JPS5810581A - Active compound as medicine - 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]

The present invention relates to a group of new compounds, processes for their preparation, their formulation as pharmaceutical compositions and their use in the treatment of disorders. West German Published Application No. 2.748.21!0.6 discloses that as a dopa-containing antagonist having use in the treatment of disorders of gastrointestinal function and/or in the treatment of emesis, (wherein B11 is 01-- It is an alkoxy group, 13'
and 凰, ′ are the same or different, hydrogen halogen h
oFlb hydroxy 7.01-.alkoxy, 0, -, acyl, amino, l or 2 01-, alkyl groups substituted), CL, acylamino, with 1 or 2 C1-.alkyl groups optionally substituted aminocar-nyl or aminosulfone, C! 4 alkyl sulfone or nitro group, X is nitrogen, in this case I'◆鳳' is 3-5,
■' is 2 to 4, mo-' is 1 to 3, or X is OH, in which case 1m'+al' is 2
~5, ■' is 1 to 5, and l' is O~4
, p is O~3, and R4' is hydrogen, C14 alkyl%7 enyl or phenyl ol → alkyl (however, phenyl S++t is C
(optionally substituted with 1-6 alkyl, 0, alkoxy, OF3 or halogen), and S' is hydrogen, or R4' and B, / are substituted with two adjacent carbon atoms. These two carbon atoms together form a fused benzene IIIJ, and this benzene ring may be substituted with 01→alkyl%O1, alkoxy, OF3 or halogen) and their pharmaceuticals. The appropriate amount of salt is listed. In the present invention, we have discovered a new group of compounds that are structurally distinct from known compounds represented by Formula 1 and have useful pharmacological activities, such as dopant antagonist activity. Therefore, the present invention provides the formula (I) Island! (wherein 几1 is 0., alkoxy%02.alkylthio, or together with R8 is 0147h kylene, &鵞h ILI and 1 out of 8 is hydrogen, and the remaining 2 are together Natsu'''CO is dioxyl 7 in alkali, or the remaining two are the same or different, hydrogen, halogen wOF l % 01-4 alkyl, 0!-alcoay, OB-@alkylthio, 01-
v acyl, 01-azilua 2), 0 μ·alkylsulfonyl s 01-1 rusulphinyl, hydroxyl, nitro or l or 2 011 alkyl s C
187 Ri ■ Alkyl, C. 10furkyl o, -4furkyl, phenylmot, < may be N-substituted with a phenylC1-4 alkyl group, or may be N-substituted with ca-allyl norylene, or amino selected from the group consisting of sulfonyl, and a certain L1f'! R1 and R11 together are 01-! alkylenedioxy, and R2 and R3 together are O,-
S alkylenedioxy, or R1 and Rs are the same or different and are selected from the group of substituents defined above. R4, R1%B6 and R1 are the same or different,
Hydrogen, Oto, alkyl, 7enyl or phenyl01-
4 full kill, and its phenyl moiety will eventually become 10, →
Alkyl, o11 alkokene, 0Fst may be substituted with halogen, and at least one of R8, R8 and R is other than hydrogen, R8 is hydrogen or C1-4 alkyl, or R
As defined in 1. p is 0 to 3, m&g is 0 to 3, and n is 0 to 3) and pharmaceutically suitable salts thereof, N
Provides oxides and solvates. Suitable examples of group 1 include methoxy, ethoxy, n- and iso-propoxy, methylthio, ethylthio and 1- and iso-propylthio, or together with R6 is methylene. Preferably bRl is a methoxy group. Suitable examples of R,, Ra and R11 include the following atoms and groups. That is, hydrogen; chlorine, bromine: CF3
; formyl, acetyl, propionyl, zen- and iso-
Butyryl; formylamino, acetylamino, propionyl aono, zen- and istubutyrylamino: methyl,
Ethyl and ethyl and iso-zorobylsulfone, -sulfinyl t+'z-thia;nitro; methoxy, ethoxy and - and iso-propoxy; hydroΦ;
aminocar-nyl and aminosulfonyl and l or 2 methyl, ethyl, n- or iso-propyl, cyclopropyl, cyclobutyl, cyclobutyl,
These are most preferred when methylenedioxymata is ethylenedioxy, where R1 and Rtt carunyl or aminosulfonyl may be substituted by cyclohexyl, cycloheptyl, phenyl or benzyl groups. 7 is ethylenedioxy. Particularly preferred R, , R, and R11 groups include hydrogen, halogen and amino, and acylamino and nitro as "intermediates" which are conveniently converted to the corresponding amine groups. For the same reason, R8 when R11 is hydrogen is generally preferred to be in the 4-position relative to the caryl side chain in order to exhibit less activity in compounds of formula σ). , it is generally preferred that 凰3 be in the 5-position relative to the carinyl chain. Particularly preferred groups include 4-amino and 4-7 sylamino. Silver is also preferably 4-amino. Preferred R1 groups include 5-halo, such as 5-chloro. In other useful compounds 5R11 is hydrogen. and am is hydrogen, 4-halo (e.g., chlorine), or amine; and 'fL3 is 5-01-4alkyl' (U)n (%i-k is 5-methylsulfonyl. -nurfinyl or -thia) or aminosulfonyl which may be substituted at the 5-position. R4s R111> Preferred examples of Rm and R7 include methyl hydrogen, ethyl, Il- and ino-zolopyl, 7-enyl and benzyl. The phenyl group in Rm, "@ and R1 is one or more ol-4 alkoxy (e.g. ethoxy)% C14 alkyl (e.g.
methyl), fluoro, kool or OFm, depending on the case, a4ms, i@ and R will be selected from hydrogen, C11 alkyl or phenyl, most preferably % R4s Kl s R1 and R, are either hydrogen or methyl. 1.1 is hydrogen and R4 is O1j alkyl, phenyl or phenyl (114furkyl), in which either (Defined above,
) may be replaced, and B. is hydrogen, C14 alkyl, phenyl or 7EL01
-4 alkyl, any phenyl portion thereof (K as defined above) may be substituted. In a second distinctive subgroup of compounds of the formula (V), R4 and R5 are both hydrogen, and R? 4-alkyl, any of its 7-modyl moieties may be substituted (as defined above). Preferred examples of R11 include hydrogen, methyl, ethyl and l- and iso-zolopyl. More preferably hydrogen or methyl, preferably hydrogen. Preferred values of p include ! and 2, preferably l. Preferred values of - include 0.1 and 2. Suitable values for I include O and 1. Preferably l.For higher activity, penoff 41 moieties and cyclic side chains may be added in compounds of formula (I). It is generally preferred that the bond between %B, the substituted nitrogen and the carbon atom on the ring to which the nitrogen atom is attached is an equatorial bond (herein referred to as an equatorial bond). is given by the double IJK drawn by trans-fusion and is also called β. The axial bond is similarly given by 4 and is also called α. include the acid addition salts with conventional II, such as hydrochloric acid, hydrobromic acid, phosphoric acid, tartaric acid, lactic acid and acetic acid. Ammonium salts are included. Examples of such salts include, for example, R1--Y (where a, . is 01-alkyl, phenyl, is an anion of an acid. Preferred examples of R1 include methyl, ethyl and o- and ino-zolopyl, and benzyl and phenylether. Examples include hag ions such as chlorine, bromine and iodide ions. , hydrogen, hegenb opm s' 1 coacyl h01-?ashi to amino%01--furkyl 80

[wherein is 0.1 or 2], 2)"bC&-1 alkoxy, hydroxy or 1 or 2 amino, 72-caryl or amino optionally substituted with alkyl groups. Sulfonyl and alkali. Or 凰! and R snow together are methylenedioxy or ethylenedioxy, in which case Rs is R1 above.
