JPH06502165A - Therapeutically useful 2-aminotetralin derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Therapeutically useful 2-amitsuchitraline derivatives Field of the invention The present invention provides novel 1.2.3.4-tetrahydro-2-naphthylamine, such methods of preparing such compounds, pharmaceutical compositions of such compounds and such compounds; The present invention relates to the use of compounds for the manufacture of pharmaceutical compositions.

Background of the invention Psychiatric diseases are linked to monoaminergic nervous system, especially serotonin (5-HT). It is thought that it is caused by dysfunction of the nervous system involving dopamine (D　A　　). It will be done.

Anxiety disorders are associated with increased activity of the 5-HT system. benzo/azepine anxiety Relaxants are effective anti-inflammatory agents in animals deficient in 5-HT. Not active in anxiety analysis. seronotjn nerve cell is the firing rate of 1.5-HT cells when activated with an agonist. ate). These receptors are 5-H It is a T1A subtype.

5-HT la agonists are anxiolytic agents. Buspirone is an anxiolytic drug. It is a commercially available 5-HTIA agonist. Gepirone has been clinically shown to have anxiolytic activity. is another 5-HTIA agonist.

Leprosy is a psychiatric condition thought to be related to the release of 5-HT. many The anti-resistance drugs act by blocking the termination of activity by reuptake into the nerve terminals. - Enhances the effectiveness of HT. 5-HT IA agonists can be activated in the posterior part of nonabuses. Therefore, they can also be anti-R agents. Gepirone has been shown to be effective in some patients. It has already been shown that it has an improvement effect on the endpoint of pushability to a certain extent in patients. has been done.

τrotonishi is also involved in the control of apposition and sexual behavior, and the control of the primary blood vessels.

Therefore, 5-HAIA agonists may be useful in treating bulimia and sexual dysfunction. It's possible. These compounds have been shown to alter mating and sexual behavior in animals. has been done. They are also useful in treating obsessive-compulsive disorder, alneal abuse and violent behavior. It can be used for D-HAI A agonists suppress sympathetic nerve discharge and therefore It is also known to lower blood pressure. Therefore, they are hypertensive, congestive heart failure (by reducing cardiovascular afterload) and heart attack (by reducing cardiovascular afterload) by removing sympathetic demands).

Schizophrenia is thought to be caused by 7c activation of the DA system. Therefore, the current However, the available antipsychotic drugs are DA antagonists. dopamine self-receptors , decreases DA neuron firing, DA synthesis and release. Therefore, D, A Self-receptor agonists can also be expected to be antipsychotics. The operating straw to D is professional Because it reduces the release of lactin, it is associated with Parkinson's syndrome and degeneration of DA neurons. It is also useful in treating diseases caused by hyperprolactinemia, and be.

Dopamine autoreceptor antagonists dissociate DA neurons from self-receptor regulation. It is a new class of drugs that increases the release of DA by releasing it. Therefore , these drugs use amphetamines and other similar stimulants that directly release DA. It can be expected to be useful for treating symptoms that can be treated. However, DA self-reception Rather than releasing DA directly, DA agonists release cells from self-receptor regulation. Because it simply increases the release associated with normal or A activity by releasing It is a much milder stimulant. Therefore, DA autoreceptor antagonists may be effective in treating dementia. Bulimia in the elderly, note! Deficiency disorders, psychiatric retardation, cognitive retardation and motor Expected to be useful in treating retardation and the nausea and dizziness associated with space travel. Wear.

The compounds of the present invention have various effects on Q-HA IA and DA receptors. and have various utilities associated with their activity.

Clinically, 5-H, AIA agonists have also been shown to have anxiolytic properties. It is. The drug buspirone is currently the only commercially available anxiolytic active It is a 5-HT IA agonist with This compound is a 5-HA, A receptor The same dose that stimulates dopamine receptors antagonizes them. Similar drug gepirone also has properties as a dopamine antagonist. However, dopamine antagonist Long-term treatment with antibiotics can cause late-onset movement disorders; Their properties as dopamine antagonists may reduce the clinical utility of these compounds. let

The search for new CNS-active compounds that do not adversely affect central dopamine receptors Discovery of a compound that has a highly selective 5-HTIA receptor agonist effect I'm concentrating on what I'm doing.

Drugs that act on central dopamine transmission are used to treat Parkinson's syndrome, psychotic syndrome, and and Wjk bud g4t; which clinically effective treatments for various central nervous system disorders. It is effective.

In Parkinson's syndrome, for example, nigro-neostriatal dysfunction is associated with postsynaptic It can be repaired by increasing the stimulation of dopamine receptors.

In schizophrenia, reducing stimulation of postsynaptic dopamine receptors This can normalize the symptoms. The typical antipsychotic effect is Directly blocks dopamine receptors in the back of the body. Appropriate nerve transmission, transport mechanisms and presynaptic events in neurons that are essential to maintain neuronal and transmitter synthesis. The same effect can be achieved by inhibiting.

Recently, a large body of pharmacological, biochemical and electrophysical evidence has shown that dopamine Identification of central autoregulatory dopamine receptors located on the agonist neurons themselves This provides important support for the existence of groups. These receptors are , which modulate the flow of nerve impulses and the synthesis of transmitters released from nerve endings. It is part of the homeostatic mechanism that controls the amount of dopamine released.

Direct dopamine receptor agonists, such as apomorphine, Activates dopamine self-receptors as well as internal dopamine receptors be able to. When apomorphine is administered at low doses, autoreceptors At higher doses, dopamine transmission appears to be predominant, whereas stimulatory effects appear to be dominant. The attenuation is more important due to the increased stimulation of postsynaptic receptors. Apomo Antipsychotic and antipsychotic effects in humans at low doses of Rufuin are similar. , due to the properties of this dopamine receptor agonist as a self-receptor stimulant. It seems that it does. This knowledge content is based on central nervous system dopamine self-receptors. Highly selective dopamine receptor stimulants may be used to treat psychiatric disorders This shows that there is a #1 value even though there is a value of #1.

Disclosure statement The following documents are important in examining this application.

Arvidsson, L.E., et al., J.A. Le of Mesoinonal Chemistry (J, 1led, Chet), 2 Vol. 4, p. 921 (1981) states that the amine moiety is one n-propyl, one n-propyl Hydroxy-2-aryl substituted with benzyl or two n-propyl substituents Minotetralin is listed. D-16-1 and 7-hydroxy compounds are Described as an active central dopamine receptor agonist, 8-hydroxy The compound lacks dopamine receptor stimulatory activity (as a central 5-HT receptor agonist) It is described as follows.

Arvidsson, L.E., et al., J.A. Le of Mesointernal Chemistry (J-11ed, Chew,), 2 7, p. 45 (1984ffi), the amine moiety contains one or two methyl, ethyl, Substituted with thyl, n-propyl, 1-propyl, n-butyl, or benyl substituents 2-aminotetralin is described. 2-piperidinyl tetrari Also listed are: Some of these compounds lack dopamine-mimicking effects. It was found to be an effective 5-HT agonist.

Arvidsson, Nil E, et al. Le of Mezzoinal Yamist Q - <J, Med, Chew,), Volume 30, page 2105 (1987) describes 8-hydroxy-1-methyl-2- (N-propylamino)tetralin has been described.

These compounds were 5-HT receptor agonists.

Also, Arbi! Doson, Nil E, et al., 8 -Hydroxy and 8-methquine traline compounds are ent) Documents 00389J, '47.949810151 and 045535J , 4g.

McDermed (CMcDermed) et al. ・Chemistry〇, Med, Chell, ), Volume 18, Page 362 (197 3) describes 5,6-dihydroxy-2-aminotetralin.

Additionally, 5,8- and 7,8-disubstituted compounds are also disclosed. Its amine part Components are mono- or di-substituted with simple alkyl, benzyl, or alkylalcoquino groups. The amine may also be substituted with a 5- or 6-membered hydrocarbon or heterocyclic amine. It may also be a cyclic amine. These compounds are said to have dopaminergic properties. Although indicated, certain compounds are reported to be inert.

McDermed et al., Journal of Mesoinnals Chemistry (J, Med, Chew), vol. 19, p. 547 (1976 5-16-1 or 7-hydroxy-2-dipropylamino tetra is listed. These compounds are described as dopaminergic compounds has been done.

Rusterholz et al., Journal of Mesoinnals ・Chemistry (J, Med, Chew,), vol. 19, p. 99 (1976 ), the amine moiety is substituted with hydrogen, methyl, or cyanopropyl groups. 5,8-disubstituted-2-aminotetralins are described. These compounds Some are effective prolactin inhibitors and are thought to be dopamine agonists. It will be done.

