JPH0272178A - Chemical intermediate - Google Patents

Abstract

NEW MATERIAL: A compd. represented by formula I [where R₅ is H or a 1-6C alkyl; R₁₀ is a 1-7C alkyl, (CH₂)₃R₇ or (CH₂)_tR₈; R₇ is a 3-9C cycloalkyl; R₈ is a 2-5C alkenyl or a phenyl capable of having 1-2 substituents (a 1-6C alkyl, 1-4C alkoxy, CF₃ or halogen); n, p, q and s are each 0, 1 or 2; and t is 1 or 2].

EXAMPLE: 3α,β-benzyl-8-azabicyclo-[3.2.1]-octane.

USE: An intermediate of a medicine useful as a remedy of gastrointestinal function failure, obesity or arrhythmia or a tranquilizer.

PROCESS: 8-Benzyl-nor-tropan-3-one oxime is reacted with LiAlH₄ and the reaction product is hydrolized to obtain the above-mentioned designated compd. A compd. represented by formula III obtained by reacting the compd. represented by the formula I with a compd. represented by formula II (wherein R₁ is a 1-6C alkoxy; and R₂ and R₃ are each H, a halogen or CF₃) is useful as the above- mentioned medicine.

COPYRIGHT: (C)1990,JPO

Description

[Detailed description of the invention]

FIELD OF THE INVENTION This invention relates to chemical intermediates, and in particular to useful intermediates for use in the preparation of novel substituted benzamides having useful pharmacological properties. N-(2-diethylaminoethyl)-2-methoxy-4
-amino-5-chlorobenzamide, 1-ethyl-2(
2-Methoxy-5-sulfamoylbenzamidomethyl)virolidi/and N-C4'-(1'-benzyl)-
Piperidylco-2-methoxy-4-amino-5-chlorobenzamide is a well-known compound with useful pharmacological activities that modulate gastrointestinal function. Certain types of substituted benzamides with structures different from these compounds have been found to have useful pharmacological activity. For example, compounds of this type can be used to treat gastrointestinal dysfunction. More specifically, most of these compounds can be used to treat vomiting, and some of these compounds can be used to treat other dysfunctions, such as delayed hunger, indigestion, flatus, esophageal reflexes, and digestive disorders. Can be used to treat ulcers. Furthermore, many compounds have beneficial effects on the central nervous system, such as tranquilizing effects. In the present invention, it has also been found that certain compounds have therapeutic effects on obesity and certain other compounds have therapeutic effects on arrhythmia. This substituted benzamide is a compound represented by formula (I) [wherein R1 is C! ~C, alkoxy group, Rt and R8 are identical, hydrogen, halogen, CF, C, ~C, acyl, C! - C acyl acylamino substituted or substituted with 1 to 2 C3-C6 alkyl groups, amino, aminocarbonyl or aminosulfo y% C8-C alkylsulfone or +h nitro, R1 is hydrogen and C1 ~C6 alkyl,
R6 is C, -C, alkyl fc'rj: -((,
Ht)! IR? (In the formula, 8 is O or 2,
R1 is C1-C, cycloalkyl group) or -(
cu, )tRs (in the formula, t is 1 or 2), R8
is C1-C, alkenyl or unsubstituted or C8-C6
a phenyl group substituted with 1 to 2 substituents selected from alkyl, C2-C, alkoxy, trifluoromethyl, and halogen), and n5p and yohiq are each independently 0 to 2] and their hydrates and medically acceptable salts. Substituted benzamides of formula (1) and their hydrates and medically acceptable salts are acids of formula (XI ) and the formula (XII
A compound represented by [) (XI ), and then, if necessary, R, 1fc and R8 in the product compound are converted into separate R2 or R8, respectively, and when R8゜ is hydrogen, this is converted into RsK, and if necessary, It has been found according to the invention that it can be prepared accordingly by forming a medically acceptable salt of the product compound of formula (I). Therefore, the present invention provides a compound of the formula (XIII) (XI[l) [wherein R1 is hydrogen or C1-C6 alkyl, R8° is C1-C, alkyl or a group -(cut)
sR? (In the formula, 1 is 0-2, R1 is C1-C
8 cycloalkyl) or the group -(CHt)tRs
In formula C, t is 1 or 2, R1 is C1-C, alkenyl, or unsubstituted or C1-Cs alkyl,
one selected from the group consisting of C1-C4 alkoxy, trifluoromethyl and halogen, or fC is phenyl substituted with two substituents) and ns p and q are each independently 0-2; Compounds indicated by ]. Or offer the salt. In particular, 3-amino^8-benzy-8-azabicyclo-(
3,2.1]octane (3-amino-8-benzylnortropane) and 3β-amino-8-benzyl-8-azabicyclo-(3,2.1)-octane (3β-amino-
8-benzylnortropane). Here, the "reactive derivative" of the formula (Xlr) means the formula (
A derivative of a compound of formula (XI[) that can react with a compound of formula (Xll) to form an amide bond between the acid group of the compound of formula (XI[) and the amino group of the compound of formula (Xll). It is. This reactive derivative is often an acid halide of the acid of formula (Xn), such as an acid chloride. In this case, the reaction is usually carried out in an inert solvent, preferably in the presence of an acid acceptor. Inert solvents include benzene, toluene,
Any solvent may be used as long as it is inert to both reactants, such as diethyl ether. Preferred acid acceptors are organic bases such as triethylamine, trimethylamine, tertiary amines such as pyridine, picoline, or inorganic acid acceptors such as calcium carbonate, sodium carbonate, potassium carbonate, and the like. It should be noted that certain acid acceptors, such as organic bases, can be used as inert solvents. Other useful reactive derivatives of acids of formula (XI) are esters such as methyl, ethyl, propyl or butyl esters, in which case the reaction is carried out by heating the reactants in an inert solvent such as ethylene glycol. This will be carried out by KotoK. In the reaction, an anhydride of the acid of formula (XII), a mixed anhydride as usual conventionally used, is prepared as usual, and this is reacted with a compound of formula (Xl[[). Alternatively, the acid of formula (XI[) and the compound of formula (XIII) can be reacted in the presence of a dehydration catalyst, for example a carbodiimide such as dicyclohexylcarbodiimide. Both of the intermediate compounds represented by formulas (XH) and (Xlll) are known compounds, or can be produced by methods similar to those for producing known compounds. As can be clearly seen, -CO-N R5 of the compound of formula (1)
The -(cax)n-bond can be in the α or β orientation with respect to the ring of the heterocyclic moiety to which it is attached. The mixture of α- and β-isomers of the compound of formula (1) can be obtained by non-stereospecific synthesis and the desired isomer can be separated from the mixture by conventional methods, e.g. chromatography. Alternatively, it can also be synthesized from the corresponding α- or β-form of the compound of formula (Xlll). Generally the corresponding α- or β of the compound of formula (XI[l)
- Preferably synthesized from isomers. In some cases, α-maroku of the compound of formula (Xlll) is β
- The types are shown in the table below, examples 3C and 4A respectively.
