MXPA98001179A - Isoquinolinas fused, novedosas as ligandos del receptor de dopam - Google Patents
Isoquinolinas fused, novedosas as ligandos del receptor de dopamInfo
- Publication number
- MXPA98001179A MXPA98001179A MXPA/A/1998/001179A MX9801179A MXPA98001179A MX PA98001179 A MXPA98001179 A MX PA98001179A MX 9801179 A MX9801179 A MX 9801179A MX PA98001179 A MXPA98001179 A MX PA98001179A
- Authority
- MX
- Mexico
- Prior art keywords
- hydrogen
- group
- compound
- alkyl
- carbon atoms
- Prior art date
Links
- ACGDKVXYNVEAGU-UHFFFAOYSA-N Guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 92
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229960003638 dopamine Drugs 0.000 claims abstract description 16
- 210000003169 Central Nervous System Anatomy 0.000 claims abstract description 12
- 230000004064 dysfunction Effects 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 20
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 19
- 239000011780 sodium chloride Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000001475 halogen functional group Chemical group 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 5
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 5
- 210000001428 Peripheral Nervous System Anatomy 0.000 claims description 4
- 230000003542 behavioural Effects 0.000 claims description 2
- 230000000926 neurological Effects 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 12
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 230000027455 binding Effects 0.000 abstract description 24
- 108050004812 Dopamine receptor family Proteins 0.000 abstract description 16
- 102000015554 Dopamine receptor family Human genes 0.000 abstract description 16
- 239000003446 ligand Substances 0.000 abstract description 7
- BGOQGUHWXBGXJW-RHSMWYFYSA-N (6aR,12bS)-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound N1CC2=CC=CC=C2[C@H]2[C@H]1CCC1=C2C=C(O)C(O)=C1 BGOQGUHWXBGXJW-RHSMWYFYSA-N 0.000 description 36
- ZQTSNGJHMUKLOM-ZDUSSCGKSA-N Dinapsoline Chemical compound C1NCC2=CC=CC3=C2[C@@H]1C1=CC=C(O)C(O)=C1C3 ZQTSNGJHMUKLOM-ZDUSSCGKSA-N 0.000 description 34
- 102000005962 receptors Human genes 0.000 description 32
- 108020003175 receptors Proteins 0.000 description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 27
- 229910052757 nitrogen Inorganic materials 0.000 description 26
- -1 but not limited to Chemical group 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 241000700159 Rattus Species 0.000 description 21
- 239000000556 agonist Substances 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- 108060006634 CAMP Proteins 0.000 description 19
- AWJUIBRHMBBTKR-UHFFFAOYSA-N Isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000010992 reflux Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
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- 239000007787 solid Substances 0.000 description 9
- 210000001519 tissues Anatomy 0.000 description 9
- SZNJHPIVJBDAIH-UHFFFAOYSA-N 2-methyl-1,3-dihydroisoquinolin-4-one Chemical compound C1=CC=C2CN(C)CC(=O)C2=C1 SZNJHPIVJBDAIH-UHFFFAOYSA-N 0.000 description 8
- GOTMKOSCLKVOGG-UHFFFAOYSA-N SCH 23390 Chemical compound C1N(C)CCC2=CC(Cl)=C(O)C=C2C1C1=CC=CC=C1 GOTMKOSCLKVOGG-UHFFFAOYSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 238000004166 bioassay Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- BTKSUULMJNNXHG-UHFFFAOYSA-N ethyl 2-(methylamino)acetate Chemical compound CCOC(=O)CNC BTKSUULMJNNXHG-UHFFFAOYSA-N 0.000 description 7
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N Boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 101700067048 CDC13 Proteins 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
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- 230000003042 antagnostic Effects 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 239000008188 pellet Substances 0.000 description 6
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- 230000000638 stimulation Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- GOTMKOSCLKVOGG-OAHLLOKOSA-N (5R)-8-chloro-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepin-7-ol Chemical compound C1([C@@H]2C3=CC(O)=C(Cl)C=C3CCN(C2)C)=CC=CC=C1 GOTMKOSCLKVOGG-OAHLLOKOSA-N 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 101700040453 DRD2 Proteins 0.000 description 5
- 108091007069 Dopamine D2-Like Receptors Proteins 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
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- 230000002194 synthesizing Effects 0.000 description 5
- UMOWOGFRHSFFOV-UHFFFAOYSA-N 1-phenyl-2,3,4,5-tetrahydro-1-benzazepine Chemical class C1CCCC2=CC=CC=C2N1C1=CC=CC=C1 UMOWOGFRHSFFOV-UHFFFAOYSA-N 0.000 description 4
- KOYGHYKOTYYVNG-UHFFFAOYSA-N 6',7'-dimethoxyspiro[2,3-dihydro-1H-isoquinoline-4,3'-2-benzofuran]-1'-one Chemical compound C1NCC2=CC=CC=C2C21OC(=O)C1=C(OC)C(OC)=CC=C21 KOYGHYKOTYYVNG-UHFFFAOYSA-N 0.000 description 4
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- ZPEIMTDSQAKGNT-UHFFFAOYSA-N Chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 4
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- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 3
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Abstract
The present invention relates to novel dopamine receptor ligands of formula I: pharmaceutical formulations of such compounds, and a method which uses such compounds to treat a patient suffering from dopamine-related dysfunction of the central nervous system or periphery.
Description
FUSIONED ISOQUINOLINES, NOVEDOSAS AS LIGANDOS OF THE DOPAMINE RECEIVER
Field of the Invention This invention is directed to novel ligands for dopamine receptors. More particularly, the present invention is directed to optionally substituted tetrahydro-lH-naf [1, 2, 3, -de] isoquinoline compounds and their use in pharmaceutical formulations for the treatment of dopamine-related dysfunction of the central nervous system and peripheral.
Background and Brief Description of the Invention Dopamine, a neurotransmitter in the central nervous system, has been implicated in numerous neurological disorders. For example, it has been hypothesized that over stimulation of dopamine receptor subtypes may be linked to schizophrenia. Additionally, it is generally recognized that dopaminergic, functional, whether excessive or insufficient activity in the central and / or peripheral nervous system may cause hypertension, narcolepsy, and other behavioral, neurological disorders,
REF: 26726 physiological and movement, including Parkinson's disease, a progressive, chronic disease characterized by an inability to control the voluntary motor system. Dopamine receptors have traditionally been classified into one of two families (Di and D2) based on pharmacological and functional evidence. The Di receptors preferentially recognize the phenyltetrahydrobenzazepines and lead to the stimulation of the enzyme adenylate cyclase, whereas the D2 receptors recognize the butyrophenones and benzamides and negatively (or not in all) coupled to the adenylate cyclase. It is now known that there are several subtypes of dopamine receptors and at least five gene codes for the subtypes of dopamine receptors: Di, D2, D3, D4 and D5. However, the traditional classification remains useful, with the class similar to Di comprising the receiver Dx (D1A) and the receiver D5 (DiB), while the class similar to D2 consists of the receivers D2, O3 and D4. Drugs for the central nervous system that exhibit affinity for dopamine receptors are generally classified not only by their receptor selectivity, but also by their agonist activity (receptor stimulation) or antagonist (receptor blockade). While the physiological activities associated with the interaction of dopamine with the various subtypes of the receptor are not completely understood, it is known that ligands that exhibit selectivity for a subtype of the particular receptor will produce more or less predictable neuropharmaceutical results. The availability of the selective dopamine receptor antagonist and the agonist compounds will make possible the design of experiments to increase the understanding of the multiple functional roles of the Di receptors and will lead to new treatments for the various disorders of the central and peripheral nervous system. Initially, studies of dopamine receptors focused on the D2 family, however, the critical role of the dopamine Di receptor in nervous system function has recently become apparent. The first work on the ligands of the Di receptor, selective focused primarily on molecules of an individual chemical class, the phenyltetrahydrobenzazepines, such as the antagonist SCH23390 (1):