Ames et al., Journal of Chemical Society (J, C Hew.

Soc, p. 2636 (1965) states that if the 5 or 8 position of the aromatic ring is ci, etquin, n- or iso-propoxy, or rl-1Sec- or It is substituted with a tert-butoxy group, and the amine moiety is hydrogen or has 1 to 4 carbon atoms. The preparation of a number of compounds substituted with alkyl groups has been described. these It is noted that the compounds are prepared for pharmacological testing. however , the usefulness or pharmacological activity of the compounds just mentioned is not yet known. Inai EPO Application No. 89304935.3 contains 2-amino-1,2, 3,4-tetrahydronaphthalene disclosed as a selective inhibitor of serotonin reuptake has been done. Its publication date is after the filing date of the patent application in question.

German license DE 28035g2 has a group R1 at the 5, 6, 7 or 8 position of the aromatic ring. Here, R1 is hydrogen, alkanoyl having 1 to 20 carbon atoms, or a group -CO(CHz) -R? , n is a number 0 to 5, R7 is a phenyl group having further defined substituents, R 2 is hydrogen, hydroxyl, halogen or alkylsulfonylamino, R3 is water element, R4 is hydrogen, CH20H1 further defined CH20-Co-R8 or C H2-○-CO-(CH2)-R1 and R5 and R6 are hydrogen, alkyl or alkyl. aryl or further defined aralkyl group, or R3 and R6 are co- 2-aminotetralin substituted with alkylene having 4 to 6 carbon atoms] is Are listed. These compounds exhibit pharmacodynamic activity, especially α- and β-addo It has been disclosed that it has a stimulatory effect on renocebuter and dovanminrecebuter. There is. The disclosed compounds have a group RIG at the 8-position, R other than hydrogen, or There is a compound having R4.

British patents 1.377 and 356 state that the 5,6,7 or 8 position of the aromatic ring is RI [herein , R1 is hydrogen or methyl], an aliphatic ring is substituted with R2, and R2 is alkyl having 1 to 6 carbon atoms], the amine moiety is substituted with R3, and R3 2-aminoteto substituted with hydrogen or alkyl having 1 to 6 carbon atoms Larin is listed. Such compounds are stated to have analgesic activity. Ru. 1゜1-dimethyl-2-(N,N-dimethylamino)-7-hydroxytet Larin is stated to be an example of a compound protected by this patent.

This compound is published in Chemical Abstracts (Cheffl ＾b,), Volume 79. 146294b is also described as having analgesic effect and intestinal motility promoting effect. .

Journal of Pharmaceutical Sciences (J, Pharm, Sci,).

Vol. 67, pp. 880-82 Cl978) describes the compound 1-methyl-2-(nocturnal). Lobrobylamino)-5-methoquinotetralin has been described and this compound has been It has been pointed out that it has significant anesthetic activity.

Dervent Reference 58.247B/32.40378^/2 3.83-72938111/32.83-729387/32.29348D /17 oyohi06733v, 105ha, 8-carpoquine aminotetralinni mentioned are doing. Furthermore, 07633V105 has 8-amino and 8-alkylamino Dotetraline is mentioned.

EPO patent application EPO 270947 (1988) describes 8-hydroxy and 8-hydroxy - Methoquinotetralin is disclosed.

EPO patent application EPO 272534 (1988) contains 8-amide compounds Aminotetralin is disclosed.

The references cited herein are disclosures that describe work related to the present invention.

Hjorth, S; Carlsson, Ei son, A): Lindberg, B. (Lindberg, P.): Sa. Sanchez, D.: Bixtron.

H (Yikstron, H,); Arbinodson, L.E. (Arv idsson, L, -E,);/%-7xel, knee (■ackse11. Nilsson, J, L.

G, ), Journal of Neural Transmission (J, Neur al Transm, ).

1982, vol. 55, p. 169.

Mellin, C; Bjork, L , ): Karshin. A (Karlen, A.): Johansson, A. M0ohansson, A, M, ); sample, varnish (Sundel l, S, ): Kenne, L (L, ): Nerlan. Di - Elle (Nelson.

D, L, ); Anden, N.E. (Anden, N, -E, ): /% Tuxel, knee (flacksell.

U, ): Journal of Medicinal Chemistry (J, Wed, C hew, ), 1988, vol. 31, p. 1130.

Cossery, J.M.: Gotulan, Gozlan, H: Spampina to, L:, ): Perdicakis.

C), Guillaumet No (Guillaumet, G, ): Bichi w’y Pichat, L; Hamon, Nym (M) ), European Journal J. Pharmacol, ), 1987, pp. 140-143.

Summary of the invention Formula T [wherein R is hydrogen or halogen, R1 is (a) -Hydrogen, (k) -C3NRsRa, (b) -0R4, (1) -050 2CR3, (c)-5R4, (d)-CONRsRs, (i)-SO2NR5R,, (j)-5-oxasilyl, R2 and R1 are independently (e)-(CH2), -(C3-CJ-croalkyl, (f)-(CH2)m -(C3-C8)nochloroalkenyl, (g)-(CH, ), -aryl, (h)-<CH2), -CO2R1, (i)-(CH, ), -OR4, R4, R5 and R6 are independently and X is (CH:), p = 0.1], the chemically acceptable acid addition +IrJ salt.

However, if R1 is hydroxy or methoxy and R2 is hydrogen, the disease , anxiety disorders, panic attacks, obsessive-compulsive disorder, senile dementia, and emotional disorders related to dementia disorders. Useful in treating central nervous system disorders including and stimulating sexual activity. Moreover, the present invention Selected compounds are useful in alleviating aggressive behavior, delirium and impotence It is. Furthermore, the selected compounds of the invention are anti-diabetic, anti-obesity, and anti-hypertensive. It is useful as a blood pressure drug and is also used to treat impotence.

Compounds of the invention are also useful as antitussive agents.

Methods of preparation of these compounds, their pharmaceutical uses and drugs using such compounds Agent compositions constitute a further embodiment of the invention.

The object of the present invention is to provide therapeutic compounds, especially compounds with therapeutic activity in the central nervous system. It is to provide a compound. Another purpose is to detect 5-HTI receptors in animals, including humans. The purpose of the present invention is to provide a compound having an effect on -. Still other objects of the invention for a subclass of dopamine receptors known as D2 receptors. The object of the present invention is to provide compounds that have an effect.

Detailed description of the invention Compounds of the present invention can be identified by referring to the method of writing the name and the structure shown in the appropriate chart. It is identified by two methods: Also, where appropriate, specific Two-body chemistry is displayed on the chart.

In this document, the term in parentheses (C, -Cyu) refers to the compound (C, -C8), for example. It is meant to include compounds having 1 to 8 carbon atoms and isomers thereof. various charcoal The elementary part is defined as follows. Alkyl means an aliphatic hydrocarbon group; For example, methyl, ethyl, D-propyl, isopropyl, n-butyl, isobutyl le, 5ec-butyl, t-butyl, n-pentyl, isopentyl, neko pliers n-hexyl, n-hex/l, isohenol, n-”\butyl, isohebyl, and n- Including branched and unbranched forms such as octyl.

-OR, in which R1 is (C,-C,)alkyl refers to an alkyl group bonded to the rest of the molecule by an oxygen, e.g. Toquine, etquine, n-prophoqui/, isopropoquino, n-butoquino, isobutoquine quin, 5ec-butoquino, t-butoquino, n-pentoquino, isopentoxy, n eo-pentoquino, n-hexoquino, isobutquine, n-hebutoquino, isoheb Toquino, and branched or unbranched forms such as n-octoquino.

Alkenyl means an aliphatic unsaturated hydrocarbon group having a double bond, e.g. Ethynyl, l-methyl-1-ethynyl, 1-propenyl, 2-propenyl, 1- Butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-butenyl, 1-pene tenyl, allyl, 3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl 3-methyl-1-pentenyl, 3-methyl-allyl, 1-hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, 1-methyl-4-hexenyl, 3-methyl-1-hexenyl, 3-methyl-2-hexenyl, 1-hebutenyl, 2-hebutenyl, 3-hebutenyl, 4-hebutenyl, 1-methyl-4-hebutenyl 3-methyl-1-hebutenyl, 3-methyl-2-hebutenyl, 1-octenyl branched and unbranched forms such as octenyl, 2-octenyl, or 3-octenyl. Including.