and 4C and can be prepared by known stereospecific synthetic methods such as those described in Examples 2.3A and B leading to the α- or β-isomers of compounds of formula (XII[). Precur+5o of the compound of formula (XII[)
r) For example, the azide (D3) of Example 2 is synthesized by stereospecific synthesis, and then converted into the corresponding target isomer of the compound of formula (Xl) while maintaining the shape under non-stereospecific conditions. You can also. Alternatively, Example 3
and oxime and imine of 4, which do not have an asymmetric center at the relevant position, and convert this into the desired isomer of the compound of formula (XI[l)] under stereospecific conditions. You can also do it. Alternatively, the α- and β-
It is also possible to non-stereospecifically synthesize a mixture of isomers and separate the mixture by conventional chromatography to obtain the desired isomer. However, in this case it is generally more convenient to react this mixture to give a mixture of the α- and β-isomers of the compound of formula (I) and optionally separate them as described above. Table 1 below illustrates stereospecific and non-stereospecific synthetic methods for obtaining intermediate compounds of formula (Xlll) when n is O. Table 1 Following Table 2 Formula when Yin is 1 or 2 (Xll
The method for producing the intermediate compound l) will be illustrated. Table 2 α (Xllll) Suβ (XI[I) (Xt[I) (The rest of the ring is omitted for clarity.) x l n= 2 (The rest of the ring is omitted for clarity.) ) The acid addition salt of the compound of formula (1) is prepared by a completely conventional method by reacting the compound of formula (1) in basic form with a selected acid! ! ! can be built. Quaternary ammonium salts of compounds of formula (1) are prepared by conventional methods for preparing such salts, for example by reacting selected compounds of formula (I) with compounds represented by 2R and Y as described above. be able to. This reaction is preferably carried out in a suitable solvent such as acetone, methanol, ethanol, dimethyl formaldehyde, etc. at normal or elevated temperature and pressure. In the compound 1'fc of formula (1), after the corresponding intermediate compound corresponding to T is produced, appropriate exchange of R7 and R8 can be carried out by a conventional method. For example, a nitro group can be converted into an amine group by a conventional method, and an acylamino group can also be converted into an amino group by a conventional method. Further, the compound of formula (T) in which R7 or R8 is hydrogen can be produced by converting the corresponding compound of formula (I) in which R1 or R1 is hydrogen by a conventional method. Therefore, R7 or R5 can be converted into other Ro or R8.
It will be appreciated that compounds of formula (1) containing groups are useful intermediate compounds and as such constitute an important aspect of the invention. When RIo is hydrogen, it can be converted into the above-mentioned R6 group by conventional methods, for example, formula (XI[) and formula (
The reaction product of the compound of XI[I] is a compound represented by QRs [wherein R6 has the meaning defined in formula (I), and Q is a group that can be easily substituted by a nucleophilic group]. It can be carried out by reacting. Preferred Q include (: 1% Br, I, 0 SOtCHs or OS OtCa EL pCus. Q is more preferably Ct% Br and )・benzyl rogenide. The reaction can be carried out under conventional alkylation conditions, such as in the presence of an acid acceptor such as potassium carbonate, in an inert solvent such as dimethylformamide. Generally, the reaction is carried out at less extreme temperatures, such as ambient to slightly elevated temperatures. When R2 or R1 is converted to another R or R1, and when R1 which is hydrogen is converted to another R2,
These transformations can be performed in any or desired order. As mentioned above, the compounds of formula (1) have useful pharmacological actions and can therefore be used for the treatment or prevention of diseases. The general action of each compound of formula (I) can, of course, be easily ascertained by conventional pharmacological tests, resulting in its optimal use as a medicine. For example, compounds that show antiemetic effects in pharmacological tests can be used to treat or prevent emesis, and compounds that show gastric motility promoting effects can treat delayed hunger, indigestion, flatulence, esophageal reflux, and peptic ulcers. Compounds that show beneficial effects on the central nervous system can be used to treat or prevent psychosis, and compounds that show appetite, elimination effects can be used to treat obesity. I can do it,
Compounds that exhibit arrhythmia suppressing activity can also be used to treat or prevent arrhythmia. Compounds of formulas (■) and (IX) as described above are believed to be particularly useful for use in the treatment of gastrointestinal dysfunctions other than emesis. Similarly, the beneficial effects of compounds of formulas (VIII) and (e) on the central nervous system may be particularly useful. However, it will be appreciated that such effects are not necessarily limited to compounds of the above formula. According to the invention, therefore, a pharmaceutical composition is obtained comprising a compound of formula (I) or a hydrate or a medically acceptable salt thereof and a pharmaceutically acceptable carrier. These pharmaceutical compositions can be in a form suitable for oral or parenteral administration, such as tablets, capsules, oral liquid formulations, powders, granules, lozenges, reconstitutable powders,
It can be in the form of solutions or suspensions for injection or infusion, as well as in herbal medicine and other forms. Orally administered compositions are generally preferred. Tablets and capsules for oral use may be in unit dosage form and may contain the usual excipients such as binders, fillers, lubricants for tabletting, disintegrants, acceptable wetting agents, etc. can. The tablets may be layered according to methods well known in conventional pharmaceutical practice. Liquid shed preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or for reconstitution with water or other suitable vehicle before use. It can also be in the form of a softening formulation. Liquid formulations of this type may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles including food oils, preservatives, and, if desired, conventional flavorings, colorants, and the like. For parenteral administration, liquid forms containing unit doses are prepared using a compound of formula (1) and a sterile vehicle. 3 Depending on the type of vehicle and concentration used, the compound may be dissolved or suspended in the vehicle. When preparing solutions, the compound is dissolved in an injection vehicle and filter sterilized before filling into suitable ampoules and sealing. It may be advantageous to include adjuvants such as local anesthetics, preservatives, and buffering agents in the vehicle. Parenteral suspensions are prepared much like solutions, except that the compound is suspended in the vehicle and sterilized by exposing the compound to ethylene oxide before suspending the compound in the sterile vehicle. Ru. It can be helpful to include surfactants or wetting agents in the composition to facilitate uniform distribution of the compound. As is common practice, the composition will normally be accompanied by instructions for use in one relevant clinical treatment. It will, of course, be understood that the dosage used to treat the aforementioned dysfunction will vary depending on which compound of formula (1) is used and on other factors such as the severity of the disease to be treated. In addition, the present invention provides a method for the treatment or prophylaxis of human diseases which consists of administering an effective amount of a compound of formula (I) or a hydrate or medically acceptable salt thereof. As with any pharmaceutical composition, an "effective amount" will vary depending on many factors, including the nature and severity of the disease being treated and the actual compound used. Usually 0.01-25% per day to achieve satisfactory treatment.
