted twice with diethyl ether and once with ethyl acetate. The combined extracts were washed with brine and dried (MgSO), the solvent removed in vacuo to obtain a reddish brown oil (0.34 g). Rapid purification was carried out by chromatography (230-400 mesh silica gel, 60% ethyl acetate / hexane) to give an orange solid. Crystallization from diethylether / hexane gave the title compound (53) as light orange crystals (0.090 g, melting point 140-141 ° C).
Procedure 38 2- (N, N-dipropylamino) -5,6-bis (4-cyanophenylsulfonylaminomethyl) indan. 54 A solution of 2- (N, N-dipropylamino) -5,6-bis (aminomethyl) indane 52 (0.276 g, 1.00 mmol) in pyridine (4.0 ml) was cooled in ice and 4-cyanobenzenesulfonyl chloride ( 0.61 g, 3.0 mmol), the mixture was stirred at room temperature for 4 hours. The mixture was diluted with 10% sodium carbonate solution and extracted three times with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to give a dark oil. Purification by flash chromatography (2300-400 mesh silica gel, 60-80% ethyl acetate / hexane) provided the title compound (54) as an oil. The compound was dissolved in ethyl acetate and an excess of ethereal hydrochloric acid was added. The mixture was diluted with diethyl ether and filtered. The precipitate was washed with diethyl ether and dried in vacuo to give hydrochloride salt 54 as toasted crystals (0.143 g).
Procedure 39 2- (N # N-dipropylamino) -5,6-bis (S-propylsulphonylaminomethyl) indane. 55 A solution of 2- (N, N-dipropylamino) -5,6-bi (aminomethyl) indane 52 (0.36 g, 1.3 mmol) in pyridine (5.0 ml) was cooled in ice and 1-propane-sulfonyl chloride ( 0.64 g, 4.5 mmol). The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 3 hours. Water (15 ml) was added and the mixture was stirred at room temperature for 15 minutes. The mixture was diluted with 10% sodium carbonate solution and extracted three times with diethyl ether. The combined extracts were washed with brine and dried (MgSO). The solvent was removed under vacuum to provide a brown oil (0.51 g). Purification by flash chromatography (silica gel 230-400 mesh, 80% ethyl acetate / hexane) gives a yellow oil in an amount of 0.131 g). Crystallization from diethyl ether / hexane afforded the title compound (55) as off-white crystals (0.092 g, mp 120-121 ° C).
Procedure 40 2- (N-dipropylamino) -5,6-bis (phenylsulfonylmethyl) indan. The title compound (56) was prepared from 2- (N, N-diproylamino) -5,6-bis (chloromethyl) indane and eodium benzenesulfinate in dimethylformamide at 100 ° C. The free base was converted to the fumaric acid salt with fumaric acid (melting point 160-168 ° C).
Scheme 1
pro .2
proc. TO
roc.5 proc ß B'X) COOMß
Pfoc. H.H
proc.10 10
7 Scheme 2 Proc X Compound # 11 CONH2 12 12 CH20H 13
47 Scheme 3
x.
P447 Scheme 4
i, NO? Prc .23 XX. ? x > 23 X Compound # H 24 s 25
Compound # CH.CH- 26 Ph 27 4-CI P 28 3-CI.4-CI Ph 29 4-IPh 30 4-AcNHPh 31 $ -0, AcNHPh 32 4-CPjPh 33 4-N02Ph 34 4-NCPh 35 3 -NCPh 36 2- CPh 37 2- (5-CF,) pyrldll 38 3- (2-CI, 5-a) thioicnoi 39
Scheme 5
Procedure 26
me »n (or 2 ß 41«
| 9 / "• Procedure 29 /" "Procedure) mlento30 >" "
-TO 1-H _ H'N ~ C - - F'C L «? _ I
43 44 < S
SJ.fr ?? w.pt.37, R. -fi -a
R. Propit
-. Procßdlmlenlo 0 - \ ^^ N - ^ - S0JPh / j G Kft M
P447
Claims (10)
- CLAIMS; 1. Use of a compound for the manufacture of a medicament that is used in the treatment of disorders of the central nervous system, associated with the activity of the dopamine D3 receptor, wherein the compound is of the Formula I or a pharmaceutically acceptable salt of the same wherein R ^ and R2 are independently H, C ^ -g alkyl or C? _? alkylaryl; X is CH2R3 or NHS02R; Y is hydrogen, CH2 3, NHSO2R4, CONR] ^, S02NR! R2, S02CH3, halogen, OS02CF3, SCH3 or OCH3; R3 is NHSO2R4, SO2R4, C0NR! R2 or aryl; and R is NR2R2, Cx-Cg alkyl, aryl or alkylaryl C ^ -Cg.
- 2. The use of claim 1, wherein Y is CONR2R2, SC ^ NR ^ Ó S02CH3.
- 3. The use of claims 1 or 2, wherein Ri and R are independently H or C ^ g alkyl.
- 4. The use of any one of the preceding claims, wherein R4 is alkyl C? _g. P447
- 5. A compound as defined in any of the preceding claims, provided that when Rj and Y are each H and R is CH3, X is not NHS0 (C? -C4 alkyl).
- 6. A compound as defined in any of claims 1 to 4 wherein X is CH2R3.
- 7. A compound according to claim 6, wherein R3 is CONR1R2 and Ri and R2 are independently H alkyl C ^ g.
- 8. The use of any of the claims 1 to 4 wherein the compound is as defined in any of claims 5 to 7. The use according to any of claims 1 to 4 and 8 wherein the disorder is schizophrenia, mania, depression, a geriatric disorder, abuse of drugs and addiction, Parkinson's disease, sleeping disorders, circadian rhythm disorders and anxiety or dementia disorders. The use according to any of claims 1 to 4, 8 and 9 wherein the compound is administered in an amount that is between 0.25 mg and 100 mg / person. P447
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US38223995A | 1995-02-01 | 1995-02-01 | |
US382,239 | 1995-02-01 | ||
PCT/US1996/000020 WO1996023760A1 (en) | 1995-02-01 | 1996-01-16 | 2-aminoindans as selective dopamine d3 ligands |
US382239 | 2006-05-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
MX9705883A MX9705883A (en) | 1997-10-31 |
MXPA97005883A true MXPA97005883A (en) | 1998-07-03 |
Family
ID=
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