Cycloalyl compounds are, for example, /clopropyl, cyclobutyl, cyclopentyl, Saturated cyclic hydrocarbons such as cyclohexyl, cycloheptyl, or cyclooctyl means an elementary group.

Bet means a 5-atom hetero-σ ring containing nitrogen, carbon, and in some cases oxygen. do. It is 2-pyrrolyl, 2-oxazinol, 2-imidazolyl, 2-ox Contains sacilinyl and 2-imidazolinyl.

Halogens include bromine, chlorine, or fluorine! Taste.

It will be apparent to those skilled in the art that the compounds of the invention contain chiral radicals. Within the scope of the invention means that all enantiomeric or diastereomeric forms of a compound of formula I are pure. pure form or a mixture of enantiomers or noastereomers Included as Compounds of formula I have an aliphatic ring moiety containing a ring adjacent to the nitrogen atom. Contains 1 to 3 asymmetric carbon atoms, including carbon atoms. Therapeutic properties of these compounds The quality depends, to a greater or lesser extent, on the stereochemistry of the particular compound. pure enanci Omers, as well as mixtures of enantiomers or diastereomers, are included in the invention. Within range.

Both organic and inorganic acids can be used to improve the pharmaceutically acceptable non-toxicity of the compounds of the present invention. Can form toxic acid addition salts. Examples of acids are sulfuric acid, nitric acid, phosphoric acid , hydrochloric acid, citric acid, acetic acid, lactic acid, tartaric acid, palmoic acid ), ethanedisulfonic acid, sulfamic acid, succinic acid, cyclohequinyl sulfur Mention may be made of minic acid, fumaric acid, maleic acid, and benzoic acid. These salts can be easily prepared by methods known in the art.

Compounds of the invention can be prepared by the following methods described below and outlined in the appropriate charts. Obtained by one.

Sensade A In step 1, substituted 2-tetralone A-1 is subjected to reductive amination. The procedure is applicable Known in the art. In step 2, when R8 is Metquin, procedures known in the art A-2 may be demethylated to obtain A-3.

Chart B In step 1 of Char) H, phenol B-1 is added according to methods known in the art. , reacted with trifluoromethanesulfonic anhydride in the presence of a solvent to form a trifluoride Obtain rate B-2. Phenol B-1 was prepared by the method shown in Chart A. They can be prepared from appropriately substituted tetralones.

In step 2, a solution of B-2 in a solvent mixture such as methanol/DMF is - Carbon oxide gas, palladium acetate, triethylamine and 1,3-bis(diphthalate) carboxylic acid methyl ester B-3 by reacting with propane Form.

In step 3, methyl ester B-3 is hydrated with sodium hydroxide in methanol. Disassemble.

Then, in step 4, the obtained acid B-4 is dissolved in a solvent such as DMF. Coupling with ammonia in the presence of nophosphonate and triethylamine Carfoxamide B-5 is obtained.

Sensade C In step 1, acid chloride C-1 is treated with ethylene in the presence of aluminum trichloride. Thus, Tetralone C-2 is obtained. C-2 is reductively aminated with a suitable amine. to obtain C-3. Next, C-3 was dissolved in a solvent such as THF, and t-butyl chloride was added. amide C In step 1, tetralone D-1 is mixed with ethylene glycol in the presence of an acid catalyst. Ketal D-2 is generated by stirring. In step 2, D-2, Yo A mixture of uride 14(1), sodium trifluoroacetate and N-methylpyrrolidone By heating the compound to 160°C, 8-trifluoromethyl compound D-3 can be easily obtained. In step 3, tetrarotide is obtained by hydrolysis using an acid aqueous solution. Obtain D-4. In step 4, this is mixed with a suitable amine acetic acid and an anoborohydride. Reductive amination to give D-,5 using known procedures of mixing sodium chloride. .

1,000--1-E In step 1, halogen is removed using a base according to alkylation methods known in the art. Alkylating the 2-position of substituted 2-tetralone E-1 by reaction with alkyl Then, E-2 is manufactured. In step 2, E-2 is subjected to reductive amination to form E-3. Manufacture. When R1 is methoxy. In step 3, E-3 is processed by methods known in the art. Depending on the order, tax methylation yields E-4.

Chart F In step 1,! In the presence of which base is the substituted tetralone F-1, L D, A r; , and dimethyl carbonate to produce F-2. In step 2, F-2 is reacted with an alkaline halide in the presence of a base to produce F-3. engineering In Step 3, F-3 is decarboxylated to produce F-4. In step 4, F- 4 is subjected to reductive amination to produce F-5. If R1 is Metkin, use F-5 as Demethylation yields F-6.

Chart G In Step 1, Bromotetralone G-1 (C-2) is added using typical conditions. Reductive amination with the appropriate amine yields G-2. In step 2, G-2 is converted to t-butyl Treatment with lithium followed by dimethylformamide yielded aldehyde G-3. Ru.

In step 3, this aldehyde is condensed with rTO3MIcj under typical conditions. Oxazole G-4 is obtained.

Thousand Seventh H In step 1, substrate H-1 is treated with t-butyllithium and then with sulfur dioxide. to obtain sulfonic acid H-2. In step 2, H-2 is treated with sodium hydroxide. After obtaining H-3, in step 3, it is treated with N-chlorosufnonimide to obtain sulfonyl chloride H-4 is obtained. In step 4, H-4 is treated with ammonia to form H-5. obtain.

In step 5, this is hydrolyzed with an acid aqueous solution to form H-6. In step 6, typical Reductive amination using appropriate conditions and appropriate amines yields H-7.

Chart■ After treating bromo compound 1-1 (C-3) with t-butyllithium, trimethyl Treatment with nlyl thiocyanate provides I-2.

Chart J Furthermore, the compound of formula I [wherein R 1 can be converted into an arylcarbonylco compound. In step 1, J- 1 in a solvent such as toluene in the presence of ethylmagnesium bromide. Reaction with virol adduct gives J-2.

In step 2, J-2 is treated with acetic acid, platinum oxide and anhydrous ethanol under a hydrogen atmosphere. Reaction with a suitable amine in the presence of the compound J-3 provides compound J-3.

Formula I where R is hydrogen, -0Ra, or -5R63 The law is chart, A1. This is illustrated by the methods shown in E and F. These people Each of the methods utilizes a 2-tetralone derivative as a starting material.

Methods for performing reductive amination are known in the art, and such methods are may also be used in the above procedure. Some of these methods use tetrahydrofuran /with amine in the presence of /sodium anoborohydride and glacial acetic acid in methanol. Including reacting.

8-amide compound B-5 or C-4 can be prepared using conditions known in the art. By reacting with ``Burgess salt'', the corresponding 8- Burgess salts, which can be converted into compounds, are organic syntheses (O rganicSynthesis), volume 56, page 40. can be manufactured.

When practiced clinically, the compounds of the invention are typically combined with a pharmaceutically acceptable carrier. The active ingredient can be added as an iM base or as a pharmaceutically acceptable non-toxic acid. Contain as salts, e.g. hydrochloride, lactate, acetate, sulfamate, etc. Depending on the pharmaceutical composition, it can be administered orally, rectally or by injection. Coming Use and administration to patients to be treated clinically will be readily apparent to those skilled in the art.

For therapeutic treatment, suitable daily doses of the compounds of the invention include 1. ~2000mg, preferably 5Q~500mg, and 0.1~500mg for parenteral administration. 100 mg, preferably 0.5-50 mg.

Compounds of the invention in which R1 is in the 8-position of the aromatic ring have little or no dopaminergic activity. It is a highly selective 5-HTIA receptor agonist with no 5-HTIA receptor agonist. Main departure 5-HA in the in vitro binding data shown in Table 1 for compounds with The IC5o ratio of dopamine D2 to IA to 5-HTI receptors is Showing selectivity. In addition, the compounds of the present invention have high oral efficacy and a long duration of action. It has been shown that All of these characteristics are advantageous for effective clinical treatment. Ru.

The usefulness of the compounds of the invention in treating central nervous system disorders has been determined by behavioral, physiological and and biochemical tests. These methods are combined as shown below. Inhibition of 8-0H-DPAT binding in mono/nate. The effect is DP AT given as the nM dose required to inhibit 50% of the reaction (IC5°). this In tests, it binds to 5-hydroxytryptamine (5-HTIA) receptors. Measure ability.

Hypothermia y”-: starting from a dose of 30 m g / k g in 4 mice. Test compounds are injected subcutaneously. After 20 minutes, the body temperature has decreased by 2°C or more. Count the number of things.