A dosage of Wli/Kg is sufficient. A preferred unit dose is 01-15IIIP. Compounds of formula (1) enhance the effect of analgesics when used simultaneously with common analgesics when treating migraines. According to the present invention, therefore, a pharmaceutical composition comprising a compound of formula (1) and an analgesic is obtained. The compound of formula (1) and an analgesic such as aspirin or valacetamol are included in the composition in amounts generally similar to their normally effective dosages. The composition may be prepared in combination, such as tablets or capsules, containing both the compound of formula (1) and the analgesic for oral administration, or the two active ingredients may be prepared for separate administration. Twin cartridges containing separately (t
win pack). Accordingly, the present invention provides a method for treating migraine headaches by administering to the patient the final compound of formula (I) and an analgesic. The following reference examples illustrate the preparation of the compound of formula (1), and the following examples illustrate the preparation of intermediate compounds for the compound of formula (1). Actual Example 1 3-Amino-8-benzyl-8-azabicyclo-(
3,2,1]-octane (DI) 4.2F (yield 75%
) was obtained. Example 2A 6 g of 8-benzylnortropan-3-one oxime in dry tetrahydrofuran (THF) 150 rnt
A suspension of 2.4 g of lithium aluminum hydride in the solution was subjected to Soxhlet extraction for 15 hours while stirring. The mixture was hydrolyzed. The decomposition product was fractionated under reduced pressure to obtain a product with a boiling point of 107-b3-hydroxy-8-benzyl-8-azabisic0- (3,2.1
]-octa73,9,! i' is R, the method of Mirza et al. (Nature, 1952.170.630) K
Thus, reduction of lithium aluminum hydride in diethyl ether to 3-hydroxy-8-benzyl-3-8-azabicyclo-(3,2.1]-octane (
D2). Although Mirza claimed that this method could stereospecifically obtain the β-isomer, subsequent researchers (A, H, Becketty N, J, Harper+
A, D,,T. Bahn and T, H, E, Watts*Tetr
ahedron 1959s L 319) demonstrated that a mixture of α- and β-isomers is produced. A, the method of Bose et al. (Tetrahedron
Letters 197L23.1977), crude 3-hydroxy-8-benzyl-8-azabicyclo-(3,2,i]-octane (D2) 3.
9 g of triphenylphosphine and 3.29 g of diethyl azodicarboxylate in 'm. Next, it was reacted with 5 g of diphenylphosphoryl azide to form an oily 3β-azido-8-benzyl-8-azabicyclo-(3,2.1).
-Octane (D3)2. ! i+ (yield 25%) was obtained. Infrared absorption spectrum (i, r, )s 2100LM
! -1

[γNs). A suspension of 0.5 g of lithium aluminum hydride in diethyl ether 5Q mA is added with stirring to 3β-azido-8-benzyl-8-azabicyclo-(3,2.1]-octane (3,2.1) in diethyl ether IQ mA. D3
) 2 g of the solution were added, the reaction mixture was stirred at room temperature for 3 hours, then hydrolyzed, extracted with ethyl acetate, and the solvent removed to give the crude 3β-amino-8-benzyl-
8-Azabicyclo-[3°2.1]-octane 1.1
(60% yield) was used in the method of Example 2 without purification. Note - Confirmation that the azide of D3 and the amine of D4 are in the β-form was obtained by stereospecific synthesis of the compound obtained via the amine of D4, as outlined in Example 3B and Volume 5. based on the fact that it is the same as the β-isomer. Example 2B N-(4-chlorobenzyl)-8-azabicyclo-[3°2.1]-octane in 100 #lj of methanol 2.
0.02 g (8.1 mm! J mole) was treated with 0.759 sodium borohydride, stirred at room temperature for 12 hours, poured into saline solution, and diluted with a strong alkali using two diluted solutions of sodium hydroxide. As a note, the resulting mixture was extracted three times with 50 m of ethyl acetate, and the K machine extracts were combined, dried over sodium sulfur, filtered, and evaporated to obtain α-Oyohi β-N-(4
-chlorobenzyl)-8-7zabicyclo(3,2.1
]-Octane mixture 2.02 g (yield 99%) was obtained. The aforementioned 3-hydroxy-8-azabicyclo-(3,2.
1] - Mixed isomers of octane were converted to 3β-azido-8-(4-chlorobenzyl)- by the method described in Example 2.