and any of the groups given for R. Rs is hydrogen or cl-4 alkyl, and RJ
s R1h as % R? % Ps m and Maro have the same meaning as in the formula ω. There is a group of compounds. From the above, it can be seen that in the compound represented by the formula σ, the moiety included in the formula And so

[B13 is a halogen] A suitable and preferred value for 5°B-11 is a molecule that would have the following formula (C in D:
The same applies to R1 when it is 1-6 alkoxy. Suitable values for B12 include acetyl and propionyl, preferably acetyl. 8° is preferably chloro. From the above, it can be seen that in a group of preferred sub-concepts of compounds represented by the formula (D), the moiety represented by the formula M is
Any of the phenyl moieties of the It will also be understood that 01-4furkyl'), soyzxxs may be substituted (5K as defined above). R1, m, m and p are as defined above. B- and B, l; an appropriate and preferred value is R. and R are as described above. Preferably, one or both of R41 and '&,1 is methyl. Suitable and preferred values for Rs, m, a and P are expressed by the formula [)
As described above in . The part represented by the formula n is represented by the formula (2) (in the formula, 1p1 is 1 or 2, preferably l, B- and 8- have the same meaning as above, and B and 1 are (preferably hydrogen). Thus, one preferred subgroup of compounds encompassed by formula 1 σ) is represented by the formula [■]. The bond indicated by 1 in formula (V[) may be an axial bond or an equatorial bond. Another preferred sub-group of compounds of formula (I) is c in which R1 is hydrogen, 0□-, alkyl, phenyl or phenylCl-4alkyl, and neither of the phenyl moieties is ( 5K) as defined above, and R7"t's 014furkyl, phenylt or 7enyl01-4alkyl, any of the phenyl moieties (as defined above ), optionally substituted]. R6, m, m and p have the same definitions as above. In some cases 'CRsj may be hydrogen. Preferably, ze is hydrogen, and 71 is methyl. Suitable and preferable values for R@, m1 and p are as described above in the formula (D). The moiety represented by the formula (■) is advantageously represented by the formula ■ (where as
”, B10 and pl have the same meanings as above). R- can suitably be axially or equatorially bonded and is very optionally hydrogen. Thus, the formula Another advantageous subgroup of compounds represented by σ) is represented by 2~ In the formula ■, the bond indicated may be an axial bond or an equatorial bond.Of course, the compound represented by the formula ■ It will be appreciated that these stereoisomers have asymmetric centers and can therefore exist as multiple stereoisomers.The present invention extends to each of these stereoisomers and to mixtures thereof (including racemates). can be separated one from the other by conventional methods, or any given isomer can be obtained by stereospecific or asymmetric synthesis. The present invention also provides a method for preparing compounds of formula σ). and this method involves reacting a compound of formula (b) 0Q1 with a compound of formula (XI[)], where Qi is a leaving group and "io or (CHz )qOR
inR15Q2 (where q is 0 or l, and 几!
4 and Rls are both hydrogen, or together form an oxo group, and Q is a leaving group,
or Ql and Q3 combine to form a bridging oxygen atom], R.1 is hydrogen or 01-4 alkyl, and the remaining variables have the same meanings as in formula σ). Then, R1, is (OH2) qOR1a Rt@Qs
and when RtS forms an oxo group, the resulting compound is reduced! , and if desired, comb

Converting the radicals Rl e R3 or 1Ltt in the compound formed into other radicals RN h B I or R11, respectively. The leaving groups Q1 and Q2 are easily substituted by nucleophilic groups 5
This is the base. Examples of such groups include hydroxy, halogen (e.g.
B together with the carbon atom to which they are attached represents a caryl group, an acyloxy group, an acyloxy group, such as a halo-1-alkanoyloxy, a C'l-4alkylcar-eloxy and an activated hydro carpyloxy,
For example, if the leaving group is hydroxy, the reaction is preferably carried out in a non-hydroxyl solvent, e.g.
Dehydration in toluene, or diethyl ether Catalyst 1% Cal I, such as dicyclohexyl Cal I diimide
0 reactions that can be carried out in the presence of shields at non-extreme temperatures, e.g. -10°C to 100°C, e.g.
It can be carried out at 0 to 80°C. If the leaving group is a halogen, the reaction is preferably carried out at non-extreme temperatures in an inert non-human adP sil-based solvent.
For example, it is carried out in benzene, toluene or diethyl ether. It is also preferred to carry out the acid acceptor 1, for example an organic base, in the presence of a tertiary base such as triethylamine, triethylamine, pyridine or picoline. Some of these can also function as solvents. Alternatively, the acid acceptor may be an inorganic compound such as calcium carbonate, sodium phosphate, or potassium legate. It is done in the same way as the customer. Suitable examples of acyloxy leaving groups include '01-4alkano, yloxy, mesyloxy, tosyloxy and trifl-at
e) is included. If the leaving group is 01-4 alkoxycarlyloxy, the reaction is preferably carried out with the acid acceptor 5 in an inert solvent, e.g. methylene chloride, at sub-extreme temperatures, e.g.
It is carried out in the presence of triethylamine. If the leaving group is an activated hydrocarbyloxy one reaction is preferably an inert polar solution #E1 e.g.
It is carried out in dimethylformamide. It is also preferred that the activated hydrocarbyloxy7 group is a pentachlorophenyl ester and that the reaction is carried out at ambient temperature. Preferably when %RIj is B1, Q is a halogen such as chlor. When RI4 and 818 are both hydrogen, ql- and Q-d are the same or different, preferably halogen, mesyloxy, tosyloxy, triflate or hydroxy. Ql may also be ol-4 alkanoyloxy or activated hydrocarbyloxy. Conveniently, the % Q weight and Q snow are the same, especially the same halogen. When R14 and Rli together form an oxo group, Q3
is preferably an activated hydrocarpyloxy group. 'Or bQ! and Qs are both 0, thus anhydrous 7 tal fl! (when q = 0) or anhydrous homo7tal*tq = i) is formed. When R14 and 81 together form an oxo group, reduction of the carzenyl group in the compound thus formed is preferably isolated, isolated, or not. At the extreme it is carried out by reduction with tin/hydrochloric acid at lukewarm temperatures. It will be appreciated that in compounds of formula (I), the bond between the -NIL moiety and the platform side chain can have an α or β orientation with respect to the ring of the bicyclic moiety to which it is attached. . Mixtures of α and β isomers of compounds of formula (I) can be synthesized non-stereospecifically, and the desired isomer can then be separated by conventional methods, for example, by dilatation, or α or β isomers can be isolated. If desired, the corresponding d or! of a compound of formula 0GI) or! Can be synthesized from the form. Alternatively, α and β of the compound represented by formula (XI[)
The mixture of isomers can be synthesized non-stereospecifically and the desired isomer separated therefrom by conventional methods, eg, by chromatography. However, in this case,
The mixture is reacted to obtain a mixture of α and β isomers of a compound of formula (D) and if desired, it is generally more convenient to separate these as described above. The intermediate represented by [) can be prepared in different ways depending on whether the α or β isomer or a mixture thereof is desired.To prepare the α or axially bonded compound represented by formula (■), , CXM). This reaction is conveniently carried out using lithium aluminum hydride under conventional conditions. Compounds of formula (XI) are themselves of formula (XW) 8 by reacting the compound to convert it into a human-like azide and at the same time reversing the stereochemistry.
Can be built. This reaction was described by A, K., Bose et.
, 〒etr@h@drow Letters l 97
It can be carried out by the general method described in 7 @ 23 @ l 977). This can be achieved using phenylphosphine, diethyl azodical I xylate and diphenylphosphoryl azide. The compound represented by formula (ff) is an important intermediate. This is because from these compounds the β isomer of the compound of formula (ff) and the α/! This is because a mixture can be produced. For example, reaction of a compound of formula (ff) with a base and fluorenone yields a compound of formula (XV). The compound represented by the formula (XV) is a compound represented by the formula (XM) [wherein R
9 is hydrogen or Ol, alkyl or phenyl014alkyl (R, preferred values include methyl and sulfur)], which can be converted by using a suitable hydroxylamine into the compound of the present invention We have found that this reaction is suitably carried out using pyridine and the appropriate hydroxylamine hydrochloride at reflux temperature. Reduction of Al1=T^lithium gives a mixture of axially perfected (φ and equatorial bonds) amines of the formula (XI[). Symmetrically, the soluble metal reduction of the compound of the formula (XW) It is essentially stereospecific, giving predominantly the β-amines of formula (■) (if there is a small proportion of the undesired isomer produced by this method, it can be separated by conventional methods). ), such reduction could suitably be carried out using sodium and an adenyl alcohol. When a is 0.-4 alkyl or phenyl-cto4 alkyl, diisobutylalkinium hydride The reduction using mainly α-(axial bond) represented by formula (XII)