If all four animals reach the criterion, the drug is considered "active" and the following The readings are taken 60 minutes and 120 minutes after drug administration. average body temperature The duration of statistically significant drug effects is expressed in minutes. All of For “active” compounds, doses that do not reduce body temperature by 2°C in any animal. The dose is decreased in Q, 51 og intervals until . The effect is Spearma mg/measured by Spearman-Karber statistics. ED50 in kg (required to reduce temperature for 2 out of 4 mice) given as required dose).

Sympathetic nerve discharge (SND) method: SND in cats anesthetized with Floralose was 50 % reduced and crossed over the dose range tested (0,001-1.0 mg/kg, intravenous). This is the intravenous dose (mg/kg) that maximally inhibits sensory nerve activity.

BP SND/MAX method: tested dose range (0,001-1,0mg/kg, 50 SND, expressed as a percentage of the control blood pressure of the same animal observed with % reduction in cats anesthetized with Floralose at doses that maximally reduce blood pressure. It's blood pressure.

CNS and antihypertensive biological data are shown in Tables 1 and 2, respectively.

CNS biological data Example Compound 0-HT+A binding method Hypothermia method lTo No, IC5o ( nM) ED, o (mg/kg) 2 2-1 26 2.3 (>100 (IC5゜(D, rese) nm)) in pigs Table■ Antihypertensive biological data Example Compound 3ND EDso Maximum reduction %BD Maximum reduction\0. No , SND% (SND EDso BP control) 2:”1>, 296 71.0 1 1-3 0.62 31.0 75.0 68.7 The compound of the present invention It is useful as a urinary agent, antiobesity agent, antihypertensive agent, and antitussive. These compounds Not all substances have all of these pharmacological activities, so certain Regarding the usefulness of a compound: =, as can be determined by one skilled in the art using the following tests: Wear.

All KKA' mice used for screening were T.Fran ( T. Fujita et al. [Diabetes, vol. 32, 804-10 (1983)]. do. Screening was performed on groups of 6 animals per group. Implemented.

Pretreated non-fasting blood glucose (NFBG) samples were prepared using the methodology previously described. , measured 5 days before starting the screening experiment. Using these blood sugar levels, Average blood! ! Groups of animals with equal levels of NFBG <250 mg,’d Exclude mouse I. On the 8th day, select the compound to be tested on the map. It is mixed in powdered powder (Purina (Purina) 5015). compound is bait Mix at a rate of 1 mg per gram. Generally, 300g of drug-containing rice cake prepared for each group. Mice fed only powdered mochi serve as a negative control. .

In addition, in each screening experiment, Tig+, ltazone (T. furan (T, Fujita et al., supra) as a positive control (05-1.0 mg per gram of feed). used as

Initial body weight and weight of the comb are measured at the first sen. persists over the duration of the experiment. Place enough food into the container. To adapt mice from pelleted to powdered food. For this purpose, mice were fed powdered food for 9 days before being used for screening. Ta. Fourth cycle of treatment, the NFBG samples were again weighed along with the nod weight and body weight. Ta. By measuring the food intake, we determined the amount of food given to the mice over the study period. The average dose (mg/kg) is determined and the effect of the compound on food intake is evaluated.

Tolerance and activity are determined by the following criteria.

A, negative control The second group should not show any significant change (p<,05) before and after treatment. If the engineered blood sugar level decreases significantly, the experiment is not valid.・0B, positive counterargument. The second group showed a significant decrease in mean blood glucose levels before and after treatment. and others! = Yes. If the activity of the second group is lacking, the experiment is still invalid □C 7 Negative control v5 Positive control This contrast must be significant. As expected, both control groups further guarantees that it behaves accordingly.

D. Compound The activity of a compound is based on several criteria: 1) the average blood glucose level before and after treatment; Significant decrease in bell.

2. Negative control vS compound If these groups are not similar, this contrast determine which compounds are required to be recognized as active. Two and two that can be decided.

■, anti-obesity activity Sprague-Daurley Rat of Upnoyon They are housed individually and given food and water ad libitum. Food intake is measured daily. these Animals were given 100 mg/kg of compound in Tween 80 or 20 Administer 0 mg,'kg orally. Controls included equal amounts of (0,25) Tween (T veen) Give 80. The daily food intake of treated animals is lower than that of control animals. The compound is considered to have appetite suppressant activity if it is within 4 grams less than the It will be done.

Experimental procedure Without further elaboration, one skilled in the art can, using the foregoing description, implement the present invention in its fullest scope. It is believed that this can be implemented to a certain extent. The detailed examples below are How to prepare various compounds of the present invention and how to use the method of the present invention However, these examples are merely illustrative, and The above disclosure should not be construed as limiting in any way. skilled in the art The person responsible for making appropriate modifications to the above procedure, both with regard to reactants and reaction conditions and procedures, shall Recognize changes immediately.

C1-trifluofmethylsulfonate (B-2, Chart B) CH2C12 7-(1-hexahydroazepinyl)-5,6,7,8-tetra in 100 mL A solution of 2.1 g of hydro-1-naphthalenol and 4.06 g of pyridine was stirred. , cooled to 0° C. under nitrogen atmosphere. Trifluoromethanesulfonic anhydride (4, 32 g) was added dropwise over 20 minutes. Warm the yellow solution to room temperature for 45 minutes Stirred. TLC of an aliquot showed no starting material present. Ta.

The reaction was quenched with saturated N a HCO3 to pH>8. Add this mixture to chloride Extracted with tyrene. The organic layer was washed with water, brine, and dried (with MgSO4). Dry, filter and concentrate to an oil. Flash on 1 kg of silica gel chromatography and extraction with hexane/ethyl acetate (11) (45 mL Both portions were collected to give a pale yellow oil (3.05 g, 95%).

Preparation 2 7-(1-hexahydroazepinyl)-5,6,7,8-tetrahydro Naphthalene-1-carboxylic acid methyl ester (B-3, Chart B) methanol 7-(1-hexahydroazepinyl)- in 9 mL and DMF 2 T mL 5,6,7,8-tetrahydronaphthalene-1-trifluoromethylsulfone A solution of 2.9 g of triethylamine and 2.13 mL of triethylamine was added to the solution using nitrogen rinsing. Degassed for 10 minutes. This solution was then bubbled through carbon monoxide for 10 minutes. Ta. During this time, 172 mg of palladium acetate and 379 m g solution was dissolved and degassed with nitrogen for 10 minutes. Add this solution to the reaction and Heat to 0° C. and bubble through carbon oxide gas overnight. Aliquot saturated NaH Treatment with C○, and EtOAc did not show any starting material. This solution Nitrogen was bubbled through and then quenched with saturated NaHC○. this mixture Extract with ethyl acetate (3X 500ml) and wash the combined organic layers with brine. and dried (over MgS04), filtered and concentrated to an oil. silica Furanoyu chromatography was performed using 400 g of gel, and hexane/acetic acid ester was used. Extraction with chill (1:1) gave an oil (1.56 g, 71%).

Sea 1-carboxylic acid (B-4, Char kB) 7- in methanol 10mL A (1-hexahydroazepinyl)-5,6,7,8-tetrahydronaphthalene/- 1~Carboxylic acid methyl ester 1.56g, 12N Na○HL 57mL, water 1 ．． 57 mL of the mixture was refluxed overnight (at 70-80°C).

TLC showed no starting material remaining. This mixture was purified with 5NHC] C white solid neutralized to H5-6 and condensed to dryness using toluene and methanol. The shapes were collected and used in their crude form.

48-bromo-2-tetralone (C-2, 1000 C) manufactured by YA Groi (A, H, Horn) No Shiny Groi (C, J, Groi ), Dijkstra (D, Dijkstra), and A.A. Chi Margoo (^, 13. Muider).

Naru of Medicine/Naru Chemistry (J, Wed, Chew, ), Vol. 2H, p. 825 (1978f:). , 2-bromophenylacetyl chloride is substituted.

8-bromo-2-doutralone <29g), ethylene glycol (24g), p- Toluenesulfonic acid (0.5 g) and benzene (250 ml) were azeotropically The mixture was heated under reflux for 16 hours while removing water. Cool the second solution and add sodium carbonate. The mixture was extracted with an aqueous solution of sodium chloride, water, and then brine. Dry the second solution with anhydrous sodium sulfate. Dry and remove the solvent with a funnel.