8-atehinc O-(3,2.1]-octane i (converted, i.e. 3-hydroxy-N-(4-chlorobenzyl)-8-asahicyclo(3,2,13 octane 3,3 ji (13 , 1 mmol] was treated sequentially with triphenylphosphine 3.779, diethyl azodicarboxylate 2,4992 and diphenylphosphoryl azide 4,1, !i' in F2. Separate the azide isomers,
Oily 3β-azido-8-(4-chlorobenzyl)-8
-azabicyclo-(3,2.1]-octane 1,1.9
(Yield: 5%) was obtained. This was reduced with lithium aluminum hydride in ether under reflux for 12 hours, hydrolyzed, extracted with ethyl acetate and removed to obtain a crude solution. M3β-amino-8-(4-chlorobenzyl)-8
-Asahi Shikuro (3,2.1) -Octane 0.82
! i (yield 82%) was obtained. Similarly, the intermediate compound 3β-
was produced in a yield of 32 cm. Practical example 3A -Me/·' (D7) 8-azabicyclo-(3,2,1]-]octane-3-
Ontropic) 3.681/ (0,0265 mol)
50 m of ethanol containing 4-5 rat pyridine
and treated with hydroxylamine hydrochloride 1,90.9. The mixture was heated to reflux for a brief period, then cooled and treated with about 10 g of solid potassium carbonate and about 5 mt of water. The ethanol was removed in vacuo, the mixture was extracted three times with 150 increments of chloroform, the extracted phases were combined, dried over KCOs,
Filtered, evaporated in vacuo, and the resulting solid was recrystallized from ethyl acetate and petroleum ether with a boiling point of 40-60°C.
8-azabicyclo-(3,2.1]- at 14-115°C
3.1 g (yield: 76 g) of colorless crystals of octan-3-one oxime were obtained. Chloro(3,2,1:l-octane (D8) 8-azabicyclo-(3,2.1)-oxime-3-one oxime 3.089 (0.02 mol) was dissolved in anhydrous amyl alcohol 100 dK. It was heated to a boiling point, about 3.0 g of sodium was added in portions over an hour, and the mixture was allowed to cool overnight. The mixture was treated with about 80 ml of 5N hydrochloric acid and 15 ml of ethyl acetate.
Extraction was performed three times with 0 mt each. The acidic aqueous phase was separated and re-extracted four times with sodium hydroxide, millichloride and 150 tnt of ethyl acetate, the combined extracts were dried over KzCOs, filtered and evaporated in vacuo to yield the intermediate compound (D8) as a colorless oil.
) 2,259 (80% yield), which was used without purification. Example 3B Similarly, 8-benzyl- in 20 ml of amyl alcohol
8-Azabicyclo-[3,2,I E-octane-3-
Stir the solution of onoxime 0.9.9 at reflux, add sodium 29 in portions over 2 hours, cool the solution and dilute with diethyl ether; acidify with excess dilute hydrochloric acid and wash the acid extraction phase with diethyl ether. 3β-amino-8-benzyl-8-azabicyclo-(3,2.1]-octane CD
4) 0.8! I got l. The intermediate compound was used in the production of Reference Example 5 without purification. The following intermediate compounds were similarly prepared from the corresponding oximes. [3,3,1 Oily liquid of a mixture of general formula Dll). The following intermediate compound, denoted by , was prepared from the corresponding oxime by a method similar to Torama Example 3D. Example 3C H2N-methyl-9-azabicyclo-[3,3,1]-nonan-3-one oxime 3.25 & (0.02 mol)
was dissolved in ethanol and cooled in the presence of ammonium acetate at °C.
, 21 was hydrogenated over Raney nickel at 9/ej (500 psi) for 24 hours. The reaction mixture was filtered, evaporated in vacuo, dissolved in diluted salt and extracted with ethyl acetate. The organic layers were combined, dried over K2CO3, filtered and evaporated in vacuo to give 3-amino-9-methyl-9-azabicyclo-[3,3,1]-nonane 2,679 (yield 90
H) was obtained and used in the production of Compound 21 without purification. The product is a single diastereomer, likely the α-isomer. Intermediate Compound for Example 3D) 9-benzyl-9-azabicyclo-(3
,3.1]-nonane-3-onogysim4.09(0,
0164 mol] in ethanol xoomt and 17.6 kg/ctd (25
Hydrogenation was carried out at (0 psi) to (i) °C, and after 24 hours the reaction mixture was filtered through cane earth and evaporated in vacuo.
The resulting oil was dissolved in 50 d of diluted hydrochloric acid, and ethyl acetate x
Extract 3 times with 5omt, make the aqueous layer basic, re-extract 3 times with ethyl acetate xomt, combine the organic extracts and extract with K
Dry over zCOs, filter and evaporate in vacuo to give 3-amino-9-benzyl-9-azabicyclo-(3,3.1
]-nonane 2.39 (yield 61%) was obtained and used for the preparation of compound 11 without purification. Example 4A eHN 8-benzyl-8-azabicyclo-(3,2,1]-]
Octan-3-one 4.409 (0.02 mol) was treated with 11% methylamine in 5Q ml of ethanol,
(a) Heating to ~70°C and hydrogenating in the presence of 400 m9 of preliminary monoatomic platinum, 8-benzyl-3 having a melting point of 77-79°C
α-Methylamino-8-azabicyclo-(3,2.1)
-Octane 3,33,! i' (yield 72%) was obtained. Example 4B 3α,β-methylamino-8-benzyl-8-zapicyclo-(3,2.1]-octane (D27)N -CH*
Ph N-benzyl-8-azabicyclo-[3,2,1]-octan-3-one 4,30 g (0,02 mol) was treated with excess methylamine in anhydrous toluene to obtain a monomer of titanium. Fifty tons of 10% xylene saliva was added, the mixture was stirred for 2 days, and the resulting mixture was filtered through a filter and evaporated in vacuo to give N-benzyl-3-methylimino-8-azabicyclo-(3,2.1]-octane. Obtained 5.0 g of N-benzyl-3-methylimino-8-azabicyclo-(3,2,1]-octane in 100 methanol.