Gives amine. The compound represented by the formula (CXW) can be produced by a conventional method.6For example, the compound represented by the formula (XW) in which both m and m are 1 can be prepared by R- from the compound represented by the formula (XW). They can be produced by different methods depending on their properties. When R, is hydrogen or substitutes a carbon other than the carbon adjacent to nitrogen, the reaction can be carried out by reduction, for example using lithium aluminum hydride. When R6 is other than hydrogen and is on a carbon adjacent to nitrogen, it is represented by the formula 1 (xvl), where 8. The compound in which is hydrogen is first converted to the silyl-ether of formula (XW) with a base, e.g. sodium hydroxide, and then with a silylating agent 1, e.g. (014)sscar or hexamethyldisiladene. This can then be done using a 86 metal complex, eg R@Li, and then using eg 1um borohydride. By reduction, it is converted into the desired compound represented by the formula (XP/). The intermediates of formula (XW) are themselves prepared by treating a compound of formula (XX) with formic acid. 1) When ay is hydrogen, a compound of formula (ff) is prepared from a compound of formula (XX) by reduction using, for example, sodium borohydride and hydrogen chloride. or It) When Rf is other than hydrogen, it can be prepared using a Karasui-like metal reagent such as FLlLi or RfMIX (wherein X is H),
The compound represented by the formula (XX) itself is a compound represented by the formula (XXI), an alkylene halide, for example, 4
-brombu)-1-ene with a base, or by reaction with the formula (XXTi)R. (XXl[) It is produced by thermal decomposition of the salt represented by IP. Note that the salt represented by formula (XXI[) can be produced from the corresponding dicarlic I acid and primary amine. Such a compound of formula (XXI[) is (Xl
It can be produced by the [)-(XX) to tXK)-(X■) route. (It will of course be understood that the reduction of (X[) from C(XX) in such a reaction sequence will give a mixture of isomers, which can be separated by conventional means). Or when both %m and meal are l, ketone (
XV) can be produced by acid-catalyzed condensation of a compound represented by the formula (XXl[)] or its ketal derivative. Ketones (XV) can also be prepared by ring closure of compounds of the formula (Xff) (OHdmY, where W and Y are either cal-7 acid ester residues having up to 12 carbon atoms or nitrile 6). Suitable values for W and Y in the case of cal-7 acid esters include 01-4 alkyl esters such as ethyl esters. The conditions for this reaction are similar to the standard Di@ckma ring closure reaction. Compounds of formula (XXI) are known or prepared by standard methods such as (XXV) and (XXM) when one of R4'' is hydrogen. (XXV) (XXVI) The above reaction of course produces a compound represented by formula (XM) in which B- is hydrogen. If a compound is desired in which B is alkyl, this can be easily prepared by alkylation from the corresponding compound where B is hydrogen.This can be prepared by any suitable method, e.g. Any enantiomer, or mixture of enantiomers, of the compound of the formulas (XIN), (IF/), ('N) and (η1) can be achieved by acylation with al2ni^lithium hydride. It is understood that it can be used if it has the spatial relationship illustrated between carbons 1 and 1, and the intermediate of formula 0[) is an omniscient compound or can be prepared by analogous methods. The intermediates of (XI), (X) and (Xl) are novel and thus form an aspect of the present invention. For example, straw can be produced by the following six principles using m-chlorobenzoic acid.The addition salt of a compound represented by formula (I)-c& can be prepared by reacting the compound represented by formula (I) in base form with a selected salt. The quaternary ammonium salts of compounds of formula (D) can be prepared in a manner conventional for such salts, e.g. The reaction mixture can be prepared by reacting with the compound RsY as described above, preferably in a suitable solvent such as acetone, methano-5-ethanol, or dimethylformamide at ambient temperature and pressure. The choice or necessity of converting the groups Is, sec3 and/or R11 to other groups RhR5 and/or Rlt will be understood by those skilled in the art in the substituents R1%'& 8%. It will be appreciated that this is governed by the nature and location of B-11. R convertible into other “2 s R1 or R11 groups,
It is clear that compounds of formula α) containing R or 81 groups are useful new intermediates. A number of such transformations are described below, as well as in the case of the final compound of formula 1. Intermediates thereof are also possible. (Hatatake) Hydrogen substituents can be converted to nitro substituents by nitration, and (b)=)El substituents can be converted to amino substituents by reduction. (c) The 014 azila Z substituent can be converted to an amino substituent by deacylation. -) The amino substituent can be converted to an ol-4 acylamino substituent by acylation. (·) Hydrogen substituents can be converted to halogen substituents by halogenation, and (f) Os-s furkylthio or 0, alkylsulfinyl substituents can be converted to 01-, Ak*#, respectively, by oxidation.
It can be converted to a sulfinyl or 0-fold 1-alkylsulfonyl substituent. The above conversions -) to (f) are merely illustrative and do not represent all possibilities. Regarding (a), the nitration is carried out according to a known method. (b) Regarding K, the j1 element is carried out using a suitable reagent to convert nitroanisole to the 72 noanisole KR element. (c) Regarding K, deacylation is carried out with MIIK using a base, e.g. an alkali metal hydroxide. -), the acylation is carried out with an acylating agent, e.g. the corresponding acid or an acid, and the formylation is carried out with the free acid. Go 5. Regarding -1), halogenation is carried out using a conventional halogenating agent. Regarding (f), the oxidation is carried out in a non-aqueous solvent at below ambient temperature;
for example in the presence of an organic peracid, such as 3-cool perbenzoic acid, in a chlorinated hydrocarbon, or a soluble strong inorganic oxidizing agent,
For example, it is carried out in water in the presence of an alkali metal permanganate or in an aqueous hydrogen peroxide solution. As mentioned above, compounds of formula (D) are dopanno-antagonists. Compounds of formula α) can be used to treat disorders associated with impaired gastrointestinal motility, such as delayed gastric emptying, dyspepsia, Can be used to treat q1 bulging, esophageal reflux, peptic ulcers, and vomiting. Accordingly, the present invention also provides a pharmaceutical composition comprising a metal compound of formula (D) or a pharmaceutically suitable salt thereof together with a pharmaceutically suitable carrier. Such compositions may be suitable for oral or parenteral administration. They can themselves be tablets, capsules, oral liquid preparations,
It can be in the form of a fistful, a syringe, a lyophilized powder, an injection solution or a suspension, and the like. The composition may be in the form of a suppository, but it is usually preferable to use a composition that can be administered orally. Tablets which may be in dosage form and which may contain conventional excipients, such as binders, fillers, tableting lubricants, disintegrants, suitable wetting agents, are well known in normal pharmaceutical practice. can be coached using the methods provided. Oral liquid preparations may, for example, be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or be reconstituted with water or other suitable vehicle before use. It may also be provided as a dry i-powder. Such liquid formulations contain the usual additives 1, e.g. suspending agents, emulsifiers, non-aqueous media (which may contain edible oils),
It may also contain preservatives and, if desired, conventional flavoring or coloring agents and the like. For parenteral administration, liquid unit dosage forms are prepared using a compound of formula α) and a sterile vehicle. Compounds are % dependent on the medium and concentration used. It can be either suspended or dissolved in the medium5. To prepare the solution, the compound is dissolved in water for injection and P
Advantageously, adjuvants such as local anesthetics, preservatives, and buffering agents can be present in the medium, which can be sterilized, filled into suitable vials or ampoules, and sealed. Parenteral suspensions are prepared by substantially the same method except that the compound is suspended in the vehicle instead of being dissolved and sterilized by exposure to ethylene oxide and then suspended in the sterile vehicle. do. Advantageously, a surfactant or wetting agent is included in the composition to promote uniform distribution of the compound. As is common practice, the compositions will usually be accompanied by handwritten or printed instructions for use in the relevant treatment. It will, of course, be understood that the precise dosage to be used in the treatment of any of the disorders mentioned above will vary depending on the actual compound, such as the extent of the disorder being treated. The present invention further provides for delayed gastric emptying in mammals, including humans, comprising administering a therapeutically effective compound of formula (I) or a pharmaceutically suitable salt thereof.