:iW6 8-trifluoromethyl-2-(spiO-1,3-nooxolane-2 -yl)tetralin (D-3, child key)D) 8-bromo-2-(spiro-13-7-year-old solan-2-yl)tetralin (12 , 4g), heptorium trifluoroacetate (25g), copper iodide <1) <17.5 g) G: PiN-methylbi=1 nodone (368ml) was heated to 160℃ under nitrogen. It was heated and kept there for 4 hours. Cool this solution and add nitil and hemokan. added. The second slurry was filtered through diatomaceous earth, and the eluent was diluted with *C3X'' and (saline solution). Washed. The solution was dried over sodium sulfate and the solvent was removed under vacuum. . Perform flash chromatography and elute with ether/hexane (1.9) Then, 9.9 g of pure liquid 8-! -Rifle comethyl-2-(spiro-1,3- )oxolan-2-yl)tetralin (9.9g), water (15ml), THF (120 ml), and 2NHC] aqueous solution (12 ml) at 50°C for 15 hours. did. This solution was cooled, extracted with Niel, and the organic layer was dissolved in aqueous sodium bicarbonate. solution and then brine. Dry with anhydrous sodium sulfate to remove the solvent. , a clear liquid was obtained.

Preparation 8 1.2.3.4-tetrahydro-2-oxo-1-(2-propenyl) -Aphthalin (E-2, Chart E) and 1.2.3.4-tetrahydro-2 -oxo-1,1-di(2-propenyl)naphthalene in 75 ml of THF in a 30 round bottom flask equipped with a gas inlet and a septum. Add 36.7 mL of LDA to a solution of 7.3 g (50 mmol) of 2-tetralone. (55 mmol, 1.5 M from cyclohexane) at -30°C under nitrogen atmosphere. Added. This solution was heated to 0°C over 30 minutes, and 5.5 mL of allyl bromide was added. (65 mmol) was added. The reaction was monitored using TLC analysis. room temperature After stirring for 24 h at Quenched. After removing THF under reduced pressure, the mixture was dissolved in ethyl acetate (2xl L), the combined organic layers were washed with brine, dried (MgSO3), Filter and concentrate in vacuo. The crude product was mixed with 800 g of silica gel 60 (2 Liquid chromatography over 30-400 m) of IL hexane followed by by eluting with 5 L of 5% ethyl acetate/hemosan and collecting 40 mL fractions. I refined it.

Fractions 65-82 contain 3.1 g (33%) of pure 1.2.3.4-tetrahydro -2-oneso-1-(2-propenyl)-naphthalene is given as a pale yellow oil. I got it.

'HNMRCCDCh, TMS) Near, 27-7.16 (m, 4H) +5.8 1-4.95 (m, 3H): (S, 3H): 3.54-2.45 (m, 7H ).

JR (Film) Shi,,, 1717.1640 and 1582cm-'.

MS: M-185, M ion is m/z 168.145.128.117°T LC (silica gel GF), R9=051. in hexane/ethyl acetate (41).

Both parts 41-64 contain 4.2g (37%) of pure 1.2.3.4-tetrahydro -2-oxo-1,1-di(2-propenyl)naphthalene as a colorless oil I gave it to you.

! ! 1.2.3.4-tetrahydro-8-methoxy/-2-oxy-1-(2 -propenyl)-naphthalene and 1.2.3.4-tetrahydro-8-methoxy -2-oxo-1-di(2-propenyl)-naphthalene (E-2, cheat E) THF25Om in a 30 round bottom flask with gas inlet and septum To a solution of 8.8 g (50 mmol) of 8-methoquino-2-tetraO in L, 40 mL of DA (60 mmo+, 1.5 M in cyclohexane) was added under nitrogen atmosphere. It was added at −30° C. under air. This solution was heated to 0°C over 30 minutes and 5 mL (75 mmol) of Ril 6 was added. Monitor the reaction using TLC analysis. I tarred. After stirring for 3 hours at room temperature and 1 hour at 40°C, the reaction mixture was dissolved in 10% sulfuric acid. Quenched with sodium hydrogen to pH 2-3. After removing THF under reduced pressure, this The mixture was extracted with ethyl acetate (2xmL) and the combined organic layers were washed with brine. , dried (MgSO,), filtered and concentrated in vacuo. The resulting oil (small By LC purification in scale experiments, approximately 3b/22b=4) can be purified. Instead, it was used in the next step. A small amount of the crude product (<Ig) was collected for analytical purposes. , Chromatograph X- on 185 g of 7 Ricagel 60 (230-400 m) and purified by eluting with hexane 71 acetone (19:1) . The TLC homogeneous fractions were combined and evaporated in vacuo. Pure title compound pale yellow It fluoresced as an oily substance.

1,2.3.4-tetrahydro-8-methane-2-oxo-2-(2-prope physical property data of naphthalene Tsuta HNMR (CDC) 3. TMS): 7.21-6.76 (m, 3 H): 0.73-4.87 (m, 3H): 3.82 (s, 3H): 3 ．． 88-3.82 (m, LH): 3, 32-2.43 (m, 6H).

JR (film): Shim, 1712.1640.1586cm-'.

MS, calculated value (CI4HI602): 216.1150° Actual value 216. 1151° Elemental analysis °meter *’l (C+4H+5Oz): C, 77, 75; 8.7.46 ゜Actual measurement value C, 77, 56: H, 7, 68゜) TLC (silica gel GF): R,=0.32. in hexane/acetone (4.1).

! 1.2.3.4-tetrahydro-8-methquin-2-oxo-1-di(2 −Propenyl) naphthalene physical property data 'HNMR (CDCl2.TMS): 7.22-6.73 (m, 3H): 5.44-4.77 (m, 6H): 3.85 (s, 3H): 4.0-2.5 2 (m, 8H).

IR (film): shi, , 1712.1639 and 1582 crn-' .

MS, calculated value (C+□H2゜02)・256.1463゜actual value・256.14 70° Elemental analysis calculated value (CI?H2O02): C, 79,65; H, 7,86 ゜Actual measurement value: C, 79, 56: H, 8, 29゜ TLC (silica gel GF): R ,=0.46. in hexane/acetone (19+1).

Preparation 10 1.2.3.4-tetrahydro-5-methquin-2-oxo-1-( 2-propenyl)-naphthalene (E-2, Chart E) and 1.2.3.4- Tetrahydro-5-methoxy/-2-year-old xo-1,1-di(2-propenyl)- THF4 in a 30 round bottom flask with naphthalene gas inlet and septum Dissolution of 5.3 g (30 mmol) of 5-methoxy-2-tetralone in 5 mL 22 mL of LDA (33 mmol, 1.5 M in cyclohexane) was added to the solution under nitrogen It was added at −30° C. under atmosphere. The second solution was heated to 0℃ over 30 minutes, and the odor was removed. 3.4 mL (39 mmol) of allyl chloride was added. Using TLC analysis, the reaction I monitored it. After stirring for 5 hours at room temperature, the reaction mixture was diluted with 10% sodium hydrogen sulfate. quenched to pH 2-3 with After removing the THF under reduced pressure, the mixture was dissolved in vinegar. Extract with ethyl acid (2X IL), wash the combined organic layers with brine, and extract (M g S O4), filtered and concentrated in vacuo. The obtained oil was mixed with 8 Liquid chromatography on 00g silica gel 60 (230-400m) and dissolved in IL hexane and 5 L hexane-ethyl acetate (19:1). Purification was performed by extracting and collecting 40 mL fractions. Fractions 45-87 are 2. 5g C32,5%) of pure 1.2.3.4-tetrahydro-5-methoxy/-2 -oxo-1,1-no(2-propenyl)naphthalene as an almost colorless oil Both portions 88-140 contain 1.07 g (6.5% I) of pure 1.2.3 ．． 4-tetrahydro-5-methquine-2-oxo-1-(2-propenyl) naph Talen was given as a pale yellow oil.

'HNMR (CDCI 3. T~Is): 7.23-6.77 <m, 3H ): 5.75-4.97 (m, 3H): 3.85 (s, 3H); 3.52- 2.49 (m, 7H).

IR (Film>: Sea, -1717, 1641 and 1586 cm-'.

MS: M-216, other lines are m, /z175.159.147゜TLC (Silica gel GF): R, = Q, 42. In hexane-ethyl acetate (41) Preparation 11 1.2.3.4-tetrahydro-8-methquin-1-(cyclopropylene) methyl)-2-oxo-naphthalene (E-2, Chart E) gas inlet and 50 mL of THF in a 30 mm round bottom flask with a septum: 8-methoxy/-2 -To a solution of 3.52 g (20 mmol) of tetralone, add 4.3 mL of LDAl. (22 mol, 1.5 M in cyclohexane) at -30 °C under nitrogen atmosphere. Added. This solution was heated to 0°C over 30 minutes, and 2.4 mL of allyl bromide was added. (24mmo I) was added: TLC analysis was used to monitor the reaction.