Add approximately 5.09 g of sodium boronate in small portions to 0 g of solution, stir the mixture at room temperature for 3 hours, then add 5.0 g of water.
0- was added, the mixture was extracted with three 100 mt portions of ether, the organic extracts were combined, dried over KxCOs, filtered and evaporated to give the axial isomer as shown in the proton magnetic resonance spectrum. (axial iso
mer ) (α) (D26) and the equa10real isomer (β
) (D28) as a mixture of about ω:40, 3-methylamino-8-benzyl-8-azabicyclo-[3°2.
1]-octane (D27) was obtained. Example 4C -Bun N-butyl-8-azabicyclo-(3,2.1]-octan-3-one 5.OF (
0.028 mol) was treated with a solution of ammonia in ethanol and allowed to stand for a while. Mixture with ammonium acetate 2.5
21 kg/cfI (300 psi) in the presence of g
Hydrogenated over Raney nickel for U hours, the mixture was filtered, evaporated under vacuum, treated with H2O and extracted with ethyl acetate. The organic extracts are combined and acidified, the phases are separated, the aqueous layer is extracted with basic KL, then ethyl acetate, and dried -<K
xCOs) 1. , evaporated in vacuo to form the intermediate compound D2
9 (2.55 g% yield 50%) was obtained and used for the preparation of compound 27 without purification. Example 5 (inclusive of all isomeric forms) 5,049 (0,026 mol) of methyl isocyanide was dissolved in (±)-8-azabicyclo-(3,2.1]-octan-2-one in 8omi of dimethoxyethane. 2 g (0,
0143 mol) K was added, the solution was cooled to OoC, 2 at.
．． 9 (6,05 mol) was added, the mixture was then heated at 50"G for 3 hours, cooled and then treated with a saturated solution of potassium carbonate 3
00mt, extracted three times with 100 parts of ethyl acetate, combined the extracted phases, dried with KxCOs, filtered,
The crude oil obtained by evaporation was dissolved in ether, adsorbed onto 40 J of grade I alumina neutralized by addition of 10% water, separated with successive gradient mixtures of ether, ethyl acetate and methanol, Oily 8-methyl-8-azabicyclo-(3j2)-octane-2-nitrile 1°IF (yield 46%) was obtained. Add 1.19 of the nitrile in 20d of tetrahydrofuran to the lithium aluminum hydride in 3OIrLt of tetrahydrofuran, stir the mixture for 3 hours, add 0.5 parts of water, 1 part of the nitrile.
0.75 m of sodium hydroxide solution and 1 g of the aqueous compound were obtained. The product is a single diastereomeric racemate believed to be (±)-α-rA cast. 4-acetamido-5-chloro-2-methoxy C (hc
g(Js 5-chloro-2-methoxy-4-methylbenzoic d2
g (0,0093 mol) of dimethylformamide (capital)
tnt K was added and the solution was treated with 4.5 pentachlorophenyl trichloroacetate & (0,11 mol) dihydrotriethylamine 1.5 IILt, the mixture was stirred at room temperature for 1 hour and the dimethylformamide was removed in vacuo. The residue was recrystallized from acetone and petroleum ether to give 5-chloro-2-methoxy-4-methylaminobenzoic acid:/pchlorophenyl, melting point 217-219°C. Example 1 3α,β-amino-8-4-acetamido-5-chloro-2-methoxybenzoyl chloride 69 in toluene 200 and triethylamine 51 was prepared as described in Example 2 in toluene 200 and triethylamine 51. Benzyl-8-azabicyclo-(3,2.1]-octane (D 1 ) 4.
2 g of a 2.5 N aqueous solution of sodium hydroxide was added and the reaction mixture was stirred at room temperature for 2 hours. nt, separate the toluene layer and dilute the aqueous layer with 150 ml of chloroform.
III/! The combined organic extracts were dried (I(2CO3)), the solvent was removed, and the product was chromatographed (neutral alumina, Brockman
11# solution, ethyl acetate) and oily formula (1)
7.2 g (yield: 84 g) of a mixture of 31α- and 3Iβ-isomers were obtained. Reference 1 row 2 NHz Compound (1) prepared as in Reference Example 1 7.29 was dissolved in 2 g of potassium hydroxide, 10 Int of water and 1 mL of ethanol.
The mixture was heated under reflux for 3 hours with an aqueous ethanol solution consisting of oo mt. The mixture was then cooled to room temperature, the ethanol was removed on a rotary evaporator, the residue was extracted with chloroform and the organic extract phase was chromatographed (neutral alumina, Bro
After elution with ckman II, ethyl acetate), 3.3 g (yield: 50 g) of compound (2) and compound (3) were separated from the bands containing compounds (2) and (3), respectively.
) 2.09 (yield 30%) was obtained. Compound (2) K nuclear magnetic resonance spectrum (n0m, r,
) by weight ratio of 3'α- and 31β-isomers 2:
It was shown that it is a mixture of 3 and its melting point is 159-1
It is 70°C1. Compound (3) Melting point 221-223°C0 n, m, r, (δ, CDCl5), 8.10 (s,
IHs aryl, 6-H) 7.6-7.1 (rn, 6 Hs P h -H
and 6.30(s, IHt aryl, 3-
H) 4.6-4.2 (m, 3H, -NHZ, C0
NH-CH= )3.93 (s, 3H,0CHs
)3.56 (s, 2H# PhcHz, N
=)3.4~3.1 (m, 2H,=CH-N(C)
b-Ph )-CH= )2.3-1.5 (m t
8T(z=CHh) Reference Example 3 Compound (4)] A solution of 1.69 of 4-acetamido-5-chloro-2-methoxyhensyl chloride in 100 of toluene and 2 ml of triethylamine was dissolved in 200 of toluene (17) Explanation 2
Crude 3β-amino-8-benzyl-8-azabicyclo-(3,2,13-octane (D
4) Treat with a solution of 1,1.9 and stir the reaction mixture at room temperature for 2 hours, then add 2.5 of sodium hydroxide.