Several of the phenyltetrahydrobenzazepines were found to be Di receptor agonists; however, agonists derived from this class [including for example SKF38393 (+) - 2] in general lacked intrinsic, complete efficacy. Even SKF 82958, appeared to be a complete agonist, has recently been shown to have no intrinsic, complete efficacy in preparations with reduced receptor reserve. The differentiation between full and partial efficacy agonists is important for the medical research community due to the difference in the effect that these compounds have on cases mediated by the central nervous system., complexes For example, dihydrexidine and the full agonist, A-77636, have exceptional antiparkinsonian effects in the monkey model treated with MPTP, whereas partial agonists are without significant activity. More recent data suggest that full and partial agonists also differ in their effects on the other neural, complex functions. Therefore, researchers have directed their efforts to design ligands that are complete agonists, which have intrinsic, complete efficacy. One such compound is dihydrexidine (3), a hexahydrobenzo [a] phenanthridine of the formula:
The structure of dihydrexidine (3) is unique from other Dx agonists because the accessory ring system is fixed or tied, which makes the molecule relatively rigid. Molecular design studies of dihydrexidine (3) have shown that the compound has a limited number of low energy coforrations, in all of which the aromatic rings are maintained in a relatively coplanar array. The recent elucidation of the configuration of the active enantiomer of dihydrexidine (3) was consistent with predictions of this model. Unlike other Dx agonists with high intrinsic activity, high affinity, similar to 3-substituted aminomethyl isochromans, dihydrexidine (3) provided a semi-rigid pattern to develop a model of dopamine ligand. The essential characteristics of this model include the presence of a portion of β-phenyldopamine transoid, a single pair of electrons equatorially oriented at the basic nitrogen atom, and near the coplanarity of the phenyl ring, slope with the catechol ring. The model based on dihydrexidine has a portion of β-phenyldopamine transoid, while dopaminergic phenyltetrahydrobenzazepines have a conformation of β-phenyldopamine cisisoid. The model based on dihydrexidine has served as the basis for the design of additional Di receptor agonists. The design and synthesis of Dx receptor agonists that have high intrinsic activity is important for the medical research community due to the potential use of complete agonists to treat cases mediated by the central nervous system, complexes and also the conditions under which Dopamine receptors, peripherals are involved. For example, the compositions of the present invention have potential use as agents for lowering blood pressure. One embodiment of the present invention is a novel class of dopamine receptor agonists of the general formula:
and pharmaceutically acceptable salts thereof, and pharmaceutical formulations of such compounds. The present compounds are useful for the treatment of patients having a dopamine related dysfunction of the central nervous system, and also the conditions in which the peripheral dopamine receptors are involved, as evidenced by a neurological, psychological, physiological disorder or behavior, apparent.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the steps of the chemical reaction of Scheme 1, which converts ethyl-o-toutoate to 2-methyl-2,3-dihydro-4 (1H) -isoquinolone. Reagents: a) NBS, benzoylperoxide, CC14, reflux; b) HCl of sarcosine ethyl ester, K2C03, acetone; c) i. NaOEt, EtOH, reflux, ii. HCl, reflux. Figure 2 illustrates the steps of the chemical reaction of scheme 2, which converts 2,3-dimethoxy-N, N'-diethylbenzamide to dinapsoline. Reagents: a) i. sec-butyllithium, TMEDA, Et20, -78 ° C, ii. Compound 7, iii. TsOH, Toluene, reflux; b) i. 1-chloroethylchloroformate, (CH2C1) 2, ii. CH3OH; c) TsCl, Et 3 N; d) H2 / Pd-C, HOAc; e) BH3-THF; f) H2S04 conc., -40 ° C to -5 ° C; g) Na-Hg, CH3OH, Na2HP04; h) BBr3, CH2C12. Figure 3 is a graphical representation of the affinity of dinapsoline (triangles), (+) - dihydrexidine (squares) and (+) - SCH23390 (solid circles) for Di striatal receptors. Rat striatal Dt receptors were labeled with [~ H] SCH23390 (1), and unlabeled dinapsolin, (+) - dihydrexidine or (+) - SCH23390 was added to determine the specific binding of each compound to the Di receptor. Figure 4 is a graphical representation of the capacity of dinapsoline (4), (+) - dihydrexidine [(+) - 3] and (+) - SKF 38393 [(+) - 2] to stimulate the accumulation of cAMP in striatal rat homogenates relative to dopamine. Figure 5 is a graphical representation of the capacity of dinapsoline (4), (+) - dihydrexidine [(+) - 3] and (+) - SKF 38393 [(+) - 2] to stimulate the accumulation of cAMP in C-6 glioma cells (expressing primate DiA receptors) relative to dopamine. Figure 6 is a graphical representation of the affinity of dinapsoline (triangles), (+) - dihydrexidine (frames) and (+) - SCH23390 (solid circles) by striatal D2 receptors. The rat striatal D receptors were labeled with [JH] SCH23390, and unlabeled dinapsolin, (+) - dihydrexidine or (+) - SCH23390 was added to determine the specific binding of each compound by the receptor
D2.
Detailed Description of the Invention A compound of the general formula is provided according to the present invention:
and pharmaceutically acceptable salts thereof wherein R and Rs are hydrogen or alkyl of 1 to 4 carbon atoms; R: is hydrogen, alkyl of 1 to 4 carbon atoms or a phenoxy protecting group; X is hydrogen, halo or a group of the formula -OR6 wherein R6 is hydrogen, alkyl of 1 to 4 carbon atoms or a protecting group of phenoxy, and R2, R3 and R4 are independently selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, halo, or a group -ORi wherein Ri is as defined above, and when X is a group of the formula 0R6, the groups R? _ and R6 can be taken together to form a group of the formula -CH2-. The term "C 1 -C 4 alkyl" as used herein refers to branched or straight chain alkyl groups comprising one to four carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and cyclopropylmethyl. The term "pharmaceutically acceptable salts" refers to those salts formed by using organic or inorganic acids, salts that are suitable for use in humans and lower animals without undesirable toxicity, irritation, allergic response and the like. Suitable acids for forming pharmaceutically acceptable salts of biologically active compounds having amine functionality are well known in the art. The salts can be prepared according to conventional methods in itself during the isolation and final purification of the present compounds, or separately by reacting the isolated compounds in the free base form with a suitable salt forming acid. . The term "phenoxy protecting group" as used herein refers to substituents on phenolic oxygen which prevent undesired reactions and degradations during synthesis and which can then be removed without effect on the other functional groups in the molecule. Such protecting groups and methods for their application and removal are well known in the art. These include ethers, such as cyclopropylmethyl ethers, cyclohexyl esters, allyl ethers and the like; alkoxyalkyl ethers such as methoxymethyl or methoxyethoxymethyl ethers and the like; alkylthioalkyl ethers such as methylthiomethyl ethers; tetrahydropyranyl ethers; arylalkyl ethers such as benzyl, o-nitrobenzyl, p-methoxybenzyl, 9-anthrylmethyl, 4-picolyl ethers and the like; trialkylsilyl ethers such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl ethers and the like; alkyl and aryl esters such as acetates, propionates, n-butyrates, isobutyrates, trimethylacetates, benzoates and the like; carbonates such as methyl, ethyl, 2, 2, 2-trichloroethyl, 2-trimethylsilylethyl, benzyl and the like; and carbamates such as methyl, isobutyl, phenyl, benzyl, dimethyl and the like. The term "C 1 -C 4 alkoxy" as used herein refers to branched or straight chain alkyl groups comprising one or four carbon atoms attached through an oxygen atom, which include but are not limit a, methoxy, ethoxy, propoxy and t-butoxy. In addition, according to other embodiments of this invention, the present compounds can be formulated into conventional drug dosage forms for use in methods for treating a patient suffering from dopamine-related dysfunction of the central or peripheral nervous system. The effective doses of the present compounds depend on many factors, including the indication being treated, the route of administration, and the total condition of the patient. For oral administration, for example, the effective doses of the present compounds are expected to range from about 0.1 to about 50 mg / kg, more typically about 0.5 to about 25 mg / kg. Parenteral, effective doses may vary from about 0.01 to about 5 mg / kg of body weight. In general, treatment regimens using compounds according to the present invention comprise the administration of about 1 mg to about 500 mg of the compounds of this invention per day in multiple doses or in a single dose. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions and syrups containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants such as wetting agents, emulsifiers and suspending agents, dulsifiers and flavoring agents. Injectable preparations of the compounds of the present invention can be formulated using the products recognized in the art by dispersing or dissolving an effective dose of the compound in a parenterally acceptable diluent such as water, or more preferably, sodium chloride solution, isotonic . Parenteral formulations can be sterilized using microfiltration techniques recognized in the art. The compounds of this invention can also be formulated as solid dosage forms for oral administration such as capsules, tablets, powders, pills and the like. Typically, the active compound is mixed with an inert diluent or carrier such as sugar or starch and other suitable excipients for the dosage form. In this way, the tablet formulations will include acceptable lubricants, binding substances and / or disintegrants. Optionally, powder compositions comprising an active compound of this invention and, for example, a starch or sugar carrier, can be filled into gelatin capsules for oral administration. Other dosage forms of the compounds of the present invention may be formulated using techniques recognized in the art in forms adapted for the specific mode of administration. A compound provided according to the present invention is (±) -8,9-dihydroxy-2,3,7,7-tetrahydro-1H-naphtho [1,2,3-de] isoquinoline later referred to as "dinapsoline". Dynapsoline is synthesized from 2-methyl-2,3-dihydro-4 (1H) -isoquinolone according to the procedure depicted in general in Figures 1 and 2. The bromination of the ethyl-o-toluene side chain (5a) with NBS in the presence of benzoyl peroxide yielded compound 5b. The alkylation of sarcosine ethyl ether with compound 5b gave compound 6, which after Dieckmann condensation and subsequent decarboxylation in acidic hydrolysis yielded compound 7. As shown in Scheme 2 (Figure 2), lithiation directed to 2, 3-dimethoxy-N, N '-diethylbenzamide ortho (8) with sec-butyllithium / TMEDA in ether at -78 ° C and the condensation of the lithiated species with compound 7 followed by reflux with p-acid. -toluenesulfonic gave the spirolactone. 9 in moderate performance. N-demethylation of 9 with 1-chloroethylchloroformate followed by methanolysis of the intermediate gave compound 10, which in the treatment with p-toluenesulfonyl chloride and triethylamine provided compound 11. The first attempts to synthesize compound 11 directly by condensation of 2-p-toluenesulfonyl-2,3-dihydro-4 (1H) -isoquinoline with compound 8 in THF or ether, followed by lactonization with acid provided only very small amounts (<; 5%) of compound 11. The enolization of 2-p-toluenesulfonyl-2,3-dihydro-4 (1H) -isoquinolone under the basic reaction conditions is an obvious explanation for the poor yield. Hydrogenolysis of compound 11 in glacial acetic acid in the presence of 10% palladium on carbon gave compound 12, which in the reduction with diborane gave intermediate compound 13. Cyclization of compound 13 with concentrated sulfuric acid at low temperature provided the compound 14. N-de-dilatation of compound 14 with Na / Hg in methanol buffered with disodium acid phosphate gave compound 15. Finally, compound 15 was treated with boron tribromide to effect the division or decomposition of the methyl ether which produced the dinapsoline (4) as its hydrobromide salt. We have compared the space filling representations of the low energy conformations for (+) -trans-10, 11-dihydroxy-5, 6, 6a, 7, 8, 12b-hexahydrobenzo [a] phenanthridine [(+) - dihydrexidine] and the llbR enantiomer of dinapsoline which is homochiral to (+) - dihydrexidine at its chiral center 12bS. Two main structural characteristics are easily evident. First, the steric volume provided by the bridge of ethane C (7) -C (8) in dihydrexidine (3) has been removed. Second, the angle of the pendant phenyl ring with respect to the plane of the catechol ring changes slightly. This is more evident, in frontal views, where the aromatic hydrogen H (l) in dihydresidine (3) is projected above the catechol ring. However, in dinapsoline this position is used to fix or tie the pendant phenyl ring through a methylene unit, to the catechol ring; this forces the pendant phenyl ring to rotate in a clockwise direction, relative to dihydrexidine (3), when viewed from above. The amino groups are in similar positions, the given degree of conformational flexibility of the heterocyclic rings. In addition, both molecules can present an N-H vector in an equatorial orientation, a characteristic of the pharmacophore that is believed to be important for Di receptor agonists. Consistent with these observations, the pharmacological properties of these two molecules are similar. Experiments have been conducted to determine the binding of dinapsoline to Di receptors. Dynapsoline was found to have almost identical affinity (Ka = 5.9 nM) as dihydrexine (3) for rat dia striatal receptors. In addition, competition experiments using the unlabeled SCH23390 (1) as a competitor demonstrated that dinapsoline competes with high affinity, which has a low competition curve (nH = 0.66) that suggests the properties of the agonist (see Figure). 3). The properties of the dinapsoline agonist in Di receptors were confirmed in vitro by measuring the ability of dinapsoline to increase the production of cAMP in rat striatum and C-6-mD?
(see experimental data presented later). In both cells of the striatum of rat and C-6-mD ?, dinapsoline has complete agonist activity with an EC50 of approximately 30 nM in synthesis of cAMP stimulation by means of Dx receptors. In this way, the pharmacological data confirm that the dinapsoline has high affinity for dopamine Di receptors labeled with [3 H] SCH23390 which is almost identical to those of (+) -trans-10, 11-dihydroxy-5, 6, 6a , 7, 8, 12b-hexahydrobenzo- [a] phenanthridine (dihydrexidine). In addition, (±) -8,9-dihydroxy-2, 3, 7, 1 lb-tetrahydro-lH-naphtho [1,2,3-de] -isoquinoline (dinapsoline) in both rat striatal membranes and in D receptors A primate, expressed, cloned, was a complete agonist relative to dompamine, similar to dihydrexidine (3) but distinct from partial agonist
(+) - SKF 38393 (see Figures 4 and 5: (+) - SKF 38393
= (+) -2; (±) -trans-10, 11-dihydroxy-5, 6, 6a, 7, 8, 12b-hexahydrobenzo [a] phenanthridine = (±) -3, and (±) -8,9-dihydroxy-2, 3 , 7, 11b-tetrahydro-lH-naphtho [1, 2, 3-de] isoquinoline = 4). Based on the fundamental model of the D pharmacoform, it is anticipated that both the affinity and the intrinsic activity of racemic dinapsoline (and substituted analogues thereof) reside in only one of its enantiomers - the absolute configuration llbR (and its homochiral analogues). Resolution of the racemate by using separation techniques, recognized in the art, is expected to produce a dinapsoline isomer with approximately twice the affinity for Di exhibited by the racemate, thus making its affinity for the Di receptor, similar to (+) -trans-10, 11-dihydroxy-5, 6, 6a, 7, 8, 12b-hexahydrobenzo [a] phenanthridine. As shown in Figure 3 and the table
1, dinapsoline has greater affinity for D2-like receptors than for dihydrexidine. When dihydrexidine was synthesized first, it was anticipated that it would be completely selective for D against D2-like receptors. However, dihydrexidine was determined to be only about ten times selective for Dx: D2. In addition, dihydrexidine, while having the expected dopamine agonist activity, also had an unusual property here called "functional selectivity". Specifically, in rats. { i n vi ve or vi n), dihydrexidine acts as an agonist at D2-like receptors located post-sinaptically, but as an antagonist at D2-like receptors, located pre-synaptically. Such is believed to be due to differences in the protein complex of the G-lignated-receptor located pos-synaptically against pre-synaptically, as determined by the specific G proteins present in the given cell milieu. It has been shown that these D2 properties of the dihydrexidine residue in the same enantiomer (i.e., 6aR, 12bS) which is a high affinity full agonist in the Di receptor. On this basis, it is expected that both the Di and D2 properties of dinapsoline also reside in the homochiral anantiomer. The optical isomers of dinapsoline, and appropriate analogs, are the significant tools for studying the phenomena of "functional selectivity". The antiparkinson effects of dihydrexidine in the MPTP model of Parkinson's disease have been previously reported, and it is anticipated that dinapsoline will show similar effects. Accordingly, dinapsoline and its derivatives have a clinical, potential utility in Parkinson's disease and in other conditions where disturbance of dopamine receptors may be therapeutic. In addition, it has been reported that the appropriate modification of dihydrexidine will produce analogues that can be targeted to the specific subpopulations of the dopamine receptor family. Similar strategies with dinapsoline should result in compounds with selectivity and / or functional profiles of the novel receptor subtype. With reference to the following experimental procedures, described, the melting points were determined with the Thomas-Hoover melting point apparatus and are uncorrected. The XH NMR spectra were recorded with a Varian VXR 500S NMR instrument (500 Mhz) and the chemical shifts were reported in d-values.