Methods of treating disorders related to impaired gastrointestinal motility such as indigestion, bloating, esophageal reflux, peptic ulcers, or vomiting are provided. An "effective amount" will usually vary depending on a number of factors, such as the nature and extent of the disease being treated, the weight of the patient, and the actual compound used. However, to illustrate, the unit dose is α005~2
It will contain a compound represented by the formula (1) of Further, by way of example, such unit dosages preferably include:
More than once every 5ect days, so that the total dose for 8 hours will be in the range of α01-20-7 hours per day. For example, 2.3, 4.5 or 6 doses per day. Compounds of formula (D) have the ability to enhance the effectiveness of conventional analgesics in the treatment of migraine when administered simultaneously with them. and an analgesic together with a pharmaceutically suitable carrier. The compounds of 2) and an analgesic, such as asgirin or racetamol, are generally administered in their usual effective dosages. The combination product 1, for example, a tablet or capsule containing both a compound of formula (p) and an orally administered analgesic agent, or both active ingredients. The present invention also relates to a method of treating a disease comprising administering to a patient a therapeutically effective amount of a compound represented by formula (D) or a pharmaceutically suitable salt thereof. Hereinafter, the production of a compound represented by the formula (p) will be illustrated by Examples, and the production of intermediates will be illustrated by Reference Examples. In the Examples, ω indicates that the compound is racemic, However, for convenience, only one type of enantiomer's structural formula was illustrated. Reference Example 1 (,a) (Support) 9α,β-methyl-1-arp-5
α-H-bicyclo(4,3,0)nonan-7-one also (D, l m ) @ compound f#7.8.9.1G. 11. Intermediate HD of 12 and 13, la 4-72 butyraldehyde diethyl acetal (&2
A mixture of jl ) and 3-pentan-2-one (25 g) was left at room temperature for 1 hour. Then Ete# (50
m ) and 2N hydrochloric acid (50 ml) to form an aqueous II
The reaction mixture was then heated in a steam bath for 2 hours, and the cooled reaction mixture was concentrated in a rotor 9, and the residue was treated with methylene chloride (lOOJllj) and a saturated potassium carbonate bath. did. The organic layer was extracted two more times with methylene chloride (SOaj). The combined extracts were dried (K, 001), concentrated and the product was chromatographed on silica (eluting with ethyl acetate). g) 9β-Methyl-1-aza-5α-H-bicyclo(4,3゜0]nonan-7-one (D, 1m) (ZOjF, 60°C) was obtained. Picrate Melting point: 179°C (decomposition) ) (ethanol/acetone) Furthermore, by elution with ethyl acetate/2-methanol, (t)9α-methyl-1-aza-5α-H-bicyclo(4,3,0)nonan-7-one 0°131 ') (α5
1. IS(O) was obtained. Picrate, melting point 190-1910 decomposed) (ethanol/acetone). Following the method described above, the following ketones 1101) to (- were prepared. (b) (k39.9-Dimethyl-1-aza-5α-
H-piacro(4,3,03 nonan-7-one (DLm
) (571G, boiling point 65℃/l W) (Vitalin 111 @ 179℃ (decomposition) at one point, compound 14s15
．． Intermediates of i6 and 17 (c) (t) 9-Methyl-3-phenyl-1-aza-5α-H-pisic (crow, 3.0) nonan-7-one (D, lc), compound i8 .19*2G. 21.22 and 23 (D intermediate isomer 1 (D, l@) 19- isomer 2◆3 (D, lc) 27 arrogant (d) (t)2-methyl-1-af-sα-H -Bishitaro (4,4
,01 decan-4-one (D, ld) compound 2<, 2S
, 26.2'1.28 and 29 intermediate D, 1m 2-β-methyl (D, 1d) 57, picrate melting point 179-180°C 2-α-methy#(D, ld') 211 , Picrin tIl
One point of salt 187-189℃ (a) (g) 5α-methyl-1-aza-bicyclo(
4,3°O) nonan-7-one (D, lc), compound 1
Intermediates of 0 and 31 (t)7β-hydro,
To a solution of 2411) in dry sphincterol (100114) was added gal9um 1eft-butoxide (8Ii) under stirring and the solution was stirred for 30 minutes at ambient temperature. The product is 5N
I[11 (extracted into SojIjJ and ethyl acetate (2X
1GG11j). The aqueous phase is neutralized and then saturated with potassium carbonate and methylene chloride (xxioom).
Extracted with. By removing the solvent, crude (a) 5α-
Methyl-1-azobiccyclo(4,3,0)nonane-7-
On (111.) (4.0#, about 100 vomit) was obtained. (f) (!J9α-ethyl-1-other 5α-H-bicyclo(4,3,0)nonan-7-one (D. If) (15s3. Intermediate of compounds 32 and 33) (g)9α- Isozorobyl-aza-5α-H-bicyclo(4,3,0)nonan-7-one (D. Ig) Reference Example 2 (1) (4) 2β-phenyl-1-aza-6α-H
-bicyclo(4,4,0)decane-4-oneoxy^C
T12m), intermediate h of compounds 1.2 and 3 (t)2β-phenyl-1-aza-60-H-bicyclo(:4,4.0)decane-4-one (5,ON) in ethanol (601j ) was treated with pyridine (51!j) and hydroxylabane 41!1m (5N) and the mixture was heated to reflux for 1 hour. After cooling, the ethanol was removed with a rotary enodecerator and the residue was diluted with dilute potassium carbonate solution for 46 minutes. The product was extracted with methylene chloride and dried (Kz OOm
), crude 2β-phenyl-1-aza-6α-H-bicyclo[4°4.0]decane-4-oneoxy A (D, 2a) (4,8,f, 90
vomit). The following oximes were prepared from appropriate droxyluane according to the method described above. (kl (t)2α-phenyl-1-af-6α-H
-bicyclo(4,4,0)decane-4-oneoxy^(
D, 2b) (95 ml), intermediate of compounds 4 and 5 (c) (t)9β-methyl-1-aza-5α-H-
Bicyclo(4,3,0)nonan-7-oneoxy A(D
, 2c) (801), compound 6.7° Intermediate of 8 and 9 (d) (g) 9α-methyA--1-aza-5α-H
-bicyclo(4,3,0)nonane-7-one-oxy7m(
D. 2d) (80%), intermediate of compounds 10 and 11 (@) (t)9α-methyl-1-aza-5α-H-
Bicyclo(4,3,0)nonan-7-one 0-methyloxy^(D,2e) (1001G), intermediate (f) of compounds 12 and 13 (4) 9,9-dimethyl-1-aza- 5α-
H-BisicEl(4,3,0)nonan-7-one oxime CD, 2f) C90), intermediate CHs of compounds 14 and 15 (2)(t)9.9-dimethyl-1-7-de5α- H-
Bisitalo (4,3,0) nonan-7-one 〇-methylome (D, 2 N ) (approximately 1001) Intermediate (k) of compounds 16 and 17 (t)9-methyl-3-phenyl- 1-aza-5α-H-piacro(4-3*0)nonane-7-
Oxime, isomer 1 (D, 2h) #100) 1 Intermediate of compounds 18 and 19 (Todoroki) (To) 9-Methyl #-3-'Phenyl-1-aza-5a-H-pi7ly aC4 , 3,03 nonan-7-one oxime, isomer 2◆3 CD. 2i) (#100 #
), intermediate (j) of compounds 20.21.22 and 23 (support) 2β-methyl-1-aza-68-1 (
-bicyclo(4,4,03decane-4-one 〇-methylox'zA(D,2j) (approximately l OOs). Intermediate Hs (kl (t)2a-methyl- 1-Aza-6α-H-
Bikuku■(4,4,0)decane-4-one O-methyloxime (D.2k) (approximately 100% 3° Intermediate 0 of compounds 28 and 29) (Support) 5α-methyl-1-7 zapisic stomach [4,3
゜0] Nonan-7-oneoxy^ (D-2 amount) (approximately io
), intermediates of compounds 30 and 35 - ω9α-Z f 1-aza-5O-H-piacro(4m3*o]nonan-7-one oxime (D, 2
Sono) (95), Intermediate of Compounds 32 and 33, 2wa m, 8. M 182L1423 (II logical value 18l82
-1411 1) ((k39α-inobuvir-1-aza-5Q-H
-bicyclo(4,3,0)nonan-7-oneoxy^(
D. 2111) (100 哄), Compound! $4 and 35 intermediate ws, 8. M 196.1569 (II spear value x9 &
xs76)D. 2p) 9β-isopropyl-1-af
-5B-bisitalo(4,3,0)nonan-7-one oxime (D,!?) (approximately 100 ml). Intermediate reference f13 of compounds 36 and 37 (a) m4α,! -Aden no zloy enil l-7!
-6α-H-bisitalo(4,4,0)decane(I)-s
a) Dry TH of hydrogen 1#S lithium aluminum (151) to intermediate P of m compounds 1.2 and 3
Crude 11(I)2β- suspended in F(load) [K under stirring
Fenik -1-other@a-H-pisik a (4゜4.
A solution of decane-4-one oxime (D,l) (481) in dry rHF (50 red) was added dropwise at a rate such that a gentle reflux was maintained. The mixture was then refluxed for a further 18 hours and cooled to decompose the excess hydride. Purification and concentration of P solution yielded crude (t) 4α, β-adenmenor 2β-phenyl-1-aza 6α-H-bicyclo(4,4,O)decane (D, 3a)
(40#, 85s) t' obtained. According to the method described above, the following i7pvm was constructed. (呵 (1) 4α, β-7 ono 2α-7 enjiru l-
af-6α-H-'cyclo(4,4,07decane (D,
Rh ) (approximately lool) m Intermediate of compounds 4 and 5 (C) (to) raml-amino-9β-methyl-1
-aza-56-H-biscou(4,3,0)nonane (D
. 3C) (approximately 100◆), intermediate of compounds 6゜7.8 and 9 (d(t)phα,β-adenno9β-inopropyl-
1-7 Day 5α-biaclo(4,3,0)nonane (D. 3-) (approximately 100 pieces), intermediate reference example 4 of compounds 36 and 37 (a) (t)7β-amino-9a-methyl -1-aza-5α-11-bicyclo(4,3,03 nonane (D. 4a), intermediate of compound IO and 11 (90-methyl-1-aza-5α-H-bicyclo(4,3,0 )-7-
amyl alcohol of one oxime (D.q)t2.0Ii) (80114)
Heat the medium solution to reflux for 1 hour while adding sodium (
Approximately 7. QI) was added little by little. After all the sodium has reacted, cool the solution and carefully add 5 Nm
Careful ICII conversion was performed with E (approximately 60 g). This amyl alcohol is converted into ethyl acetate (2XlooMt).