The toluene layer was separated, the aqueous layer was extracted three times with 5Q vtt portions of ethyl acetate, the combined extracts were dried over KzCOs, the solvent was removed and the resulting oil was extracted with diethyl ether. 4-acetamido-5-chloro-2-methoxy-N-(-[81-benzylco-8-azabicyclo-
[2,1]-octyl)benzamide (compound 41.5
．． 5' (yield 70%) was obtained. Reference Example 4 Compound (4) produced as described in Reference Example 3 1.5
,! i' is hydrolyzed in an aqueous ethanol solution consisting of 0.5 g of potassium hydroxide, 2 mt of water and 20 mA of ethanol with heating to reflux for 2 h, the mixture is then diluted with ml of water, cooled to room temperature and the product The precipitate was collected, dried and recrystallized from ethyl acetate and petroleum ether to give pure 4-amino-5-chloro-2-methoxy-N-(3'β-[8I-benzylco- 8-Azabicyclo-(3,2.1]-octyl)benzamide (
Compound 5) 1.1,! 9 (yield 80%) was obtained. Melting point 188°C n, m, r, (δCDCl5) 8.08 (s, LH, aromatic 6-H), 7.60-7
．． 10(m, 6H*C5Hs and C0NH), 6
．． 28 (a, IH, aromatic δ-3-H), 4.6
−4.2(m + 3 He-NH:2 and C0Nf
(, CH=), 3.87 (s, 2H-PhC
Hs). 3.4-3.1(me2H,=CH-N(CHz-P
h)-CH=), 2.3-1.5(m e 8 Hp
-CHt ) :s Example 5 η According to the method described in Example 3, 4-amino-5-chloro-2-methΦcybenzyl chloride was converted to 3β-amino-8
-benzyl-8-azabicyclo-(3,2.1]octane to react with 4-amino-5-chloro-2-methoxy-N-(3'β-[sl-benzylco-8-azabicyclo-(3, 2.1]octyl)benzamide was obtained.The obtained compound was then recrystallized according to the method described in Example 4 to obtain pure 4-amino-5-chloro-2-
Methoxy-N-(3'β-[81-benzylco-8-azabicyclo-(3,2.1]octyl)benzamide (
5) C64%) melting point of 188-9°C was obtained. This compound was the same as that obtained in Example 4 above in terms of n, m, r, and melting point of the compound. Reference example 6 4-amino-5-chloro-2-methoxy-N-(3'β
-[81-methyl-8'-azabicyclo-[3゜2.1
]-octyl])benzamide (compound 19) NHI
(19) 4-acetylamino-5-chloro-2-methoxybenzoic acid 4,09 (0,016 mol) was dissolved in thionyl chloride 4Qmj at 30'C, evaporated in vacuo, and anhydrous toluene ca.
It was azeotropically evaporated twice at 00N. The resulting 4-acetylamino-5-chloro-2-methoxybenzoyl chloride was redissolved in about 100% of hot water toluene, and triethylamine 5M
and 3β-amino-8-azabicyclo-(3,2.1]-octane prepared as previously described and the reaction mixture was stirred at room temperature for 2 hours before sodium hydroxide 2
．． The toluene layer was separated and the aqueous layer was extracted with chloroform. The combined extract phases were evaporated in vacuo, and the resulting solid was dissolved in 2.5 g of potassium hydroxide.
The mixture was heated to reflux for 1.5 hours, the mixture was cooled, the ethanol was evaporated, and the resulting mixture was extracted five times with 100 portions of hot chloroform. The organic extracts were combined, dried over KCOs, evaporated in vacuo, and the resulting solid was recrystallized to give 4-amino-5 with a melting point of 249-250 °C.
-Chloro-2-methoxy-N-(3'β-[81-methyl-81-azabicyclo-(3,2.1]-octyl)-benzamide colorless microcrystals 1.3 g (yield 30%)
I got it. The following compounds were similarly prepared. The compounds in the 8 bags with the suffix A are 4-acetylamino condensation compounds prior to hydrolysis with salt aiK to form the corresponding unsuffixed compounds. B Table +: Manufactured as described in Description 4A, ←: Manufactured as described in Description 3DK. ■: Preliminary confirmation of hemihydrate precipitation in crystallization The following compound was also able to be produced in the same manner. NHM. The decomposition products were chromatographed on silica gel, eluting with ether and ethyl acetate to give 4-amino-5-chloro-4-amino-5-chloro-, the latter having a melting point of 180° C., tyr.