After stirring for 2 hours, TLC analysis showed very little reaction.

Therefore, the reaction mixture was treated with 1.1 mL (12 mmo) of allyl bromide, The two mixtures were heated to reflux for 72 hours. The second reaction mixture was diluted with 10% sodium hydrogen sulfate. The mixture was quenched to pH 2-3 using After removing THF under reduced pressure, this mixture was Extracted with ethyl acetate (2x1L) and washed the combined π organic layers with brine (MgS After drying (over O4), filtering and condensing in vacuo, the resulting oil was mixed with 400 g of 7+51 Kakeru 60 (with liquid chromatograph nol 2 at 230-400mJ2) and eluted with hemo←acetone (91) and collected 40 mL fractions. and purified.

The two homogeneous parts were combined by TLC and compressed in vacuo to give 4.5 g (97.8%). The pure title compound was obtained as an almost colorless oil.

'HNMR (CDCl2.7M5): 7.20-6.75 (m, 3H): 3 ．． 91 (t, J=7Hz, IH) + 3.81 (s, 3H) + 3.33-1.6 2 (m, 6H); 0.64-0.09 (m, 5H).

IR (film): v-11711Cm-'.

MS: Calculated value CC1581802): 230.1307° Actual value 230. 1290° Elemental analysis Calculated value (C+4H+5Oz): C, 78,23; H, 7,88° Actual measurement Value: C, 77,93: H, 8,06° TLC (silica gel GF): R, = 0 ．． 46. In hexane-acetone (4:1).

Preparation 12 1.2.3.4-tetrahydro-8-methquin-2-oxo-1-na Phthalene-carboxylic acid methyl ester (F-2, Chart F) gas inlet and 8-methoxy in 20 OmL of THF in a 30 mm round bottom flask with a septum. LDA86,7 was added to a solution of 17.6 g (0.1 mo) of N-2-tetralone. mL <0.13 mo I, 15 M in cyclohexane) under nitrogen atmosphere - Added at 30°C. This solution was heated to 0°C over 30 minutes and dimethyl carbonate was added. 84.3 mL (1.0 mol) of Nate was added. R flowed for 24 hours (bath temperature 7 After 0° C.), TLC analysis showed no starting material remained. this reaction The mixture was quenched with 1N HCl to pH 2-3. THF was removed under reduced pressure Afterwards, the mixture was extracted with methylene chloride (2x IL) and the combined organic layers were edible. Washed with brine, dried (over MgS04), filtered and concentrated in vacuo.

The obtained oil was evaporated as a liquid on IKg of silica gel 60 (230-400 m). Chromatography was performed using hexane IL, 2 L of 10%, and 8 L of 20% acetic acid ethyl chloride. Purification was achieved by eluting with chill/hexanes and collecting both 500 mL aliquots. picture Minutes 7 to 9 gave 0.5 g of 2% yellow old fall material, which was determined by 'HNMR. It was shown to be a 1,1-7 carbomethoquino product. Ryobu 11-22 , 21.1 g (90%) of pure title compound as a yellow oil.

'HNMR (CDCh, TMS): 7.28-6.77 (m, 3H); 4 ．． 72 (s, LH): 3.80 (s, 3H): 3.72-2.17 (m, 7H).

IR (Film): Sea, l 700, 1718 and 1588 cm-'.

MS: lvl"234. Other ions are m/z 202.191.174.14 7.131°115,. 103.91° Elemental analysis, calculated value (CI3H1401): C, 66, 65: H, 6,02゜actual Measured value: C, 66,49: H, 5,93° TLC (silica gel GF): R, = 0. 33. in hexane/ethyl acetate (3.1).

Preparation 13 1,2.3.4-tetrahydro-8-methoquino-2-oxo-3-( 2-propenyl)-1-naphthalene-carboxylic acid methyl ester (F-3, cha -) F) 1 in 108 mL of THF in a 30 mm round bottom flask equipped with a dropping funnel. ．． 2.3゜4-tetrahydro-8-methquine-2-oxo-1-naphthalenecal A solution of 10.2 g (43.5 mmol I) of boronic acid methyl ester was added to 63.8 mL (95.7 mmol) of LDA (1.5 M in cyclohexane), It was added dropwise at -30°C to -40°C under a nitrogen atmosphere. This solution was heated to 0°C, 6.0 mL (69.6 mmo) of allyl bromide was added. This mixture was After stirring for 1 hour at room temperature, TLC analysis showed that no starting material remained. did. The reaction was quenched with 3N hydrochloric acid to pH 2-3 and quenched with ethyl acetate (2X I Extracted with L). The combined organic layers were washed with brine and dried (over MgSO,). S-l! ! and a-condensed in vacuo. Obtained. 800g of rice cakes The hexane - Purification by elution with acetone (31) and collecting 40 mL fractions.

Both fractions 36-63 contain 10.3 g (87%) of the pure title compound as a yellow oil. and gave it.

'HNMR (CDCl2.T~Is) + 7.27-6.76 (m, 3H): 5.89-5.02 (m, 3H) +4.75. 4.59 (two s, I H)+3.80. 3.81 (2 s, 6H): 3.32-1.64 (m, 5H).

IR (Film) Shim-z1751.1717 and 1589cm-'.

MS ~1-274. Other ions are m/z 242.233.214, 201.1 87°173.159.145° Elemental analysis: Calculated value (CI6HI804): C, 70,05:H, 6,61°Actual measurement Value: C, 69,73; H, 6,65° TLC (silica gel GF) R, = 0.3 4. In hexane-ethyl acetate (3:1).

Preparation 14 1.2.3.4-tetrahydro-8-methoxy-3-(2-propenylate) )-2-oxo-naphthalene (F-4, Chart F) 26.3 mL DMSO and 1.2 of 10.3 g (37.6 mmol) in 1.1 mL of water. 3.4-tetrahydro-8-methquin-2-oxo-3-(2-propenyl)- 1.9 g (45.1 mm ol) of lithium chloride was added. Heat the reaction mixture at 125°C (bath temperature) for 5 hours. did. TLC analysis showed that none of the starting material remained. Cooled to room temperature and extracted with ethyl acetate (IL). Organic layer with 10% calcium sulfate Wash with aqueous solution (in a manner sufficient to remove DMSO from the organic layer) and (MgS O4), filtered and concentrated in vacuo. The crude product was added to 800 g of silica. Liquid chromatography on Kagel 60 (230-400m) Purify by eluting with 3:1 chlorine-ethyl acetate and collecting both 40 mL aliquots. Manufactured. Fractions 26-53 provide 7.65 g (94%) of the pure title compound as a yellow color. It was given as an oil.

'HNMR (CDCl2.TMS): 7.18-6.74 (m, 3H) + 5 ．． 95-4.95 (m, 3H) + 3.82 (s, 3H); 3.70-2.0 8 (m, 7H).

TR (Film) Niji,,, 1756.1710 and 1589 cm-'.

MS: M-216, other ions m/z 185.174.159.146. 134°115.104° Elemental analysis "Calculated value ('C14H + gOz): c, 77, 75: H, 7, 4 6゜ Actual measurement value C, 77, 21: H, 7, 65゜ LC (silica gel GF): R ,=O153, in hexane-ethyl acetate (3:1).

Preparation 158-Aminosulfonyl-2-(spiro-1,3-nooxora/-2-y ) Tetralin (H-2, Chart H) Magne/Rum (3.83 g, 0.158 mo+) was dissolved in dry tetrahydrofuran (2 50 ml) and coated with 8-buOmo2-(subio-1,3-dioki7ran- 2-i/l/)tetralin (28.29 g, 0.105 mol) was added. Yo A few crystals of uride are added and the mixture is heated on a steam bath until the reaction becomes exothermic. The mixture was heated to reflux.

The reaction was stirred at ambient temperature until the reaction subsided. Place the reaction mixture on a steam bath and The mixture was refluxed for an additional 40 minutes. Needle stock (needle 5tock) ) and cooled to -15°C. Rejected. Sulfur dioxide was bubbled through the solution for 30 minutes. Add this mixture The solution was diluted with ester and washed with dilute hydrochloric acid and brine containing sodium bicarbonate.

The solution was dried (~fgsOt) and the solvent removed under vacuum, resulting in a sulfuric acid The acid remained as a slightly off-white solid (27.26 g).