(ppm) relative to TMS. The IR spectra were recorded as pellets of KBr or as a liquid film with a Perkin Elmer spectrometer
1600 series FTRI. The chemical ionization mass spectra (CIMS) were recorded on a Finnigan 4000 quad mass spectrometer. The high resolution Cl spectra were recorded on a Kratos MS50 spectrometer. The elemental analysis data were obtained from the microanalytical laboratory of Purdue University, West Lafayette, IN. THF was distilled from benzophenone-sodium under nitrogen immediately before use; 1,2-dichloroethane was distilled from phosphorus pentoxide before use.
Example 1 Preparation of 2-methyl-2,3-dihydro-4 (1H) -isoquinolone
Ethyl 2-bromomethylbenzoate (5b). A solution of ethyl o-toluate (41.2 g, 0.25 mol) in carbon tetrachloride (200 mL) was added dropwise to a stirring mixture of benzoyl peroxide (100 mg), carbon tetrachloride (200 mL) and NBS (44.5 g, 0.25 moles) at 0 ° C. The mixture was refluxed for 3.5 hours under nitrogen, and allowed to cool to room temperature overnight. The precipitated succinimide was removed by filtration and the filter cake was washed with carbon tetrachloride. The combined filtrates were washed successively with
NaOH 2N (100 mL), and water (2 x 100 mL), and the solution was dried over anhydrous MgSO4, filtered
(Celite), and evaporated under vacuum to produce the product as an oil. Drying under high vacuum overnight gave 60.5 g (99%) of the crude compound 5b; 1 H NMR of the product showed the presence of approximately 15% unreacted starting material. Since the mixture was not readily separable by chromatography or vacuum distillation, it was used in the next step without further purification; RMN L
(CDCl.) D 1.43 (t, J = 7 Hz, 3H, CH2CH3), 4.41 (q, J
= 7 Hz, 2H, CH2CH3), 4.96 (s, 1H, CH2Br), 7.24 (m, 1H, ArH), 7.38 (m, 1H, ArH), 7.48 (m, 2H, ArH).
N- (2-carboethoxy) sarcosine ethyl ester (6). A solution of compound 5b (60.7 g; 0.25 moles of ethyl-o-toluate, conversion of 85% to compound 6, 0.21 moles calculated) in acetone (100 mL) at room temperature under nitrogen. The mixture was stirred at reflux for 2 hours and then left at room temperature for 20 hours. The solid was removed by filtration (Celite) and the residue was washed with acetone. The filtrates were combined and evaporated under reduced pressure to give an oil. The oil was dissolved in 250 ml of 3 N HCl and washed with ether. The aqueous layer was basified with aqueous NaHCO 3 and extracted with ether (3 x 250 mL). Evaporation of the ether solution produced an oil which was distilled off in vacuo to give 45.33 g (77%) of compound 6: p.e. 140-142 ° C (0.5 mm Hg) [e.g. 182-183 ° C (10 mm Hg)]; XH NMR (CDC13) d 1.24 (t, 3H, J = 7.1 Hz, CH3), 1.36 (t, 3H, J = 7.1 Hz, CH3) 2.35 (s, 3H, NCH3) 3.27 (s, 2H, CH2Ar), 4.00 (s, 2H, NCH2), 4.14 (q, 2H, J = 7.1 Hz, CH2CH3), 4.32 (q, 2H, J = 7.1 Hz, CH2CH3), 7.28 (t, 1H, J = 7.4 Hz, ArH) 7.42 (t, 1H, J = 7.6 Hz, ArH), 7.52 (d, 1H, J = 7.8 Hz, ArH), 7.74 (d, 1H, J = 7.7 Hz, ArH).
2-Methyl-2, 3-dihydro-4 (1H) -isoquinolone (7) Freshly cut sodium (10.9 g, 0.47 g-atom) was added to pure ethanol (110 mL) under nitrogen and the reaction was heated to reflux. After the metallic sodium had disappeared, a solution of compound 6 (35.9 g, 0.128 mol) in dry toluene was slowly added.
(160 mL) to the reaction mixture. Then it was heated to reflux and the ethanol was azeotropically separated by means of a Dean Stark trap. After cooling, the solvent was evaporated under reduced pressure. The remaining yellow, semi-solid residue was dissolved in a mixture of water (50 mL), 95% ethanol (60 mL) and concentrated HCl (240 mL), and heated to reflux for 26 hours. After cooling, the mixture was concentrated under vacuum and cautiously basified with solid NaHCO 3. The basic solution was extracted with ether, dried
(MgSO4), and evaporated to an oil which was distilled to give compound 7 (17.11 g, 83%), e.g. 130- 132 ° C (5 mm Hg) [e.g. 81-83 ° C (0.4 mm Hg); p.f.
(HCl) 250 ° C]; IR (pure) 1694 (C = 0) cm "1; XH NMR
(CDC13) d 2.48 (s, 3H, CH3), 3.31 (s, 2H, CH2), 3.74
(s, 2 H, CH2), 7.22 (d, 1H, J = 7.7 Hz, ArH), 7.34 (t, 1H, J = 7.9 Hz, ArH), 7.50 (t, 1H, J = 7.5 Hz,
ArH), 8.02 (d, 1H, J = 7.9 Hz, ArH).
Synthesis of 8, 9-dihydroxy-2, 3, 7, 1 lb-tetrahydro-lH-naphtho [l, 2,3-de) isoquinoline To a solution of 2,3-dimethoxy-N, N '-diethylbenzamide (compound 8) (14.94 g, 63 mmol) in ether (1400 mL) at -78 ° C under nitrogen and sequentially added, dropwise, N, N, N ', N'-tetramethylenediamine (TMEDA, 9.45 mL, 63 mmol) , and sec-butyllithium (53.3 mL, 69 mmol, 1.3 M solution in hexane) through a rubber diaphragm by means of a syringe. After 1 hour, freshly distilled compound 7 (10.1 g, 62.7 mmol) was added to the heterogeneous mixture. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature for 9 hours. The solution of NH4C1, saturated
(400 mL) was then added and the mixture was stirred for 15 minutes. The ether layer was separated and the water layer was extracted with dichloromethane (4 x 100 mL). The organic layers were combined, dried
(MgSO4), and evaporated to a brown oil. The oil was dissolved in toluene (500 mL), and heated at reflux for 8 hours with 3.0 g of p-toluenesulfonic acid, cooled and concentrated under vacuum. The residue was dissolved in dichloromethane, washed with aqueous NaHCO3, diluted, water and then dried (Na2SO4), filtered and evaporated to a gummy residue. On trituration with ethyl acetate-hexane (50:50), a solid precipitated. Recrystallization from ethyl acetate-hexane gave 12.75 g (63%) of compound 9 (2 ', 3' ~ Dihydro-4,5-dimethoxy-2'-methyrospiro [isobenzofuran-1 (3H) -4 '(l' H) isoquinoline [-3-one]: mp 193-194 ° C; IR (KBr) 1752 cm "1 (C = 0); NMR aH (CDCI3) d 2.47 (s, 3H, NCH3), 2.88 (d, 1H, J = 11.6 Hz), 3.02 (d, 1H, J = 11.7 Hz), 3.76 (d, 1H, J = 15.0 Hz), 3.79 (d, 1H, J = 15.1 Hz), 3.90 (s, 3H, OCH3), 4.17 (s, 3H, OCH3), 6.83 (d, 1H , J = 8.4 Hz, ArH), 7.03 (d, 1H, J = 8.2 Hz, ArH), 7.11 (m, 3H, ArH), 7.22 (m, 1H, ArH), MS (Cl) m / z 326 ( 100); Analysis (C? 9H? 9N04) C, H, N.
2 ', 3' -Dihydro-4, 5-dimethoxy-spiro [isobenzofuran-1 (3H), 4 '(1' H) isoquinoline] -3-one (10). 1-Chloro-ethylchloroformate (5.1 mL, 46.3 mmol) was added dropwise to a suspension of compound 9 (6.21 g, 19.2 mmol) in 100 mL of 1,2-dichloroethane at 0 ° C under nitrogen. The mixture was stirred for 15 minutes at 0 ° C, and then heated to reflux for 8 hours. The mixture was cooled and concentrated under reduced pressure. To this mixture was added 75 mL of methanol and the reaction was heated to reflux overnight. After cooling, the solvent was evaporated under reduced pressure to give the hydrochloride salt of compound 10 in almost quantitative yield. It was sufficiently pure to be used in the next step without further purification: p.f. (HCl) 220-222 ° C; p.f. (base) 208-210 ° C; IR (CH2C12, base) 1754 cm "1 (C = 0); XH NMR (CDCl ,, base) d 3.18 (d, 1H, J = 13.5 Hz), 3.30 (d, 1H, J = 13.5 Hz), 3.84 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 4.02 (s, 2H, CH2N), 6.67 (d, 1H, J = 7.5 Hz, ArH), 7.12 (m, 2H, ArH), 7.19 (d, 1H, J = 7.5 Hz, ArH), 7.26 (t, 1H, J = 7.5 Hz, ArH), 7.41 (d, 1H, J = 8.5 Hz, ArH), MS (Cl) m / z 312 ( 100); HRCIMS Calculated for d8Hi7N04: 312.1236; Found 312.1198; Analysis (C? 8H? 7N04) H, N; C: calculated, 69.44; found, 68.01.