Identical to compound 6 prepared in Reference Example 6 from intermediate compound D26 prepared as described in Example 4AK. Reference example 8 5-sulfamoyl-2-methoxybenzoic acid 2.0.9
(0,009 mol) in anhydrous dimethylformamide 20
Triethylamine 0.83 p(0,
009 mol), cooled to 0°C, 695 g (0,009 mol) of ethyl chloroformate O was added dropwise, and the solution was diluted with 1
Continue stirring for 5 minutes. 3β-Amino-8-benzyl-8-azabicyclo-(3,2.1)-octane (Compound D 4 ) prepared as outlined in Example 3BK
1.9 g (0.09 mol) were added in one portion at 0° C., the mixture was left overnight, evaporated to dryness and diluted with 5 at of water and dilute aqueous ammonia IQ m! melting point 213-214℃
5-sulfamoyl-2-methoxy-N-(3'β-
(8-benzyl-8-azabicyclo-(3,2.1)-
Octyl)-benzamide was obtained in a yield of 38 cm. Reference Example 9 1,039 ml (yield: 63 ml) was obtained. Reference example 10 3β-amino-8-benzyl- in 15m dry toluene
1,01 g (4,0 mmol) of 8-azabicyclo-(3,2.1]-octane (compound D 4 ) was mixed with thionyl chloride and 0.789 anisic acid in dry toluene containing triethylamine 2-. was added to the solution of 2-methoxybenzoyl chloride produced by the reaction. The mixture was stirred at room temperature for 12 hours and then poured into water made alkaline with the addition of solid sodium carbonate. The mixture was diluted with 200 parts of ethyl acetate in 3 parts. The extraction phase was extracted twice and the extracted phase was subsequently dried over NazSO4, the solvent removed and chromatographed on silica gel, the HCl salt having a melting point of 269
4-Amino-5-chloro-2-methoxy-N-[3'β-(8'
-Benzyl-8-azabicyclo-(3,2.1]-octyl]]-benzamide (compound 5) 1. Add 5 rnt of bromomethane to Og, leave the solution at room temperature for 3 days, and mix the resulting solid with methanol and acetic acid. Recrystallization from ethyl gave -81-azabicyclo-(3,2.1]-octyl).Reference Example 11 3α,β-AZno-9-benzyl-9 produced as described in Seed Example 3BK -Azabicyclo-C3,3.1]-
Reacting nonane (compound D9) with 4-acetylamino-5-chloro-2-methoxy-benzoyl chloride as outlined in Example 6, hydrolyzing the product, chromatography of the product on silica gel, Eluted with ethyl acetate and petroleum ether with a boiling point of ω~()°C, with a melting point of 224~
4-Amino-5-chloro-2-methoxy-N at 225°C
-(3'β-[91-benzyl-91-azabicyclo-
(3,3.1]-nonyl)benzamide (compound 12)
4-amino-5-chloro-2-methoxyN-(3'α-[9'-benzyl-9
'-azabicyclo-(3,3.1]-nonyl)-benzamide (compound 11) was separated from 10 to 20 t, and the latter compound with a melting point of 199°C was prepared as described in Example 3D. Same as compound 11 prepared in Example 6 from the α-amine of DIO. Reference example 12 4-amino-5-chloro-2-methoxy-N-(2'-
(±) -(8'-methyl-81-azabicyclo-(3
,2,13-octylcomethyl)benzamide (compound 37) This compound is produced from intermediate compound D31 in the same manner as in Reference Example 6, and its melting point is 218-219°C. The product is a single diastereomeric racemate, likely the (±)-α-isomer. Reference Example 13 Product 33) 3β-Amino-8-benzyl-8-azabicyclo-(3,3.1]-octane in 15 ml of methylformamide was treated with 0.479 °C for a controlled period of time, and the mixture was evaporated to produce U. A thin film is poured onto the water while stirring, the white crystals are filtered out, vacuum dried, and chromatographically processed (
Deactivated alumina with deactivation degree '5), Brockm
an 1. Eluent, ethyl acetate) The recovered product was recrystallized from ethyl acetate and 4M petroleum with a boiling point (a) ~ 80'C to give 5-chloro- 2-Methoxy-4-methylamino-N-(3'β-(
8'-benzyl-81-azabicyclo-(3,2.1)
-octyl)benzamide was obtained. 5-Chloro-2-methoxy-4-methylamine)benzoic fflpentachlorophenyl (D32) 1.9 by the method of Ern5t (Psychopharmacolo
gia (Berl,) 10.316-323 (19
The doses for complete inhibition determined by 67)) are shown in Table 1. Compounds denoted by IAO are indicated by the dose in parentheses (
■/kg S, C,) indicates inertness. This test was performed using the method described by Protaia et al.
P., Con5tantinyJ., and Schwar.
tz+J,C,yPs)'choph-armacol
og)'p50 + 1-6 (1976) ] l Immediately/kg of apomorphine administered subcutaneously causes mice to climb the walls of a wire cage (an inverted 11 x 7, 5 x 18 m high food cage). Mice, habituated to resident cages in groups of 5, were placed under wire cages immediately after subcutaneous administration of apomorphine 1//:g, 10 min post-dose, addition and post-dose. Score climbing behavior. Observe the behavior of the mouse for a leap second,
A negative rating for spending most of the time, a rating of 0 is a 4
A score of 1 was given to the case in which the animal placed its limbs on the floor of the cage, a score of 1 was given to the case in which only the forelimbs were hung on the wall of the cage, and a score of 2 was given to the case in which all four limbs were hung on the wall of the cage. Scores for each mouse are combined three times in total and mice that receive test compound orally are compared to mice that receive apomorphine alone. Groups of animals receiving saline alone are also scored, and scores for bed heights below 0.5 inches are generally considered. Table 1 shows the dosage of complete suppression or EDso. Compounds marked IA indicate inactivity at an oral dose of 10/klli'. [3H]-spiroberidol (5piroperido
l) has been shown to bind with high affinity to dopamine receptors in the brain spinal cord (GreeseeIpSchn
eider*R0 and 5nyderes, H, pE
uroPean J, Pharmac, 46 (19
77) 377'381, Le)'sen+J, E,
+Gommeren W, and Laduron*P,
H,*Biochern,Pharmac*27
p (1978) +307-316]. Compounds that displace this ligand from dopamine receptor membranes may therefore have neurotic therapeutic effects. Hooded Llster weighing 200-3009
Flu male rats were decapitated, the massed nerves were rapidly severed, and the tissues were soaked in ice-cold Tris buffer at a concentration of 10 rv/ml (2
Homocynate in pH 7,7) at 5°C, 10-5M
test compound and standard curve 10-6 to 10-'M spiroberidol to humans in a tube with KO15 nM (
Add 3H)-spiroperidol. 500 μl of the membrane sample is mixed with this, and the test tube is incubated at 37° C. for 15 minutes. After this incubation, add ice-cold Tris f to each test tube.
Add 4 ffL of solution and filter the solution through a pre-soaked glass separation filter, wash the filter twice with 4 ml each of buffer solution, and transfer to a scintillation vial to count scintillations. A single dense flash is a substitution (3H
)-spiroperid/. Table 1 shows the conversion rate or the concentration of 50 substitutions (ED, .) for compounds at 10-'M concentrations. Compounds that substitute less than 50 molecules at 10@-5 M are not shown in Table 1. subcutaneously administering the compound (subcutaneously) minutes before administration (subcutaneous administration);
Same; Comparison was made with the emetic response when apomorphine H (J) and vehicle alone were administered in animals. In the same example, the dose that completely suppressed the emetic response and in another example, the ED relationship was determined. 5: Lower limit Not measured, +: Slight at 1, Rei: Slight at O, aS, -: Not tested.