(H-3, Chart H) Sodium hydride (5.3 g, 50% in oil, 0.11 Rn o I coated with l). The above sulfinic acid in dry tetrahydrofuran (300ml) (26.38 g, 0.104 mol) was added using a did. The two mixtures were stirred at room temperature overnight and then heated to reflux for 15 minutes. This mixture Dilute the compound with 1,000 liters of nonythyl ether and precipitate it while blowing argon onto the surface of the compound. The precipitate was filtered. This compound was washed several times with ethyl ether and dried in vacuo. Upon drying, sodium sulfinate remained as a solid (26.77 g).

(H-4, Chart H) Sodium sulfinate in methylene chloride (400 ml) A suspension of 26,7'7 g, 0.0969 mol) was cooled with ice, and +succinimide (13.75 g, 0.103 mol) was added. this mixture was stirred at room temperature for 2 hours. ether and the mixture was immersed in water and food. Washed with 1 water. The solution was dried (with MgS O4) and the g medium was removed in vacuo. Upon removal, the sulfonyl chloride remains as an amber solid (23.3 g). did.

(H-5, Chart H) Sulfonyluk in tetrahydrofuran (80ml) A solution of loride (23.3 g) in acetone (500 ml) was prepared with aqueous ammonia (1 00 ml) of the water-cooled solution. Remove the water bath and stir the mixture for 2 hours. Ta.

The solvent was evaporated and the residue was dissolved in diethyl ether/tetrahydrofuran and brine. distributed to. This solution was combined with 2% hydrochloric acid, saturated sodium bicarbonate solution and saline solution. Washed twice with Dry the solution (MgSO+) and remove the solvent under vacuum. The sulfonamide remained as a tan solid (19.8 g). Sample (0 , 75 g) from ethyl acetate/hexane to give a slightly off-white color. Crystalline sulfonide (0.68 g, m, p, 127-128°C) was obtained.

Preparation 168-Aminosulfonyl-2-tetralone (H-6, Char)H)8-A Minosulfonyl-2-(spiro-1,3-dioxolan-2-yl)tetralin (18.36g, 0.0682mol) was dissolved in acetone (400ml), p -Toluenesulfonic acid (1.85g, 9.7mmol, 14mol%) was added . The two mixtures were stirred at room temperature for 21 hours. Sodium bicarbonate saturated solution (50 m l) was added and the solvent was removed under vacuum. The residue was diluted with wood and cooled with ice. . The precipitate was filtered, washed with water and dried in vacuo. This compound is ethyl acetate (350-400ml), boil and heat until most of the solids are dissolved, then It was filtered with When hexane is added, crystallization occurs and the ketone forms an orange solid. (10.34 g, m, p, 173-175°C) remained.

8-Trifluoromethylsulfonyl-2-disbirose 2-(1,3-)oxoly Balanoum acetate (2,8 8g, 7mol%), bis(/phenylphosph7))propane (6.81g, 9so %), /isobucobylamine (70.3ml 2.2 equivalents), methanol ( 183mi): H; r with dimethyl sulfoquinide (550ml), in a round bottom flask. I put it in SC. Flush the flask thoroughly with carbon monoxide and then This solution was bubbled. The solution was heated to 70°C and stirred for 4 hours. This solution Cooled and added 400ml methylene chloride and 800ml ether. child The solution was washed with water (4X, 100ml) and brine (400ml) and soaked in anhydrous sulfuric acid. dried with sodium chloride.

The solvent was removed in vacuo and evaporated using ethyl acetate/hexane (25 min. After filtering through a Tsuyu/Licagel plug (6 cm x 30 cm), the solvent was removed and 39 g of the title compound (85% yield) was obtained as an oil.

Preparation 18 (1,2,3,4-tetrahydro-2-oxonaphthalen-8-yl )(2-pyrrolyl)ketone (J-2, Chart J) Dissolve pyrrole (3.17 ml) in toluene (40 ml) and add ethyl magnesium. 0° C. while adding umbromide (15.2 ml of a 3M solution in ether). It was cooled to The solution was heated to 25" and stirred for 30 minutes. Toluene (20 m 1,2.3.4-tetrahydrospiro-2-72-<1.3- dissolved in l) dioxolane)]] methyl naphthalene-8-ylcarboxylate 5.15 g, 20 ．． 8 mmol) was added and the solution was refluxed for 24 hours. Cool this solution and quenched by adding saturated aqueous ammonia chloride solution. ether (100 ml) was added and the solution was extracted. Combine the organic layer with water (2X100ml) , a saturated aqueous solution of sodium hydrogen carbonate (50ml) and a saline solution (50ml) ). Dry over anhydrous sodium sulfate and remove the solvent in vacuo to give a dark color. I got an old one. This was added to a solution of acetic acid/THF, water (31 L), and 50 ’ for 5 hours. After cooling, the solvent is removed in vacuo and the residue is Apply to Kel column (3cm x 40cm) and add ethyl acetate/hexa/(40:60) (methylene chloride is added to dissolve the crystallized product from the column). Ta. Removal of the solvent gave 3.7 g of the title compound (74% yield) as light yellow needle-like crystals. (m, p, 174°C).

Example 1 - Octahydro-1-(1,2,3,4-tetrahydro-8-methoxy -2-7phthalenyl)-azene hydrochloride (A-2, Chart A) MeOH,'TH F (1:1) 1.76 g (10 m mol) and heptamethylene amino, in a solution of 5.66 g (50 mmol) , HO, Ac were added dropwise to adjust the pH to 4-5. The reaction mixture was heated under N2 for 15 Stir for 1 minute, then add 1.26 g (20 mmol) of NaCNBH. .

When the reaction is complete (24 hours) by TLC, is SaOH (25 mL) and H The reaction was quenched by the addition of 2O (200 mL). This solution is CH, CI .

(2X 500 mL), the combined organic 1 was washed with brine and (Mgso ), filtered, and concentrated in vacuo. 400g of silica Liquid chromatography on Kel 60 (230-400m) Purified by eluting with acetone/acetone (51). Homogeneous fraction by TLC Combined and concentrated in vacuo to give the pure compound as an oil. MeOH/HC The HCI salt was formed by using I solution. EtOAc/MeOH(2 , 65 g, 86%) to give the title compound as a white solid. Collected m, p, 211-213°C.

'HNMR (CDCl2.TMS) 7.13 (t, LH): 6.69 (t, 2H); 3.81 (s, 3H) + 3.54 (m, 3H), 3.31-3.1 8 (m, 3H); 2.94-2.67 (m, 4H): 2.17 (m, 2H ): 2.1-1.46 (m, 8H).

IR (Iaull) Niji, 2529.2503.1585.14 70.1463.1453.1251 cm-'.

Elemental analysis: Calculated value (CI8H2□NO・HCI): C, 69,769: 8.9. 108:N, 4.521° Actual value: C, 69,6:H, 9,24:N, 4.65° Substitute an appropriate starting material Using a procedure similar to that of Example 1, except that .

hexahydro-1-(1,2,3,4-tetrahydro-8-methquin-2-naph (tarenyl)-1H-azepine hydrochloride, white solid m, p, 236°-237 ℃.

'HNMR (CDCLs, TMS): 7.12-7.04 (t, IH): 6.71-6.64 (q, 2H) + 3.81 (s, 3H): 3.03-2. 76 (m, 7H); 2.45 (q, LH): 2.0 (m, IH): 1.62 (m, l0H).

IR (mull) 3000.　2600.　2550.　 1590.　1480cm".

Elemental analysis/weighing (i(C+1H25NO'HCI): C, 69,017: H, 8 ,859:N,4.7350 Actual value: C, 68,91:H, 9,04:N, 4.67゜hexahydro-1-( 1,2,3,4-tetrahydro-2-naphthalenyl)-1H-azepino hydrochloride, As a white solid mp, 243-245°C - Compounds 1-3 Example 2 ( 1-hexahydroazepinyl)-5,6,7,8-tetrahydronaphthalene-1 - Rupoxamide (B-5, Chart B) - Compound 2-1゜Ammonia gas, 7-(l-hexahydroazepinyl)-5°6.7.8-te in 30 mL of DMF of trahydronaphthalene-1-carboxylic acid and triethylamine 2.25 mL Whisk through the solution. After 10 minutes, add 1.75 mL of diethylnoanofosuccinate. The solution was stirred overnight while adding and bubbling ammonia through the solution. . Direct spot TLC showed no starting material remaining.