2 ', 3'-Dihydro-4, 5-dimethoxy-2'-p-toluenesulfonyl-pyr [isobenzofuran-l (3H), 4' (l'H) iso-quinoline] -3-one (11). 7 mL of triethylamine was added dropwise to a mixture of p-toluenesulfonyl chloride (3.6 g, 18.9 mmol), compound 10 (as the HCl salt, obtained from 19.2 mmol of compound 9) and chloroform (100 mL) at 0 ° C under nitrogen. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. It was then acidified with 100 mL of aqueous 0.1 N HCl, cooled, extracted with dichloromethane (2 x 100 mL), and the organic extract was dried (MgSO), filtered, and evaporated under vacuum to give a viscous liquid which trituration with ethyl acetate-hexane at 0 ° C gave a solid. Recrystallization from ethyl acetate-hexane gave 8.74 g (97%, total of compound 9) of compound 11: p.p. 208-210 ° C; GO
(KBr) 1767 cm "1 (C = 0); XH NMR (CDC13) d 2.43 (s, 1H, CH3), 3.22 (d, 1H, J = 11 Hz), 3.88 (d, 1H; J = 11 Hz ), 3.90 (s, 3H, OCH3), 3.96 (d, 1H, J = 15 Hz), 4.17 (s, 3H, OCH3), 4.81 (d, 1H, J = 15 Hz);
(d, 1H, J = 7.7 Hz, ArH), 7.16 (m, 3H, ArH), 7.26
(m, 1H, ArH), 7.38 (d, 2H, J = 8 Hz, ArH), 7.72 (d, 2H, J = 8 Hz, ArH); MS (Cl) m / z 466 (100); Analysis
3, 4-Dimethoxy-6- [(2-p-toluenesulfonyl-1,2,3,4-tetrahydroisoquinoline) -4-yl] benzoic acid (12). A solution of compound 11 (2.56 g, 5.51 mmol) in glacial acetic acid (250 mL) was stirred with 10% palladium on activated carbon (6.30 g) in a Parr hydrogenator at 3.513 kg / cm2 (50 psig) for 48 hours at room temperature. The catalyst was removed by filtration, and the solvent was evaporated to give 2.55 g (99%) of compound 12 which was sufficiently pure to be carried in the next step. An analytical sample was recrystallized from ethanol-water: m.p. 182-184 ° C; IR (KBr) 1717 cm "1 (COOH); XH NMR (DMSO-dg) d 2.35 (s, 3 H, CH 3), 3.12 (m, 1 H), 3.51 (dd, 1 H, J = 5, 11.5 Hz) , 3.71 (s, 6H, OCH3), 4.10 (m, 1H, Ar2CH), 4.23 (s, 2H, ArCH2N), 6.52 (d, 1H, J = 7.5 Hz, ArH), 6.78 (d, 1H, J = 7.5 H, ArH), 6.90 (m, 1H, ArH), 7.07 (t, 1H, J = 8 Hz, ArH), 7.14 (t, 1H, J = 6.5 Hz, ArH), 7.20 (d, 1H; = 7.5 Hz, ArH), 7.38 (d, 2H, J = 8 Hz, ArH), 7.63 (d, 2H, J = 8.5 Hz, ArH); MS (Cl) m / z 468 (16), 450 (63 ), 296 (100); HRCIMS calculated for C25H25NO6S :: 468.1481; Found 468.1467; Analysis (C25H25NO6S) C, H, N.
2-N-Toluenesulfonyl-4- (2-hydroxymethyl-3,4-dimethoxyphenyl) -1,2,4,4-tetrahydroisoquinoline (13). It was added to a solution of compound 12 (1.4 g, 2.99 mmol) in dry tetrahydrofuran (30 mL), borane-tetrahydrofuran 1.0 M (8 mL) at 0 ° C under nitrogen. After the addition was complete, the mixture was stirred at reflux overnight. Additional diborane (4 mL) was added and stirring was continued for another 30 minutes. After cooling and evaporation under reduced pressure, methanol (30 mL) was carefully added, and the solvent was removed at low pressure. The process was repeated three times to ensure the methanolysis of the intermediate borane complex. Evaporation of the solvent gave 1.10 g (81%) of the crude compound 13. An analytical sample was purified by flash chromatography (silica gel, EtOAc / Hexane) followed by recrystallization from ethyl acetate / hexane: m.p. 162-164 ° C; NMR lH (CDC13) d 2.38 (s, 3H, CH3), 3.18 (dd, 1H, J = 7.5, 11.9 Hz), 3.67 (dd, 1H, J = 4.5, 11.8 Hz), 3.81 (s, 3H, OCH3 ), 3.85 (s, 3H, OCH3), 4.27 (d, 1H, J = 15 Hz), 4.40 (d, 1H), J = 15 Hz), 4.57 (t, 1H, J = 6 Hz, CHAr2), 4.71 (s, 2H, CH2OH), 6.58 (d, 1H, J =
8. 5 Hz, ArH); 6.74 (d, 1H, J = 8.6 Hz, ArH), 6.84
(d, 1H, J = 7.7 Hz, ArH), 7.08 (t, 2H, J = 7.6 Hz,
ArH), 7.14 (t, 1H, J = 6.6 Hz, ArH), 7.27 (d, 2H, J
= 8 Hz, ArH), 7.65 (d, 2H, J = 8 Hz, ArH); MS (Cl) m / z 454 (2.57), 436 (100); Analysis (C25H_.7NO.3S) C, H, N.
8, 9-Dimethoxy-2-p-toluenesulfonyl-2,3,7, 11b-tetrahydro-lH-napht [1,2,3-de] isoquinoline (14). Compound 13 powder (427 mg, 0.98 mmol) in several portions was added to 50 mL of concentrated sulfuric acid, cooled (50 mL) at -40 ° C under nitrogen with vigorous, mechanical agitation. After the addition, the reaction mixture was heated at -5 ° C for 2 hours and then poured into crushed ice (450 g) and allowed to stir for 1 hour. The product was extracted with dichloromethane (2 x 150 mL), washed with water (2 x 150 mL), dried (MgSO 4), filtered and evaporated to give an oil which on trituration with ether at 0 ° C produced Compound 14 (353 mg, 82%) as a white solid which was used for the next step without further purification. An analytical sample was prepared by rotary chromatography, centrifuged using 50% ethyl acetate-hexane as the eluent followed by recrystallization from EtOAc / Hexane: m.p. 204-206 ° C; 1H-NMR (CDC13) d 2.40 (s, 3H, CH3), 2.80 (m, 1H, lilac), 3.50 (dd, 1H, J = 4.5, 17.5 Hz, H-lb), 3.70 (dd, 1H, J = 7, 14 Hz, H-3a), 3828 (s, 3H, OCH3), 3832 (s, 3H, OCH3), 3.9 (, 1H, H-llb), 4.31 (d, 1H, J = 17.6 Hz, H -7a), 4.74 (ddd, 1H, J = 1.7, 6.0, 11.2 Hz, H-7b), 4.76 (d, 1H, J = 14.8 Hz, H-3b), 6.77 (d, 1H, J = 8.3 Hz , ArH), 6.87 (d, 1H, J = 8.4 Hz, ArH), 6.94 (d, 1H, J = 7.6 Hz, ArH), 7.13 (t, 1H, J = 7.5 Hz, Ar-H-5), 7.18 (d, 1H, J = 7.2 Hz, ArH), 7.33 (d, 2H, J = 8.1 Hz, ArH), 7.78 (d, 2H, J = 8.2 Hz, ArH); MS (Cl) m / z 436 (55), 198 (86), 157 (100); HRCIMS Calculated for C25H25NO4S: 436.1583; Found 436.1570; Analysis (C25H25N04S) C, H, N.