The aqueous phase was basified and saturated with potassium carbonate and re-extracted with methylene chloride (3 [4°3.0] Nona 7
(D.4a) CL51. I got about 80-). The following amines were produced according to the method described above. <b) (g)7β-amino-9,9-dimethyl-1
-aza-5α-H-bicyclo(4,3,0)nonane (D
, 4b) IJloos), intermediates of compounds 14 and 15 l-aza-5α-H-bicyclo(4,3°0]nonane, isomer 1 (D, 4e) (about 100s), compound 18
and 19 intermediate T), 4c (d) (e) 7-β-azuno 9-methyl-3-7
Enyl-l-aza-5α-H-bicyclo(4,3゜0)
Nonane, isomers 2 and 3 (D, 4 您) (approximately 90 degrees), intermediate D of compounds 2Q, 21.22 and 23, 4d (·)(t)7β-amino-5α-methyl-1-aza C
Schiff H (4,3,01 nonane (D, 4e) (50 fluent),
Intermediates of compounds 30 and 31, 4s Voice point 60-63°C/l (f) (g) 7I-Aino9α-ethyl-1-7
Day 5 (1-H-pisic0(4,3,0) nonane (D,
4f) (100%, member), intermediate of compounds 32 and 33,
-aza-5α-1(-bicyclo(4,3,0)nonane(
D-4g) (100-1 crude), compounds 34 and 3
Intermediate Reference Example 5 (a) (e) 7α-Aino9α-methyl-1-aza-5α-H-bicyclo(4,3,03 nonane (D.
m)+# Intermediate of compounds 12 and 13 Dissolved diisozorobylaluminium hydride in toluene i
Dry Ti of 5α-H-bisitalo(4-3a O)nonan-7-one O-methyloxime (D2c) (1371)
1 l' (100 μ) of the solution was added under stirring, and the solution was diluted to 1
The mixture was heated for 8 hours at m current. After cooling, the excess hydride A was decomposed and the reaction mixture was filtered. By concentrating P solution, crude (2) 7α-amino-9α-methyl-1-aza-5α
-H-pisict”[4,3,0)nonane(D,5m)(
1.OJF. Approximately 100 arrogance) was obtained. According to the method described above, the following seven compounds were manufactured. (b) (g)7α-amino-9,9-dimethyl-1
-aza-50-H-bicyclo(4,3,0)nonane (D
, 5b), (contains about 90% and 25% of the 7β isomer), Intermediates of compounds 56 and 17 (c) (g) 4α,! -Annor2β-methyl-1
-aza-6α-H-bicycloC4,4,0]decane (9
, 5c) (approximately 10011), intermediate (d) of compounds 24°25.26 and 27 @+-β-amino-2α-methyl-1-aza-6α-H-bicyclo(4,4,0)decane (D , 5d
) (approximately 1001, intermediate Hs 11k 5m of compounds 28 and 29 Example 1 (e) 4-7cetamido 5-chloro-2-methoxy-
N-(4'-(1'-aza-2'β-7enyl6'α
-H-2cyclo(4,4,0)decyl)]benzand (1m) and (1b) toluene (250d)Ji[)1
4-a7door 2do-5-chloro-2-methoxypenzoyl chloride (57,
9) Crude m (support) 4α, β in toluene (2011J)
-Amino-2β-7enyl-1-af-6α-H-bicitaro (4#4.0) Decane (D, 3m) (40II) (
The reaction mixture (prepared as in Preparation Example 31) was stirred at room temperature for 4 hours and then treated with ``Z5N hydroxide hydroxide 91ml 11JIj).The toluene layer was separated and the aqueous phase was diluted with chloroform (2x 109g) and the combined extracts were dried (Ks 00g).
*The solvent was removed, and the resulting oily substance was subjected to atomography (Arunna/3 water, ethyl acetate) to obtain a mixture of isomers. Trituration with petroleum gave one isomer of the title compound (1 g) (LO#, 1396) as a sticky solid. The other isomer of the title compound (
An oil containing lb) (319,47s) was obtained. Example 2 (a) 4-amino-5-chloro-2-methoxy-N-(
4/ ++ (l I-aza-2β-phenyl-6α′
-H-bisic*[+,4.0]decyl)]benzP4ha1 (1m) (1-0,9) (prepared as in Example 1) in ethanol (2011j) and aqueous sodium hydroxide solution ( Z5N: 21fj) was heated under reflux. After cooling, water (loOjlj) was added and the resulting solid was collected. Ethyl vinegared rice/By recrystallizing from petroleum (g)
4-amino-5-chloro-2-methoxy-N-(4'-
(1'-aza-2'β-722-5'α-H-bisic"(4,4,0)decyl)]4 isomer of dzamide (2)^ (α71.'lS tatami), 8 A point of 228-230° C. was obtained. (Note: For isomers) is either the axially bonded (or equatorially bonded) form of the title compound. Example 3 Lk34-amino-5-ri-2-methoxy 7-N-(
4'-(1'-aza-2'β-phenyl-6'α-H-
Bicyclo(4,4,0)decyl)] sulfonamide (3)
isomer...) According to the method described in Example 2, (t)4-acedoamide-5-chloro-2-methoxy-N-(4'+ l I
-aza-2'β-phenyl-6'β-H-pylaci
a4*o) Decyl) The crude second isomer (3,6 g) of benzami F' (2) was converted into (t)4-amino-5-chloro-2
-methoxy-N-(4'-(1'-aza-2'β-phenyl-6'α-H- to 'Schiff-linked (4,4,O)decyl]]penzaide 13) (] 2N, 35'l), melting point 204-206°C. (Note) Isomer (2) is the axially bonded (2)) or equatorially bonded form of the title compound, isomer (A) (Example 2) That is not the case. According to the method described in Examples 1 and 2, the following 4-72
and 4-acedooxide compounds were produced. yield(%)
is shown in parentheses. Example 4 (a) 4-7cetamido-5-ri-a-2-methoxy-
N-(4'α,β-(1'-aza-2'a-phenyl-6'α-H-bicyclo(4,4,0)decyl)]penzuad(4) (2613, as oil Example 5 tIJ4-a1)-5-chloro-2-methoxy-N-(
4'Q, β-(1'-Aza-2'α-7E-6'α
-H-Bincro C+a4*o〕def)h)〕Pevenzukid (5) (80-3, melting point 233~2'J4℃(0HO
JP3 /; 5 oil) Example 6 ω4-acetamido 5-restomy 2-methoxy-N-
(7'β-(9'β-methyl-1'-azo-5a-H-
463 (4,3,0)nonyl)
(38 capsules), by ethyl acetate trituration of the mixture of a and β isomers. N, m, r, (δ, 0DOII) * 3-7.4 (e
a a 4 H*Ar0ON)i. onsc, ONli, eg ais. S and &Q3. s, both Xi (. aromatic B); 4.5-! 9(a.
-,31(.J"6Hz,=OHOH1) Example 7
5′α-H-bicyclo(4,3,01]nyl)]benzamide (7) (approximately 50%), from concentration of the mother liquor of Real Jltflll (6), N, wbr, (J, ODOIm): &5 −
7.7(m, 4H, Ar0ON)I. c) 1sUON)1. For example, &16°S and &
0+*se Both are IH. Aromatic! Ri: 447-1O(,6H, fatty yCH. For example b'92*I@3)1#00
轡): Z7-LO (Peng, 16H, remaining Zoloton, e.g. %'L24 @ @ # JIIeo
00 H, and L12. d, 3H. J-@kl breath, 0HOHs). Example 8 (t)4-Amino-5-recognized-2-methoxy-N-(
7'/-(9'/-methyl-1'-aza-5'α-H-
Bicyclo(4@3.0)nonyl)]benzamide (8)
(6011J, mp 170-171u (ethyl acetate/petroleum) (prepared from compound 6) K & r, (J, 0DO
jsL-&03 (s e AH# aryl 611.)
;7.7 7.3 (m * l ki-0ONIJ
) ea23(s, 1)1. Aryl 3H): 46-1
6 (Peng* 6 kl m H* N@fatkang Ho analogy fu8 Q -s @ 3H,0OHs); ! 445-3LO (, 1B, aliphatic H); Z5-a9
(m, 14)1. The remaining protons, e.g. Lll, d
, 3H. J"6Hz,=OHC)jl). Example 9 (t)4-amino-6-chloro-2-methoxy-N-[
7'α-(9'!-Methyl-1'-aza-5'α-H-
Bicyclo(4,3,03]nyl)]benzamide (9)
(40 liters) 111 to 238°C (ethyl acetate) (manufactured from compound 7) NH.
O(s#lj(a aryl 6M); &l'-79
(m-I Hs 00 NH); Out 41 (#*l)
i, aryl 3H];46-43(Peng, 3H,N)I,
and 0ONHOH); :L, 91 (s -:j Ha OOH2) ;3-
4-ml (m, 114 a & aliphatic H); 22-5-
LX(, 14H, remaining protons, e.g. Li2.d. 3H,J=龜lHzgOH1). Example 1O (t)4-acetamido-5-chloro-2-methoxy7-
N-(7'β-(9'α-methyl-1'-7d5'α
-H-bicycloC4,3,0)nonyl)]benzamide α1 (75 pieces), oil as K&R. (J, 0
DOII): &15-7.4 (so, 4H1A
tt. NH, OH, 0ONH, for example. & 15 @ @ * and &05. s, both IH,
Aromatic H): 45-3.7 (m, 4B, aliphatic dan. Example &'4 3.89.s, 3B, OOH,); 16-
0.9 (am −19H*remaining protons, e.g.