Changes in intragastric pressure in unanesthetized but restrained rats previously deprived of food were measured using a saline-filled catheter inserted into the gastric lumen via a permanent blue fistula. It was measured using The catheter was connected to a physiological pressure transducer and pressure changes were recorded on a hot wire Ven recording device. For each animal tested, a 40 minute period prior to dosing was utilized to obtain an index of natural activity. The activity index is calculated by measuring the average wave height of the pressure waves during a period of 10 minutes and 10 minutes during the measurement of natural activity.
Four measurements of minutes each and 40 minutes after subcutaneous administration of the compound.
The significant difference test number of the mean values obtained for the natural activity and for the fish after administration of the compound was determined.
Punt's t test was applied. Table Ⅲ shows the lowest doses showing significant differences in activity. The compound indicated by 10 in the table indicates that it is inactive when administered subcutaneously to the administered bone /IcFI in parentheses. Table 1 Rats with permanent dual-use fistulas were used, and a 51-kg test diet (5 tnj of phosphorous salt warm solution of PL 9) was administered through the fistula and collected. The rate of recovery of the standard meal after it remained in the stomach for 10 minutes was taken as the hunger index. For slow hunger, take apomorphine HCl 5m9/9
The test compound was administered subcutaneously 15 minutes prior to subcutaneous administration of the test compound. Test meal recovery was measured 15-25 minutes and 45-55 minutes after compound administration and compared to animals receiving vehicle alone at the same time. Six rats were used for each #1 group. Table 1 shows the rate of increase in hunger in response to administration of compound 10/9. 5 x 10', slight, +: See separate note,: Not tested. In addition, the recovery rate for Compound 2 is shown in the following table. The confidence level p of the significant difference from the apomorphine and vehicle treatment groups is <0.01 and 1111) is (0,0
It is 01. After subcutaneous administration, the recovery rate of the test diet was 15-5.
and 45 to 55 minutes,
Hunger therefore increased. Compound 5 shows a significant increase in hunger when administered subcutaneously at 0.05 kg/kg, c. ■ The anorexigenic activity of the compounds was tested by measuring the decrease in food intake in hungry rats after administering the anorexigenic active compound. The results are shown below. No toxic effects were observed in the aforementioned tests at toxicological test doses. Using the compound of Reference 1 and Example 8 as an illustration of toxic effects, a standard Irwin profile for adverse effects was used.
ne Profile) test was conducted. The effects of the compounds on the inhibition of arrhythmias generated in the right ventricle of anesthetized and ventilated guinea pigs were tested at a dose level of 90rd9/9, either by oral or subcutaneous administration (5 Zekeres and Papp preparations,
Naunyn-8chmiedebergs Arc
k,exp,Path,Pharmak,+1963
+245,70). Compounds were administered intraduodenally prior to challenge addition. Intraduodenal administration of the initial compound at a dose of 32/n9 increased the arrhythmia critical flow by 48.5%. There was little loss of normality in the posture of the mice, limbs, body and abdomen. Hair raising was observed after oral administration and subcutaneous administration of 300 m9/#. 300 m9/kg subcutaneously or 900 m9 at the highest dose level tested
There were no deaths of mice after oral administration of 7 to 9. Further general observations were made using an illustrative c%, lzJ 8 compound. 10 m9/kFl and 30
Upon intravenous administration of m9/ky, hypersecretion of tears and hypersalivation were observed in 2/3 and 3/3 of the anesthetized canine test animals, respectively. The dose of 30Tn9/g was administered intravenously and was not lethal to the test animals. The unfavorable CNS effects of benzamides at a dose of 5 kg/kg orally were not seen in dogs with restricted bilateral fistulas used for gastric starvation experiments.

Claims (12)

[Claims] (1) Formula (XIII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (XIII) [In the formula, R_5 is hydrogen or C_1 to C_8 alkyl, and R_1_0 is C_1 to C_7 alkyl or a group -
(CH_2)sR_7 (in the formula, s is 0 to 2, R_7
is C_3-C_8 cycloalkyl) or the group -(
CH_2) tR_8 (where t is 1 or 2, R_
8 is C_2-C_3 alkenyl, or unsubstituted or C_1-C_6 alkyl, C_1-C_4 alkoxy,
phenyl substituted with one or two substituents selected from the group consisting of trifluoromethyl and halogen) and n, p and q are each independently 0 to
2]. (2) R_1_0 is C_1 to C_7 alkyl, or the group -(CH_2)sR_7 (in the formula, s is 1 or 2,
R_7 is C_3-C_8 cycloalkyl), or the group -(CH_2)tR_8, where t is 1 or 2 and R_8 is unsubstituted or C_1-C_6 alkyl,
The compound according to claim 1, which is phenyl substituted with one or two substituents selected from the group consisting of C_1 to C_4 alkoxy, trifluoromethyl and halogen. (3) A patent claim in which R_1_0 is unsubstituted or substituted on its phenyl ring with one or two substituents selected from the group consisting of C_1-C_6 alkyl, C_1-C_4 alkoxy, trifluoromethyl, and halogen. A compound according to item 2 in the range. (4) The compound according to claim 3, wherein R_1_0 is unsubstituted benzyl. (5) The compound according to any one of claims 1 to 4, wherein R_5 is hydrogen. (6) A compound according to any one of claims 1 to 5, wherein n is 0. (7) A compound according to any one of claims 1 to 6, wherein p is 0. (8) A compound according to any one of claims 1 to 7, wherein q is 1. (9) HR_5N-(CH_2) n- part is N-R_1
9. A compound according to claim 8, which is bonded to the bicyclic ring in the para position to the _0 moiety. (10) The compound according to claim 9, wherein the bond between the HR_5N-(CH_2)n- moiety and the tricyclic ring is equatorial. (11) The compound according to claim 1, wherein the compound is 3-amino-8-benzyl-8-azabicyclo-[3.2.1]octane. (12) The compound is 3β-amino-8-benzyl-8-azabicyclo-[. 2.1]-Octane The compound according to claim 1, which is octane.