The reaction mixture was evaporated and dissolved in 10 mL of methanol. this mixture was subjected to Furaso/Uchromatography on 200 g of 7-silicon gel, and first the chloro Elute with form, then chloroform in methanol inlet 74 MNHz < 905) was eluted. Homogeneous samples were combined and agglomerated to obtain 1 g of solid.

c crystallized from acetone (Mpt, = 141°C) Example 3 (-)-1,2 ,3,4-teirahydro-2-pyrrolidino-8-promotetralin (C-3, Chart C) - Compound 3-18-bromo-2-tetralone (40g, 177m mol) and pyrrolidine (3 equivalents) with bromocresol glycol as indicator. It was dissolved in methanol (350 mL) along with the sample. Hydrochloric acid (3 parts) in methanol amount) was added. Pyrrolinone (2 eq.) was added and the solution was stirred at 0°C for 30 min. Stirred. Sodium noanoborohydride (2 eq.) was added and the solution was incubated at 0°C. The mixture was further stirred for 1 hour. Stirred at room temperature for 1 hour, then the solvent was removed under vacuum.

Ether was added and sodium carbonate (saturated aqueous solution) was added. Eclipse the ether layer Washed with brine, dried over sodium sulfate, and stripped of solvent under vacuum. . After chromatography, the yield of pure oil was 29 g, 58.5%. there were. The racemate (21,6 g) and D-tartaric acid (1 eq.) were dissolved in acetonitol. Dissolved in Lil (1800 mL) and methanol (50+TIL). obtained Recrystallize the white solid from acetonitrile until the optical rotation of the salt is constant. did. [αko”=+34.07°, 165.0-1665℃mp, as oily substance The yield of the title compound was 2 g. [α]D25-carfoxamide (C-4, Chart C) - Compound 4-1(+)-8-bromo-2-pyrrolidinotetralin ( 1.84 g, 6.57 mmol) was dissolved in tetrahydrofuran (13 mL), Cooled to -78°C. t-Butyllithium (1.7M in hexane, 2.1 eq. ) was added. After 10 minutes, trimethyllinyl isocyanate (2.5 equivalents) was added. added. After 10 minutes, the bath was removed and the solution was allowed to warm to room temperature. sodium carbonate (saturated aqueous solution) was added and the product was extracted with nityl/chloroform. organic The layers were washed with water, brine, then dried over sodium sulfate. solvent under vacuum Stripping gave a white solid. Recrystallized from acetonitrile, 63 g (39.3%) of the hydrochloride salt of the title compound was obtained as white needle-like crystals. 22 0.0-224.0℃. [α]D25=-1-90.62° (Light on hydrochloride, 228.0-230.　D℃mp).

A procedure similar to that of Example 4 was followed except that the appropriate bromotetralin was substituted. By using it, you can get the following:

(>4.2.3.4-tetrahydro-2-pyrrolidino-naphthalen-8-yl- Carboxamide (mp228.5-230.5℃)C-)-1,2,3,4-te Trihydro-2-(1-piperinonyl)-naphthalen-8-ylcarboxami (mp229℃) (-)-1,2,3,4-tetrahydro-2-(1-piperinonyl)-naphthalene -8-yl-carboxamide (mp229℃) The above compound (〒)-1,2,3,4-tetrahydro-2-(1-bilorinyl ) naphthalen-8-yl-carboxamide and its salts, methods for preparing the compounds; The methods and methods of using the compounds therapeutically represent the best mode of carrying out the invention.

king! Chart A -IA-2 Chart B Chart C c-i C-2 G3 Chiseto D G1 (α2) D-2 D-3D-4 Chart E Chart F =-IF-2 F-3F-4 F-5F-6 Chart G G-1 (C-2) G-2 (C-3) G-3G-4 Chart H H-1CD-2))! -2 H-3 1L4 H-5H-6 chart d LL (C-3) ■-2 Chart J J-1J-2 I? Group 1 investigation report kllpctnw+e 1 山-Loku v tute r white fermentation 1111---(1 211Pwl) me bishi^-1 international investigation report US9106863 S^　52732 Continuation of front page (51) Int, CI, 5 Identification symbol Internal reference number A61K 31/ 445 ABU 9360-4C31155ACV9360-4C ADP 9360-4C (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IT, LU, NL, SE), 0A (B F, BJ, CF, CG, CI, CNi, GA, GN, ML, MR, SN, TD, TG), AU, BB, BG, BR, CA, C5, FI, HU, JP, K.P.

KR, LK, N C, MG, MN, MW, NO, PL, RO, SD, SU, US FI (72) Inventor: Romero, Arthur Gee, Michigan, USA 49008 , Karama (72) Inventor Darlington, William H. 4524 Moonlight Street, Kalamazoo, Sigan 49009

Claims (8)

[Claims] 1. Formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼I [wherein R is hydrogen or halogen, R1 is (a) -Hydrogen, (k) -CSNR5R6, (b) -OR4, (l) -OSO 2CF3, (c)-SR4, (d)-CONR5R6, (e)-CN, (f)-het, (g)-C(O)het, (h)-CF3, (i)-SO2NR5R6, (j)-5-oxazolyl, R2 and R3 are independently (a) - hydrogen, (b)-(C1-C8)alkyl, (c)-(C2-C8)alkenyl, (d)-(C2-C8)alkynyl, (e)-(CH2)m-(C3-C8)cycloalkyl, (f)-(CH2)m -(C3-C8)cycloalkenyl, (g)-(CH2)m-aryl, (h)-(CH2)m-CO2R4, (i)-(CH2)m-OR4, R4, R5 and R6 are independently (a) - hydrogen, (b)-(C1-C4)alkyl, (c)-(C1-C4)alkenyl, (d)-(C3-C8)cycloalkyl, and X is (CH2)n, m=0~4, n=4-8, p=0, 1] and pharmaceutically acceptable acid addition salts thereof; However, if R1 is hydroxy or methoxy and R2 is hydrogen, ▲ formula , chemical formula, table, etc. ▼ cannot be piperidino, and furthermore, the above compound is , cis-2,6-dimethyl-4-(1,2,3,4-tetrahydro-8-meth xy-2-naphthalenyl)-morpholine, trans-2,6-dimethyl-4-(1,2,3,4-tetrahydro-8-methane) Toxy-2-naphthalenyl)-morpholine, 4-(1,2,3,4-tetrahydro-8-methoxy-2-naphthalenyl)-thi omorpholine and its hydrochloride, 7-(hexahydro-1(2H)-azevinyl)-5,6,7,8-tetrahydride rho-1-naphthalenol and its hydrochloride, 7-(hexahydro-1(2H)-azevinyl)-1-methoxy-5,6,7, 8-tetrahydronaphthalene and its hydrochloride, 2-(1-pyrrolidinyl)-1,2,3,4-tetrahydronaphthalene and its It cannot be the hydrochloride of 2.2-(1-piperidinyl)-1,2,3,4-tetrahydronaphthalene, mono hydrochloride, (7-hexahydro-1(2H)-azotinyl)-5,6,7,8-te Trahydronaphthalene, hydrochloride, hexahydro-1-(1,2,3,4-tetrahydro-2-naphthalenyl)-1 A compound according to claim 1 selected from the group consisting of H-azepine and its hydrochloride salt. . 3. 2. A compound according to claim 1, wherein R is halogen. 4. (+)8-bromo-2-(1-pyrrolidinyl)-1,2,3,4-tetrahydryl 4. The compound according to claim 3, which is dronaphthalene. 5. 2. A compound according to claim 1, wherein R1 is -CONR5R6 in the 8th position. 6. (-)-1,2,3,4-tetrahydro-2-(1-piperidinyl)naphtha ren-8-yl-carboxamide, (+)-1,2,3,4-tetrahydro-2-(1-piperidinyl)naphthalene -8-yl-carboxamide, (-)1,2,3,4-tetrahydro-2-(1-pyrrolidinyl)naphthalene- 8-yl-carboxamide, (-)1,2,3,4-tetrahydro-2-(1-pyrrolidinyl)naphthalene- 8-yl-carboxamide, 7-(hexahydroazevinyl)-5,6,7,8-tetrahydronaphthalene- 1-carboxamide, (-)-1,2,3,4-tetrahydro-2-(1-pyrrolidinyl)naphthalene 6. A compound according to claim 5 selected from the group consisting of -8-yl-carboxamides. 7. (+)1,2,3,4-tetrahydro2-(1-pyrrolidinyl)naphthalene 7. The compound according to claim 6, which is a -8-yl carboxamide. 8.7-(1-hexahydroazevinyl)-5,6,7,8-tetrahydronaph 2. The compound of claim 1 which is talen-1-trifluoromethylsulfonate.