8, 9-Dimethoxy-2, 3, 7, Hb-tetrahydro-lH-naft [1, 2, 3-de] isoquinoline (15). A mixture of compound 14 (440 mg, 1.01 mmol), dry methanol was stirred under nitrogen.
(10 mL) and disodium acid phosphate (574 mg, 4.04 mmol), at room temperature. To this mixture was added 6.20 g of 6% Na-Hg in three portions and the reaction was heated to reflux for 2 hours. After cooling, water (200 mL) was added and the mixture was extracted with ether (3 x 200 mL). The ether layers were combined, dried (MgSO 4), filtered (Celite), and evaporated to give an oil that solidified under vacuum. After rotary chromatography, 142 mg (50%) of compound 15 was obtained as an oil. The oil darkened rapidly on exposure to air and was used immediately for the next step. A small portion of the oil was treated with ethereal HCl and the hydrochloride salt of compound 15 was recrystallized from ethanol-ether: m.p. (HCl salt) 190 ° C (dec.); XH NMR (CDC13, base) d 3.13 (dd, 1H, J = 10.8, 12 Hz, H-la), 3.50 (dd, 1H, J = 3.4, 17.4 Hz, H-lb), 3.70 (m, 1H, H-llb), 3839 (s, 3H, 0CH3), 3842 (s, 3H, OCH3), 4.03 (dd, 1H, J = 6, 12 Hz, H-7a), 4.08 (s, 2H, H-3) ), 4.33 (d, 1H, J = 17.4 Hz, H-7b), 6.78 (d, 1H, J = 8.24 Hz, ArH), 6.92 (m, 3H, ArH), 7.11 (t, 1H, J = 7.5 Hz, ArH), 7.18 (d, 1H, J = 7.5 Hz, ArH); MS (Cl) m / z 282 (100); HRCIMS Calculated for C? 8H? 9N02 :: 282.1494; Found 282.1497.
8, 9-Dihydroxy-2, 3, 7, 1 lb-tetrahydro-1 H-naft [1,2,3-de] isoquinoline (4). It was added to a solution of compound 15 (25 mg, 0.089 mmol) in dichloromethane (5 mL) at -78 ° C, boron tribromide (0.04 mL, 0.106 g, 0.42 mmol). After stirring at -78 ° C under nitrogen for 2 hours, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 5 hours. It was then cooled to -78 ° C and methanol (2 ml) was carefully added. After stirring for 15 minutes at room temperature, the solvent was evaporated under reduced pressure. More ethanol was added and the process was repeated three times. The resulting gray solid was recrystallized from ethanol-ethyl acetate to yield a total of 12 mg (41%) of the hydrobromide salt of compound 4: p.p. 258 ° C
(desc.); NMR XH (salt of HBr, CD30D) d 3.43 (t, 1H,
J = 12 Hz, H-la), 3.48 (dd, 1H, J = 3.5, 18 Hz, H-lb), 4.04 (m, 1H, H-llb), 4.38 (dd, 2H, J = 5.5, 12 Hz, H-7), 4.44 (s, 2H, H-3), 6.58 (d, 1H, J = 8.5
Hz, ArH), 6.71 (d, 1H, J = 8.5 Hz, ArH), 7.11 (d,
1H, J = 7.5 Hz, ArH), 7.25 (t, 1H, J = 7.5 Hz,
ArH), 7.32 (d, 1H, J = 7.5 Hz, ArH); EM (Cl) m / z
254 (100); HRCIMS Calculated for C? 6H? 5N02: 254.1181; Found 254.1192.
Pharmacology of Dinapsoline
Methods Sprague Dawley rats, males, adults (200-250 g) were obtained from Charles River Breeding Laboratories (Raleigh, NC) or Harlan Laboratories (Indianapolis, IN). The rats were sacrificed by decapitation, and the whole brains were removed and cooled rapidly, briefly in ice-cold saline. The brains were sliced with the help of a block or dissection piece, and the striated, central bodies were then divided from two coronal sections containing the majority of this region.
The tissue was immediately frozen on dry ice and stored at -70 ° C until the day of the test. Cell cultures. C-6 glioma cells expressing the rhesus macaque DXA receptor (C-6-mD? A, Machida et al., 1992) were cultured in a DMEM-H medium containing 4,500 mg / L glucose, L-glutamine , 5% fetal bovine serum and 600 ng / mL of G418 or 2 μg / mL of puromycin. The cells were kept in a humidified incubator at 37 ° C with 5% C02. Preparation of the membranes. The cells were cultured in 75 cm 'flasks until confluent. The cells were rinsed and used with 10 L of ice-cold hypoosmotic buffer (HOB) (5 mM Hepes, 2.5 mM MgCl 2, 1 mM EDTA, pH 7.4) for 10 minutes at 4 ° C. The cells were then scraped from the flasks using a cell scraper, sterile by Baxter (McGaw Park, IL). The flasks received a final rinse with 5 L of HOB. The final volume of the cell suspension recovered from each flask was about 14 L. The scraped membranes of several flasks were then combined. The combined cell suspension was homogenized (10 strokes or attacks), 14 L at a time, using 15 mL of Wheaton Teflon glass homogenizer. The cell homogenates were combined and centrifuged at 43,000 x g (Sorvall RC-5B / SS-34, Du Pont, Wilmington, DE) at 4 ° C for 20 minutes. The supernatant was removed and the pellet was resuspended (10 strokes or attacks) in 1 mL of ice cold HOB for each original homogenized cell flask. This homogenate was then centrifuged again at 43,000 x g at 4 ° C for 20 minutes. The supernatant was removed and the final pellet resuspended (10 strokes or attacks) in ice-cooled storage buffer
(50 mM Hepes, 6 mM MgCl 2, 1 mM EDTA, pH 7.4) to produce a final concentration of approximately 2.0 mg protein / mL. The aliquots of the final homogenate were stored in microcentrifuge tubes at -80 ° C. Before use for the adenylate cyclase assays, protein levels for each membrane preparation were quantified using the BCA protein assay reagent (Pierce, Rockford, IL) adapted for use with a microplate reader (Molecular Devices; Menlo Park, CA). Dopamine receptor binding assays. The striated bodies of the frozen rats were homogenized by seven strokes or manual attacks in a Wheaton Teflon glass homogenizer in 8 mL of a 50 mM HEPES buffer cooled with ice with 4.0 mM MgCl 2 (pH 7.4). The tissue was centrifuged at 27,000 x g for 10 minutes, the supernatant was discharged, and the pellet was homogenized (five strokes or attacks) and resuspended in ice-cooled buffer and centrifuged again. The final pellet was suspended at a concentration of 2.0 mg wet weight / mL. The amount of tissue added for each test tube was 1.0 mg, in a final assay volume of 1.0 mL. The Dx receptors were labeled with [5H] SCH23390 (0.30 nM); D2 receptors were labeled with [JH] spiperone (0.07 nM); unlabeled ketanserin (50 nM) was added to hide the binding to the 5-HT2 sites. Total binding was defined as radioligand binding in the absence of a competent drug. The non-specific binding was estimated by adding unlabeled SCH23390 (1 μM) or unlabeled chlorpromazine (1 μM) for the binding assays of Di and D2 receptors, respectively. As an internal model, a compendium curve with six concentrations of unlabeled SCH23390 (Di binding) or chloropromazine (D2 binding) was included in each assay. The triplicate determinations were made for each drug concentration. The test tubes were incubated at 37 ° C for 15 minutes, and the binding was terminated by filtration with ice-cooled buffer in a Skatron 12-well cell harvester (Skatron, Inc., Sterling, VA) using filter mats of fiberglass (Skatron No. 7034). The filters were allowed to dry and 1.0 mL of Optiphase HI-SAF II scintillation fluid was added. The radioactivity was determined in a LKB Wallac 1219 RackBeta liquid scintillation counter (Wallac, Gaithersburg, MD). Tissue protein levels were estimated using the BCA protein assay reagent (Pierce, Rockford, IL). Data analysis for radio receptor assays. The binding data of each assay was analyzed separately. The data were normalized by expressing the average dpm in each competing concentration as a percentage of total binding. These data were then subjected to non-linear regression analysis using the algorithm for the sigmoid curves in the InPlot curve fitting program (Graphpad Inc., San Francisco, CA) or EBDA and the software component (software) LIGAND, as adapted for the IBM PC by McPherson, to generate K0.s' values and a Hill coefficient (nH) for each curve. The analysis of residual amounts indicated an excellent fit; the r values were above 0.99 for all the curves in the present experiments. The activity of adenylate cyclase in the striatum of rats. The CLAP method, automated by Schulz and Mailman, was used to measure the activity of adenylate cyclase by separating cAMP from other labeled nucleotides. Briefly, the striatal tissue of the rat was homogenized with eight strokes or manual attacks in a Wheaton-TefIon glass homogenizer in 5 mM HEPES buffer (pH 7.5) containing 2 mM EGTA (50 mL / g tissue). After the addition and mixing of 50 mL / g of 50 mM HEPES buffer (pH 7.5) containing 2 mM EGTA, an aliquot of 20 μL of this tissue homogenate was added to a prepared reaction mixture (final volume 100). μL) containing 0.5 mM ATP, isobutyl ethylxanthine 0.5 mM, [32 