Z25. s, 3H. 000Hs and LO5,d,3H. J-6HzlOHOH1). Example 11 (1) 4-amino-5-cool-2-methoxy-N-[
7'β-(9'α-methyl-1'-aza-5α-H-bicyclo(4,3,0)nonyl]]4-dzamide Ql (7
0%), #111 point 164-166℃ (equipment ethyl/petroleum) approximately 1r, (δeODO1g) * 8.06 (@
# l) 1m aryl 6B) Near, 6-7.4 (m, lH, published by OOH: &30 (m, I
H, aryl 3H); 4.65-18 (m, 6H, N!!j. Aliphatic H, e.g. -0
．． 9(m, 14H, remaining protons, fII, 1.
06. d, 3H. J"6.8Hz 0HOH1). Example 12 (g)4-7cetamido 5-chloro-2-methoxy-
N-(7'α-(9'α-methyl-1-aza-5'α-
H-bicyclo(4,3,0)nonyl)]benzamide (
b) (70s)% oily substance, r,
(J, 0DOjl): 126-7.4 (me 4H
a For example, 3265 m5 and &14゜easy, both IH, aromatic H): 4.5-F4 (+n, 5H, fat visiting and 1 For example, F93.s*3iis 00) (3); 3. 2-α8(lfi, 17)1. remaining professional)
flited Z26, *, 38°000H wealth and α9g, 41.3)i. J=7Hz, 0klOHs). Example 13 (Support) 4-amino-5-chloro-2-methoxy-N-
7'α-(9'α-Methyl-5'-7-5α-H-bicyclo(4,3,0)nonyl)]
(40% tri-fused A169-171 C (ethyl acetate/petroleum) H3 N, wbr. (δ, CD0II): ax 2
(1@IH#aryl6H);78'L 5
(mal I($ 00 N II) 16.32
(@@1Hs71J-ru3H);47-3.8(m,
6H, aryl NH snow, aliphatic Hl e.g. 3.89 s s * 311,0cHS); 3.8-
1.0 (m, 15B, remaining protons, e.g. 1.1
2, 1, 3H. J=6Hz,0CHI) Example 14 (Support) 4-7 Cetamido 5-chloro-2-methoxy-
N-(7'/-(9',9'-dimethyl-1'-aza-5'α-H-bicyclo(4,3,0)nonyl)] Penzadendo(b) (65 whisper), oil as a substance

[N, rrb r. (J, 口I) Oli:
13-7.4 (sa, +ii -mu r
o. are &11-$lH and &Ql. &, IH, both aromatic H); 46-18 (a, 4M, aliphatic Ho, e.g. 1lla, s, 311°0014,); i, 3H, OOH@ and 11'l@*: 4H and 101 m@#3H (all three Q-o11s). Example Is (Support) 4-P2 No 5-Kuru 2-Methoki 7-N-
7'β-(”*, s'-dimethyl-1'-azo-5'α
-H-bicyclo(4,3,0)noni-k)] benzua chloride (75 ring), 5114112-115℃ (ethyl acetate #
/oil) N1. re (J, 0 DOI,): N08 (se
ll(s aryl 6→;7.7-7.3(so, IH,
0ONB);45-3.7 (III*61(a
NHj#Aliphatic Hl e.g.
s @ 3 H @ both OH @). Example 16 (Support) 4-acetoand-5-chloro-2-methoxy-
N-(7'α-(9,9'-dimethyl-1'-aza-5
'α-H-bicyclo(4,3,0)nonyl)]benzy
tl"@, (80s, containing about 2rh% 07'l isomer) as an ilk-like substance. K&r, (J, 0DOII): &3-"7-4
(Peng, 4H, Ar0ONH, O)j@CjONH*
For example, JImo IL! 1. s, llI and &13゜@@I H@all aromatic H0 However, 7'a isomer: &oi. S but 7'/isomer): 46-λ6 (ugly, 4H1 aliphatic Ho e.g. 111a #3H. oans and:tSSO scrap, but 7eil isomer); &l-(L7(m,24)i(-remaining proton, f#
For example, L22mma3Ha 000H, and 117, 1.12 and 101 but OH,). Example 17 (t)4-amino-5-t4-2-methoxy-N-(
7'tX-(9',9'-dimethyl-1'-azo-5
'α-H-biscou(4,3,0)nonyl)] Penzua H'so (6o duck, containing about 25% of 7β' ulcerative body), Peng point 188-189C (ethyl acetate HaN, m, r, (δ, ODOhos):
JL 12 (s # 0.7 S Ha aryl 6H
): &08 (i, α25H, aryl 6H) (β isomer): [15-7,9 (m, a7sH. 0ONM); 7,7-7.3 (rn, α25H. 0ONH) (β isomer) : 6.30 (2g) (2 single wires, 1H1 to 3
H); 47-4.0 (wa, 3 H-N Hs and aliphatic!ri; 347 (1g4) (two heavy electric N Ha OOHm); 3-2-α'9 (1,18) 1 .Remaining zone m) zone 1 eg 118°112 and t041 single & 0Hs). Example 18 (g)4-7cetoide-5-ri-2-methoxy-N-(7'β-(9'-methyl-3'-7aeru')
-aza-5'α-H-pintaro[4,3°O]nonyl)
] 4nzamide @ (approx. 100 mu). Ni (00 (IHm isomer theory, ah r, (J, ODO heavy B) as an oily substance
: 1L3-7.4(ms411.AroONu,
0Hs0ONIH, analogy & 13. s, IB and &07. @. In, both aromatic Hl; 120, s, 3H, 0001js and 110
, d, 3H, 0) 10) 1. . J = 6H recommended). 1.1. M, 45&19@7 (theoretical value: 455.1
975) Example 19 (to) 4-amino-5-riru 2-methoxy N-(
7'/-(9'-Methyl-3'-phenyl-!-Ather 5'α-H-piacro(4,3,...]nonyl)]]Penzua Dendo Hydrochloride @55 Tatami) Melting point 161-171C (
ethanol/ether) fia ws, r, (
δ, d@DM80) a 8.0-7.1 (m, 7
H, OONM and aryl H]; 6.55 (s, lH, aryl 3H): 4.4-3.0
Cm, 11 H, aliphatic proton 10 NHz Jf
if aliphatic 1 field 5゜d H* s s 00113)
e2.6-1.6 (n, 6i1. aliphatic ° proton); 1.35 (d, 3B, 0HOH,. J = 6H window) Example 20 Ta4-A7toAndo5-Chlor-2- Meto life sea N-
(7'β-

[9'-Methyl-3'-phenyl-1'-azo-5'α-H-bicyclo[4,3゜01]2k) 3benzado-4, isomer 2 (56 liters), as an oily substance [Fraction (1), N-m-r-('5ODO11)a &3-7. S
(m-4)1 @A r OON H, OHs 00
7.25-[95(brs, 5N. Aryl H): (4-1g (s*21H#!l protons, e.g. %龜87.@. :iH , OOH, ;zzs, s*:i H,0OOH, and 113°d ,3H,0HOHs ,J4H slack]. -, Lu, M 45 & 1976 (II Noodle Direction: 45
5.1975). Example 21 (to) 4-amino-5-cool-2-methoiminocy N-
,7'β-(9'-methyl-3'-phenyl-r-7za5'a-n-pink!(4,3,0)nonik)]penzaden F-ring isomer 2 (S@ 11 points 98~9#C (ethyl acetate/petroleum) 9&re (J, 0DOIB): JLO
9 (s, 1B, Ally #6dan); 'L 75-'L S (b t d # l lj
-0ONi(); 7.3 7.1(bri, 5B, aryl H]: 6.28(s, IH, aryl 1...; 45-3.2(zen, 8H1 aliphatic CH and aryl Nu(snow 1) For example, 186 # I @ 3H # 00Hs ); 2,
$-18 (Rin, 7B, aliphatic OH); 11@(d, 311,0HOH,. J=6.2Hz)・Example 22 (T)4-acedokendo-5-kuru-2-methoxy-
N-(7'β-(9'-methyl-3-phenyl-1'-
Aza-5'α-H-bicyclo(4,3°O]nonyl)
Qi Zuan 11 isomer! (15 arrogance), fraction (2) as an oily substance, silica/suryo ethylka 2^ chroma dog 2 fee. N, m, r, (J, ODOlg): &3-
6.9 (m a 9fi *Ar0ONH,0R30
ONH. For example, &t9. Crow, lH and &10 # I # i) j and 717° b r a,
all aromatic H); 44-LO(Ill, 211(, remaining protons, e.g. 186.s. 3H,OOH@e Z23 m 5a3H,0001
1m and 4°d, 3H,0HOj(,.J=]H wisteria). m, a. M 455.1180 (theoretical value: 45
5.1975). Example 23 (e)4-amino-5-chloro-2-methoxy-N-[
7'β-(9'-Methyl-3'-7AE-1'-aza-5'α-H-bisic α(4,3,0)nonyl]] Benzamide isomer 3 (55%) Melting point 229~ 230℃ (
Ethyl acetate/petroleum isomer 3 N, & r, (a, oDoil): aQs (
s, l)I, aryl 6M); Z65-7.4 (brd, 111°aONH); 7.25 (krs, 5H, aryl H); 6.28 (a,, IH, aryl 3H); 4. 6-4.0 (candy, 3) (, N & 4 Ri and N) IOH
-); 3.86 (s, 3H, OOH@); 165-1
．． 0(m, 14H, remaining proton, e.g. L13.d. 3 HOHOOs * J ” & 8 Hυ. Example 24 (Support) 4-acetamido-5-chloro-2-methoxy-
N-(4'/-(7'/-methyl-1'-aza-6'α
-H-bicyclo(4,4,0)decyl)]Penza ζ Do (TO 茶) From the crude reaction mixture, triturate with ether (as a sticky solid) to obtain mono-N, &r. (J, 0001g):
&3-7.5 (m, 4H, Ar0ONH. OH2OOON H# e.g. aztsssIH and &lO
, Hatake, IH, Aryl H); 44-10 (m -24Ha remaining proton, e.g. 3.8g, s, 3H. 00 H3; 2.23 #I, 3H-ooon, and Li2.d, 31° 0HOHs, J-6Hz). Example 25 (Support) 4-amino-5-chloro-2-methoxy-N-
[4'β-(7'β-methyl-1'-aza-6'α-H
-Bicyclo(4#4-0)decyl) Copenzua 1F
HC58%) Melting point 184-188℃ (ethyl acetate/petroleum) N, &1°((OD013): 8.07(S*)
IHs aryl June); '1.7-7.4 (brd, IB. 3,4-3.1 (w -111m aliphatic H): 1G-10 (m, 16)1. The remaining protons, e.g. 112. Hajime. 3H,0HOH3, J=6.1H1]. m,,s,M” 3511736 (Theoretical value: 35L1
''759). Example 26 (t)4-acedoide-5-chloro-2-methoxy-
N-[4'α~(7'β-methyl-1'-aza1r, α
Ni100011m was isolated from the ether-soluble fraction of Example 24 as an oil containing about 10 4'β isomers. N, &t, (J,0DOII): [3
-7,5(m, 4B, 7suni0ONH,OH,0O
NH For example, a19. s, l) i and &09- s*l H-all 7 reels H)
; 446-1O(,2414, remaining protons e.g. 3.91s 3H,0OH8; 2.23 ms s3H,0OOH
3 and L12*d* 3H,0HO)11, J=6Hg). Example 27 4-72-5-chloro-2-methoxy-N-[4
'α-(7'β methyl-1'-aza-6'α-H-bicyclo(4-4*0)decyl)] Impurity's Eyed @ (65%
), melting point 205-208℃ (ethyl acetate/petroleum) approx. 10
N, & r, (J, ODO
Im): &10 (s a Iflm aryl 6
H,); &25-7.9 (ShoslH*AroO NH); 6.32 (1, 1) (#Aryl 3H): 556-18 (, 6H, Aryl N) J2; NHO dan y 3,94, 1゜3H,OO
H, ): 3.5-3.2 (an, IH, fat N 1: Z5 = 1.0 (m, 16H, remaining 9 zones a)n Example t4tiiwd. 3H,0HOH 龜, J-6) 11 ). me s, M 3511700 (theoretical value: 35L1
711). Example 28 (4) 4-acedokendo-5-chloro-2-methoxy-
N-[4'/-(7'α-methyl-1'-azo-6'a
-bicyclo(4,4,0)decyl)]benzamide@C
'1Sfk) N, & re (J, CD
OIg): JL3-7.6 (so, 4H, 79k
oONH, 0HsOOON)i. For example, &19-s-IH&09e@5x
lL both aryl H): 4.4-α9(Ifl, 24B, remaining protons, e.g. 187sss 3H, 0OHI e 223 @I*3H,
0QOH, and LIO, d. 3ii, 0HOHI, J"7Hz) Example 29 (4J4-A) -5-chloro-2-methoxy-N-(
4'/-(7'α-methoxy-1'-aza-6'α-H
- Pisik ■ (4m 410 ] decyl)] Penza Dendo (65 bags) Melting point 18G-183℃ (ethyl acetate/petroleum) N, m-r- (J, CD0IB): 8.08
(@# IH*Aryl 6H) Near, 8-7.5 (brd, IH. 0088); 6.31 (s, IH, Aryl 3H): 47-3.7 (m, 6H, Aryl NH,, NIiOM = For example, λ85.mm3H@()OR,); 3.4-LO(Mackerel, 17B, remaining protons, For example, LX l @d, 31(,CHOHs. J-6,5Hm).tm,s, M”3511720 (Theoretical value: 35L171
0) Example 30 (g) 4-7 setoa-5-chloro-2-methoxy-
N-(7'/-(5'α-methyl-1'-aza-bicitalo(4,3,0)nonyl)]4nsuadendo■(7echi)
NHOOOHs N, m, r as oily substances. (δ, 0DOII): &3-7
．． 9 (sm, 3H, 0HICONH, e.g. IL13
．． s, IH and aox, s, in, all completed - #H); 7.67.1 (brd, IH, aryl 0ONii); Table 146 (Peng, 4H, NHO =. For example, J, 1lli, s , 3H, 00111); &2
-a9(m, 18H, remaining protons, e.g. z2i*5e 3H,0OOH, and 1.07.I.yoQOHs) Example 31 Out 4-amino-5-chloro-2-methoxy-h-[7'
β-(5′α-methyl-11-aza-bicyclo(4,3
, 0) Nonyl)] Benzamide (3) (33) Melting point 169-171°C (ethyl acetate/petroleum) N, m, r
, (δ, ODO!1): fLo8 (1
@IH*aryl 6H); 7.6-7.3 (brd, IH. 0ONH): [28 (s, IH, 7 reel 3d); 46-175 (nz, 6H, -N aryl. NHOH- , for example, 18g, s. 3)i, -0088); ! ! -LO(R1,15B, remaining proton, e.g. LO8, OH@()E) Example 32 (support) 4-acetamido-5-chloro-2-meth N-(7 '/-(9'α-ethyl-1'-azo-gi-H
-bicycloC+ms, 0) nonyl)] penzuaado ring (
90 saliva) Melting point 108℃ N, vn, r, (J, QQ□凰s
): &3-7.4 (m a 4H#, e.g., &23.L, and &lO1, both IM, aromatic H); 4.5-0.7 (■*34He remaining proton, e.g., 3. 82.S.3H,00)1. and 120 @I @3H,000
Hs)-Peng-so M! 9λ1827 (II logical value = 3911
819) Example 11 (4) 4-amino-5-thalu-2-methoxy7-N-(
7', #-(g'a-19-, b-1'-7za5'
α-H-bicyclo[4s3sO)nonyl)]penzua(7516), converted to -salt f11 salt, 1 point 119
~121C (ethanol/ether) NH. K & r. (J, 00C1m) free am group: &0
9 (s, IB, aryl 6) J); 7.7-7.4 (m
, IH, 0ONH); 6.27 (IB6 aryl 3H); 4.5 3.8 (tn, 6H, MHI aliphatic H, e.g. 3.85. 3H0008s) 12- (18(a+ # 17H - remaining protons, e.g. α93.t, 3H, J = 6.9 H1', COHs). wa, s, M 351.1695 (theoretical value: 35
1.1711) Example 34 (Support) 4-acedokendo-5-chloro-2-methoxyN
-(7'/-(9'α-isopropyl-1/-aza-5
'-α-H-bicyclo(4@s-0)nonyl)]]
Benzamide 55), NHUOOMs N, ? as an oily substance? vi, & (δ, opats) * a,
s-L4 (u+ @ 4HmA r L) ON H
, OHI OONH. For example, cl, 26. &, && Muro. 8. All are IH, aromatic μ), 4.5-α7(m, 26H, fi protons, e.g. 3.92.s. 3ii, oon@ ; Z2S # m * 3H, 00H1 and α98-d * 68.0HC01 (1h). Intestine, Lu.M 40&2064 (Theoretical value: 40&2
051) Example 35 (t)4-amino-5-chloro-2-methoxy-N-[
7'β-(9'a-inozolopyl-1'-aza-5'
-α-R-Pisic o(4,3,03]nyl)]benzamide ■ (5011) Melting point: 53-155°C (ethyl acetate/petroleum) NH:N6!11-r-(J a OD 01 g)
: ' 10 (' @1 ' @ Ally 26H); 7.7-7.3 (Ugu, IH, 0ONH); &2g (@,
lH, aryl 3H): 4.77-17(, @H, NH-rich aliphatic H, e.g. 3.8g, ss 3 n * OCHs)" λ4-α7(m, 19) 1. Remaining protons, e.g. , α97.d. 5H, J==&3Hn; OH(0Hs)*). lime lo M 327-1317 (JJ theoretical value: 32Z1322) Example 36 C+J4-7 Cetamido 5-chlor-2-meth conflict 7"
'-(7' a, / -(g pβ-inopropyl-1'-7f-5' a-H-pyy1wxc4.3
．． 0〕Nonyl)〕Kanzua Dendo (3b) (651) 01
p (011 &)
β-isoprobi-1'-azo-5'α-H-bicyclo(4,3,03nonyl)]benzand (30%) was obtained. This contained about 25 pieces of 7'α^ isomer. The mother liquor contains the 7′α and 7′β isomers (
35'S). Example 17 (to) 4-Annor S-chloro-2-methoxy-N-
7′β-(9′β-isozorobyl-1′-azo-5′
a-11-pick" (4a 3 #0) / niru)) benzua ζ de 匈 (75 chi) (7'a of about 2s
isomers] melting point 174-176°C. Hs NM] iL (J, OD (l 1 B)
LIO(1#IH-aryl6)ri8.1-
7.8; 7.77-7-4 (,18゜0ONHa and β isomers each) 6.28 (s #l He aryl 38147-
3.8 (m, 4sH, MHI. Aliphatic Hl e.g. 19G, λ86°2s, 3H,
oon,, a and! each isomer) 13-Z9 (m, IH, aliphatic H) z3-α7 (m -i 8 Ha l!l protons, e.g. a88.櫨, 6H1 J''& 5 I(t # Oif (OHg)
g). Pharmacological data Increase in intragastric pressure with prior fasting. Changes in intragastric pressure were recorded from conscious but restrained rats using a saline-filled catheter inserted into the gastric cavity via a permanent gastric foramen tube. The catheter was connected to a live water pressure transducer and pressure changes were recorded on a hot wire pen recorder. Each animal was allowed a 40 minute pre-medication period to obtain measurements of spontaneous activity. The activity index was obtained by determining the average height of the pressure wave for 10 minutes. Four such period Kll values were obtained during the assessment of spontaneous activity and over a 40 minute period following compound administration. 81m