P] ATP (0.5 μCi), 1 mM cAMP, 2 mM MgCl2, 100 mM HEPES buffer, 2 μM GTP, 0-100 μM dopamine, DHX, or SKF38393, 10 mM phosphocreatine and creatine phosphokinase 5 U. Determinations were made in triplicate for each drug concentration. The reaction proceeded for 15 minutes at 30 ° C and was terminated by the addition of 100 μL of 3% sodium dodecyl sulfate (SDS). Proteins and many of the non-cyclic nucleotides were precipitated by the addition of 300 μL each of 4.5% ZnSO4 and 10% Ba (OH) 2. The samples were centrifuged (10,000 x g for 8-9 minutes), and the supernatants were injected into a CLAP system (Waters Z-module or RCM 8 x 10 module equipped with a 10 micron cartridge, C18). The mobile phase was 150 M sodium acetate (pH 5.0) with 23% methanol. A UV detector (254 nm detection) was used to quantify the unlabeled cAMP added to the samples to serve as an internal model. The radioactivity in each fraction was determined by a radiation detector through the flow (Inus Systems, Tampa, FL) using a Cerenkov counter. Sample recovery was based on UV measurement of unlabeled, total cAMP peak areas, quantified using a Model 900 data collection module, Nelson PE (Cupertino, CA) and the TurboChrom logic component. Tissue protein levels were estimated using the BCA protein assay reagent (Pierce, Rockford, IL). Adenylate cyclase assay in C-6 cells, D1A. The frozen membranes were thawed and added to test tubes (10 μg protein / tube) containing a prepared reaction mixture [100 mM Hepes, (pH 7.4), 100 mM NaCl, 4 mM MgCl 2, 2 mM EDTA, 500 μM isobutyl methylxanthine (IBMX), 0.01% ascorbic acid, 10 μg pargyline, 2 mM ATP, 5 μM GTP, 20 M phosphocreatine, 5 units of creatine phosphokinase (CPK), 1 μM propranolol] and selected drugs . The final reaction volume was 100 μL. The basic cAMP activity was determined by incubating the tissue in the reaction mixture without added drug. The tubes were tested in duplicate and, after 15 minutes of incubation at 30 ° C, the reaction was stopped by the addition of 500 μL of 0.1 N HCl. The tubes were swirled briefly, and then centrifuged in a HermLe Z BHG microcentrifuge. 230 M for five minutes at 15,000 'xg to precipitate the particulates.
Radioimmunoassay (RIA) of cAMP. The concentration of cAMP in each sample was determined with an RIA of acetylated cAMP, modified from that previously described. The iodization of cAMP was performed using a method reported by Patel and Linden. The buffer of the assay was 50 mM sodium acetate buffer with 0.1% sodium azide (pH 4.75). The curves of the cAMP model were prepared in a buffer at concentrations of 2 to 500 fmol / test tube. To improve the sensitivity of the assay, all samples and models were acetylated with 10 μl of a 2: 1 solution of triethylamine: acetic anhydride. The samples were tested in duplicate. Each test tube (total volume 300 μL) contained 25 μL of each sample, 75 μL of buffer, 100 μL of primary antibody (sheep anti-cAMP, 1: 100,000 dilution with 1% BSA in the buffer) and 100 μL of [12EI] -cAMP (50,000 dpm / 100 μL buffer). The tubes were swirled and stored at 4 ° C overnight (approximately 18 hours). The radioactivity bound to the antibody was separated by the addition of 25 μL of goat anti-goat, BioMag rabbit (Advanced Magnetics, Cambridge MA), followed by swirling and incubation at 4 ° C for 1 hour. To these samples were added 1 mL of 12% polyethylene glycol / 50 mM sodium acetate buffer (pH 6.75) and the tubes were centrifuged at 1700 x g for 10 minutes. The supernatants were aspirated and the radioactivity in the pellet was determined using a Wallac LKB gamma counter (Gaithersburg, MD).
Data analysis for studies of cislase adenylate. The data for each sample were initially expressed as pmol / mg / min of cAMP. The cAMP baseline values are subtracted or subtracted from the total amount of cAMP produced in each condition of the drug. The data for each drug was expressed in relation to the stimulation produced by 100 μM DA.
Results Binding and functional effects of dinapsoline on Di receptors in rat striatal homogenates. As shown in Figure 3, dinapsoline competed with high affinity in Di receptors in rat striatal homogenates, which have almost identical affinity as dihydrexidine, a full Di agonist. Both dinapsoline and dihydrexidine had less sloping slopes for their competition curves than did the prototypic Di antagonist SCH 23390 (1). Table 1 summarizes the affinities of (+) - 3 and (±) -4 in the dopamine receptors in the rat brain. Radioligand binding studies for dopamine receptors were conducted in striatal rat homogenates, using 3 H-SCH23390 0.3 nM (Di sites) and 0.07 nM 3 H-spiperone in the presence of unlabeled quetanserin 50 nM
(sites D2). The competition curves were analyzed by non-linear regression to determine the calculations or estimates for the slope K0.s and Hill (nH). The data represent the average and normal error of the three independent tests for each test compound.
Table 1. Summary of affinities of (+) - 3 and (±) -4 in dopamine receptors in rat brain.
binding of D1 binding of D2 Compound K0.5 (nM) nH K0.5 (nM) nH (±) -4 5.93 + 0.45 0.66 ± 0.01 31 .3 ± 4.4 0.71 ± 0.03
(+) - 3 4.59 ± 0.28 0.65 ± 0.01 43.2 ± 3.2 0.72 ± 0.04
(+) - 2 17 ± 4 0.75 ± 0.08 Not Tested (+) - 1 0.30 ± 0.01 1 .05 ± 0.01 Not Tested Chlorpromazine Not Tested 0.92 ± 0.12 0.93 ± 0.01
The ability of test compounds
[(+) - SFK 38393 = (+) - 2; (±) -trans- 10, 11-dihydroxy-5, 6, 6a, 7, 8, 12b-hexahydrobenzo [a] phenanthridine = (±) -3; and (±) -8,9-dihydroxy-2, 3, 7, 11b-tetrahydro-lH-naphtho [1,2,3-de] isoquinoline = 4] to stimulate accumulation of cAMP was examined in striatal homogenates of rats . The high affinity (±) -3 complete agonist and the partial (+) - 2 agonist were included for comparison. The data from these experiments are shown in Figure 4 as the mean ± SEM of at least three experiments. Saturation concentrations (10 μM) of both dinapsoline and dihydrexidine caused the same degree of increase in cAMP synthesis (95.8% ± 4.7 for dinapsoline and 91.3% ± 4.6 for dihydrexidine) as did a maximally effective concentration of dopamine (100 μM). The other way, the partial (+) - 2 agonist caused less than 50% stimulation (40.7 ± 7.0 for SKF 38393). These effects were blocked by the antagonist The functional efficiency of dinapsoline was also tested on primate D1A receptors, cloned, expressed in C-6 glioma cells (C-6-mD? Cells). As shown in Figure 5, the dinapsoline compound also exhibited complete efficacy in this preparation, with an EC50 of approximately 30 nM (the data represent the average of two experiments conducted in duplicate). (+) -trans-10, 11-dihydroxy-5,6,6a, 7,8,12b-hexahydrobenzo [a] phenanthridine (dihydrexidine) also exhibited complete efficacy in this preparation, while (+) -2 was only partial effectiveness. Union in the D2 receivers. The ability of dinapsoline to compete for D2 receptors in rat striatal homogenates was investigated. As shown in Figure 6 and Table 1, the affinity of dinapsoline for D2-like receptors in striatal homogenates of rats (K9.5 = 31 nM) is actually greater than the affinity of dihydrexidine for receptors similar to D2 (K0.5 = 50 nM). As can also be seen in Figure 6, the slope of the competition curves for both dinapsoline and dihydrexidine was less steep than for chlorpromazine antagonist Di, prototypic. When using the same general procedures described in Example 1 above, the compounds of Examples 2-48, as set forth in Table II below, are synthesized using start compounds corresponding to those illustrated in Schemes 1 and 2 (FIGS. 1 and 2), but substituted with functional groups, appropriate to provide the substitution patterns represented in the fused naph-isoquinoline product, shown for each Example. Thus, for example, substituted analogues 3, 4 and / or 5 of compound 5a (scheme 1) provide the corresponding substituents Ri, R3 and R2, respectively, in Formula I. Substitution of esters of N-methyl alanine or N-methyl valine for the sarcosine ester in Step b of Scheme I will provide the corresponding compounds of Formula I wherein R5 is methyl and isopropyl, respectively. The use of the other substituted benzamides 2 and 3 (analogous to compound 8 in scheme 2) provided the corresponding substitution patterns at C8 and C9 in Formula I.