The d@mt "electronic" test was applied to the difference between the mean values obtained for spontaneous and post-compound activities. Compounds 8, 9 and 11 are L O'l / C, c,
significantly increased the activity index after administration at a dose level of . Compounds were injected subcutaneously and 30 minutes later a standard dose of amomorphine 1104 (αI JIF/4, sc) was administered and the emetic response was compared to that obtained when the same animals were administered apomorphine HO4 and vehicle alone. did. HD of inhibition of emetic response determined for compounds 11 and 13
,・The value is LO■/Immediate, and for compound 33, au
Iv/4, and for compound 3S it was αO1/3. A compound! Apomol2in-induced inhibition of climbing was tested in mice. The exam is PratJI
! S,P,OomstamtihoeJe and 8ckwa
rt breath J, O, (li)7g), Psyckep
karmacol*gy. 50.16. Apomorphine 1MII/Mori&C, is a wire cage (
Reverse 11K food hots” -11X7.sXIJla
Let the mouse climb the wall. Mice, 5 per group, acclimated in their own cages, were placed under holanaud immediately after injection of apomorphinda/S,C.
%1G after injection, 20. And record the climbing process in 30 minutes.
The mice are observed for 30 seconds and noted according to the position they encountered for the majority of that time. 0 points: All 4 legs are on the floor of the cage, 1 point: Only the front legs are on the wall, 2 points: +# is also on the wall of the cage, add up the scores for each mouse in all 3n. Oral treatment with medicine! ? Including the group treated with 0 saline only compared to the mice given only the amino acid.
Any score exceeding the maximum value will be taken into account. The results were as follows. Compound Effect 1. ψS.C0 81O 950 1134 13I 50 ■ = Inactive Toxicity No toxic effect was observed in any of the above O tests. Agent: Patent attorney Masamitsu Akizawa and 1 other person (r yen) Showa was a tough year? Month:＞□Japan Patent Office Director 1, Display of h items Gansho Taku No. 1 O Yu 2 Noa Branch Location Taiyo Building, 12-1 Nihonbashi Kabuto-cho, Chuo-ku, Tokyo Name (5792) F Monument 1 Akisawa Date of Masamitsu 5, I9.C!I11□1.,1 Showa year
Month, day (shipping) 6, number of inventions increased by amendment 7, subject of amendment θ @ phase 1

Claims (1)

[Scope of Claims] (1) Formula (D) (wherein 凰1 is 01-6 alkoxy, 0 troalkylthio, or together with R, Ko, *alkylene, R, 凰3 and One of R11 is hydrogen, and C
The remaining two together are Oi, Ani Kilene Dioxi7, or the remaining two are the same or different, hydrogen, halogen, OFI, 0s-sA Kill%01 −
Alpoxy, 01- alkylthio, Cl-7 acyl, 01-! Acruamino, at-a-6-mer sulfonyl, cμ-alkylsulfinyl, hydroxy, nitro or l or 2 Cμ-alkyl, 0 to cycloalkyl 10 μl, 7-alkyl Cl-4, 7
Oa-m or phenyl Cμ47 may be N-substituted with a kill group, or Oa-m 11M methylene with N-substituted
-optionally di-substituted acylate Z]m #/= or aminosulfonyl, or 81 and 1L11 together are 0-, acylenedioxy, and R, and Rs together are 01
4-fulkylenedioxy, or R, and R, are different or different and are selected from the group of substituents defined above. R4s ILi s 凰・and 凰ma are the same or different, 9, hydrogen, 0μ・alkyl, 7e#tNj! 7e to 01-a to kill, and the phenyl part is izn
BS may be substituted with alkoxy, OF, or halogen, and at least 5% of Ri and R are other than hydrogen. BS is hydrogen or Alkyl, or R1
(p is O~3, Peng is 0~3, and Intestine is O~TE) or a pharmaceutically suitable salt thereof, N
-Oxide or solvate. (2) Formula (W) Grave & Nouti (In the formula, 几!l is 01- alkoxy, and 几1-
is hydrogen or 0! -4 alkanoyl. B,1 is halogen, R4M and H,1 are Ol-(alkyl, phenylma or phenyl-4furkyl, and both of the heptadyl moieties are as defined in claim 11). (B111 is also hydrogen, pl is 1 or 2, and the indicated bonds can be axial or equatorial) The compound according to claim (1). (3) The compound according to claim (2), wherein Rs" is hydrogen and pl is 1. In Cjt, R, 2 is hydrogen, 01-4 alkyl , 7E2k
or phenyl01-4alkyl, any of whose 7-modyl moieties may be substituted as defined in Claims (11), and Rγ'it O1-alkyl% phenylt or 7enyl C1-4 alkyl, any phenyl moiety thereof may be substituted as defined in claim (1)) Compounds described in Section. (5) Claim No. (1) in which Rs″ is hydrogen.
Compounds described in Section. (6) The bond between the benzamide moiety and the cyclic a chain (that is, between the Ra-substituted nitrogen and the carbon atom on the ring to which this nitrogen atom is bonded) is an equatorial bond.
) to (5). (7)
5'α-H-bicyclo[4,3,03)nyl)] bebenzamide (branch) 4-annor-5-chloro-2-methoxyv-N-[
7'α-(9'β-methyl-1'-aza-5'α-H-
Bicyclo[4,3,0)nonyl]benzamide. C+J+-amino-5-chloro-2-methoxy-N-[
7'β-(9'α-methyl-1'-aza-5α-H-bicyclo[4m3#0)nonyl)]benzand, or C))4-aminol5-chloro-2-methoxy7-N- [
7′α-methyl-1′-aza-5α-H-bicyclo(4
, 3,03nonyl]4nzamide, or a pharmaceutically suitable salt thereof. (8) A compound of formula (N) is reacted with a compound of formula (XI) - where 91 is a leaving group and Rls is 8! as defined above. , or (0)1. ) 噌OR
14. and . are bonded to form a substituted oxygen atom], B , 1 is hydrogen or 0., alkyl, and the remaining variables are the same as in claim (1). It has a significant meaning, and then 8!Ru ga (OHI)QOILI 4 Ru
Qx Y: ali, and when 11 forms an oxo group, the resulting compound is reduced and, if desired, the groups R, , R, or R11 in the compound thus formed are replaced with each other group Rs A method for producing the compound according to claim (1), which comprises converting to s 1m or R11. (9) A pharmaceutical composition comprising the compound according to any one of claims (1) to (7) or a pharmaceutically suitable salt thereof together with a pharmaceutically suitable carrier.