Example R R1 R2 R3 R4 Rs X
Number 2 H H CH3 H H OH
3 H H H CH 3 H H OH
4 H H H H CH 3 H OH 6 CH 3 H CH 3 H H OH
7 C3H7 H H CH3 H H OH
8 H H C2Hd H H OH
9 H H H C2Hs H H OH
H H H CH3 CH3 H Br 12 C2Hs H H CH3 CH3 H Br
13 CH3 H H H C 2 Hd H OH 15 H H CH 3 OH H OH OH 16 H H H H H OH
17 H H OH H H H Br
18 H H Br H H H OH
19 H CH3 H Br H H 0 CH3
H CH3 H H Br H 0 CH3
21 H CH3 CH3 Br H H 0 CH3
22 CH3 H F H H OH
23 CH3 H H F H H OH
24 CH3 H H H F H OH
C3Hs H H OH H H F
26 C2Hs H CH3 OH H H F
27 C2Hd H CH30 H CH3 H F
28 C3H7 H H CH3O H H Cl
29 C3H7 H H CH3 CH30 H Cl
C3H7 H C2H50 H H OH
33 C-1H9 H OH OH CH 3 OH
37 H H H H H H H
38 H H CH3 H H H H 39 H H H CH 3 H H H
40 H H H H CH3 H H
41 H H H H H CH 3 OH
42 H H H H H CH 2 (CH 3) 2 OH
43 H H H H H CH3 H
44 H H H H H CH 2 (CH 3) 2 H
45 H H CH 3 H H CH 3 OH
46 H H H CH 3 H CH 3 OH
47 H H H H CH 3 CH 3 OH
48 H H H H H CH 2 CH 3 OH
The above examples are illustrative of the invention and are not intended to limit the invention to the disclosed compounds. Variations and modifications of the exemplified compounds, obvious to one skilled in the art, are proposed to be within the scope and nature of the invention as specified in the following claims.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following claims is claimed as property.
Claims (10)
- A compound of the formula and pharmaceutically acceptable salts thereof, characterized in that R and R5 are hydrogen or alkyl of 1 to 4 carbon atoms; Ri is hydrogen, alkyl of 1 to 4 carbon atoms or a phenoxy protecting group; X is hydrogen, halo or a group of the formula -OR6 wherein R6 is hydrogen, alkyl of 1 to 4 carbon atoms or a phenoxy protecting group, and further when X is a group of the formula OR, -,, R groups: and R. can be taken together to form a group of the formula -CH2-; and R2, R3 and R are independently selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, halo or a group -ORi wherein Ri is as defined above.
- 2. The compound according to claim 1, characterized in that X is hydroxy and Ri is hydrogen.
- 3. The compound according to claim 1, characterized in that R and R are hydrogen.
- 4. The compound according to claim 2, characterized in that R and R5 are hydrogen.
- 5. The compound according to claim 1, characterized in that R2, R3, R4 and R; they are each hydrogen.
- 6. The compound according to claim 1, characterized in that X and Ri are hydrogen.
- 7. The compound according to claim 1, characterized in that R5 is hydrogen.
- 8. The compound according to claim 1, characterized in that R 5 is alkyl of 1 to 4 carbon atoms.
- 9. A method for treating a patient who has a dysfunction related to dopamine of the central or peripheral nervous system as evidenced by an apparent neurological, psychological, physiological or behavioral disorder, the method is characterized in that it comprises the step of administering to the patient a compound of the formula: wherein R and R5 are hydrogen or alkyl of 1 to 4 carbon atoms; Ri is hydrogen, alkyl of 1 to 4 carbon atoms or a phenoxy protecting group; X is hydrogen, halo or a group of the formula -0R6 wherein Rβ is hydrogen, alkyl of 1 to 4 carbon atoms or a protecting group of phenoxy, and furthermore when X is a group of the formula -0R6, the groups Ri and R can be taken together to form a group of the formula -CH2-; R2, R3 and R are independently selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, halo or a group -ORi wherein Ri is as defined above; or a pharmaceutically acceptable salt thereof in an amount effective to reduce the symptoms of the disorder.
- 10. A pharmaceutical composition for treating a dysfunction related to dopamine of the central nervous system, the composition is characterized in that it comprises a therapeutically effective amount of a compound of the formula: or a pharmaceutically acceptable salt. thereof, wherein R and R5 are hydrogen or alkyl of 1 to 4 carbon atoms; Ri is hydrogen, alkyl of 1 to 4 carbon atoms or a phenoxy protecting group; X is hydrogen, halo or a group of the formula -OR6 wherein Re is hydrogen, alkyl of 1 to 4 carbon atoms or a phenoxy protecting group, and further when X is a group of the formula -OR,; the groups Ri and R6 can be taken together to form a group of the formula -CH; -; R2, R3 and R4 are independently selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, phenyl, halo or a group -ORi wherein Ri is as defined above; and a pharmaceutically acceptable carrier thereof.
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JP2005504717A (en) * | 2001-01-16 | 2005-02-17 | パーデュー・リサーチ・ファウンデーション | Treatment of dopamine-related dysfunction |
ATE365040T1 (en) | 2001-08-10 | 2007-07-15 | Purdue Research Foundation | CHIRAL DINAPSOLINE |
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US9359303B2 (en) | 2009-04-21 | 2016-06-07 | Purdue Research Foundation | Octahydrobenzoisoquinoline modulators of dopamine receptors and uses therefor |
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- 1996-08-16 PT PT96928941T patent/PT845988E/en unknown
- 1996-08-16 DK DK96928941T patent/DK0845988T3/en active
- 1996-08-16 IL IL12297496A patent/IL122974A/en not_active IP Right Cessation
- 1996-08-16 EP EP96928941A patent/EP0845988B1/en not_active Expired - Lifetime
- 1996-08-16 NZ NZ316312A patent/NZ316312A/en not_active IP Right Cessation
- 1996-08-16 AT AT96928941T patent/ATE209915T1/en not_active IP Right Cessation
- 1996-08-16 US US08/727,451 patent/US5959110A/en not_active Expired - Lifetime
- 1996-08-16 ES ES96928941T patent/ES2169257T3/en not_active Expired - Lifetime
- 1996-08-16 MX MX9801179A patent/MX9801179A/en not_active IP Right Cessation
- 1996-08-16 WO PCT/US1996/013416 patent/WO1997006799A1/en active IP Right Grant
- 1996-08-16 AU AU68513/96A patent/AU700688B2/en not_active Ceased
- 1996-08-16 JP JP9509550A patent/JP2000505046A/en not_active Ceased
- 1996-08-16 DE DE69617700T patent/DE69617700T2/en not_active Expired - Fee Related
- 1996-08-16 BR BR9610323-0A patent/BR9610323A/en not_active IP Right Cessation
- 1996-08-16 CN CN96197477A patent/CN1199338A/en active Pending
-
1998
- 1998-02-18 NO NO980688A patent/NO308658B1/en unknown
-
1999
- 1999-08-13 US US09/374,423 patent/US6194423B1/en not_active Expired - Lifetime
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