JPS5913769A - Novel 1-phenyl-2,5-benzoxazocine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A 1-phenyl-2,5-benzoxazocine derivative shown by the formula I (R is phenetyl, substituted phenetyl containing OH, halogen, nitro, amino, amido, or imido on aromatic ring, or p-fluorobenzoylpropyl) or its salt. EXAMPLE:1- Phenyl-5-( p-hydroxyphenetyl- 1,3,4,6-tetrahydro- 5H-benz[ f ]-2, 5-oxazocine. USE:A nonnarcotic analgesic. Having improved safety. PROCESS:For example, a 1-phenyl-1,3,5,6-tetrahydro-5H-benz[f]-2,5-oxazocine shown by the formula II is reacted with a compound shown by the formula III(X is halogen; R1 is H, halogen, or acetoxy) in the presence of a reducing agent, a corresponding site of the reaction product is decomposed when R1 is acetoxy compound, to give a compound shown by the formula IV (R2 is H, halogen, etc.), part of the compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 1-phenyl-2,5-penzoxazocine derivative and a process for its preparation.

Administration of morphine-based analgesics is unavoidable in order to alleviate severe pain such as cancer pain, but its high narcotic properties make it unsuitable for long-term administration or even for short-term intensive use. It is. This is because it has the potential to cause toxicosis fc and, in some cases, to lead to incompetence. On the other hand, even with drugs that have traditionally been considered non-narcotic analgesics,
Some drugs with strong effects have been found to have narcotic properties, and it is therefore inevitable to think that there is some kind of correlation between the high analgesic effect and narcotic properties.

For this reason, there is currently a strong desire for analgesics that are non-narcotic, have a wide safety margin, and have mild effects.

Therefore, an object of the present invention is to provide a compound that can be used as an active ingredient of this type of analgesic drug with mild action, and a method for producing the same.

Compounds according to the invention may be of the formula (wherein R is a phenethyl group, or a substituted phenethyl group bearing a hydroxy group, a halodane atom, a nitro group, an amino group, an amide group or an imido group on the aromatic ring, or a p-fluorinated group). The present invention is a novel 1-phenyl-2,5-penzoxazocine conductor represented by the olpenzoyl globil group or a pharmacologically acceptable salt thereof.

The compound represented by the formula I and its salt are new substances that have not been described in literature, and according to the method of the present invention, the compound represented by the formula 1-
Starting from phenyl-1,3,5,6-tetrahydro-5H-benz[r)-2,5-oxazocine, a) in the presence of a reducing agent the formula (wherein X means a halogen atom and R1 is hydrogen , )・represents a rogone atom or an acetoxy group), and in this case, when the reaction is performed using a compound of formula 111 in which R1 is an acetoxy group, the corresponding part of the reaction product is decomposed. or b) react with a compound represented by the formula (where This reduction product is reacted with a compound represented by the formula % (in the formula, X has the above meaning and R3 means a lower alkyl group or a lower alkenyl group) to produce the above reduction product. -N) 12 groups -N
HCOR, group (R, has the meaning given above), or by reacting the above reduction product with maleic anhydride to convert the one NH2 group in the reduction product into C) (wherein X is the above meaning) A free base is obtained by reacting with a compound represented by (having a meaning), and a salt thereof can be obtained by treating the base in a conventional manner.

Incidentally, the compound of formula (2) used as a starting material is 2-
It can be synthesized starting from benzoylbenzoic acid as shown in the reaction formula below [Japanese Patent Publication No. 1985-8512
Publications and - Bull, Soc, Chim' Vol. 10, p. 347 (1943)].

H Next, the present invention will be explained in detail in connection with production examples and pharmacological test examples.

Production example 1 1-phenyl-1,3,4,5-tetrahydro-5H-
Benz(f'-2,5-oxazosine oxalate 24.5
g (5,!1.5 mmol) as the free base, dissolved in dry iCHfJ55oomi, triethylamine:ys7 (v9.x mmol) was added, -5~
p-acetoxyphenylacetyl chloride J at -10℃
4,! iJ (70,52 mmol) of CHCt,
5,100 ml of the solution was added dropwise over 40 minutes, then stirred at room temperature (the temperature rose to 15°C in 20 minutes), the solvent was distilled off, 1 somt of tetrahydrofuran and 150 ml of ethyl ether were added, and LIAtH41 was added under stirring under water cooling.
2g was added, refluxed for 5 minutes, decomposed with water, and C
Extract with H2C42, further extract with ethyl acetate, combine the extracts, dry, distill off the solvent, dissolve in a mixture of CH2Cl2 and ethyl acetate, and purify by silica glu column chromatography to obtain the desired product. A compound is obtained.

Converting the target compound to its hydrochloride and recrystallizing it from methanol yields colorless needle-like crystals J4. sg(6z, s%) is obtained.

Hydrochloride melting point: 247-248℃ Elemental analysis: C24H25N02・HC1 calculation: C72
, 81H6, 62N3.54 actual measurement; C73, 02H6
,61N3.66IR spectrum y"'cm-'
: 2250-2700ax (-NH) lag eater type e free base NMR spectrum (cDct3) δppm: 2.47-
3.07 (6H, m, NCH, CH2O and >NC
! i2CCH2C42 3,60-4,50 (2H, m, NCH2CH20
-6,2s (zH, wide, OH [disappeared at D20) 6.58-1.50 (fJH,m, Ar -H
) Production Example 2 In place of p-acetoxyphenylacetyl chloride, m-
It was synthesized in the same manner as in Production Example 1 except that acetoxyphenylacetyl chloride was used.

Hydrochloride yield: 64. s% Melting point: ~220℃ (decomposition) Melting start temperature unclear Elemental analysis: C24H25NO2・HC/- Calculation: C72,
81H6, 62N3.54 actual measurement: C72, 60H6,
70N3.53 free base MS spectrum: M+: ,? 5! ? (FJI), J60 (CI) millimus analysis: 359,1867 (error; -1,5)
C24H25NO2 NMR spectrum (CDCl2) δppm: 2.50
-3.05 (6H, m, N-CH2CH2O and N-C
H, -C di-tunyl) 3.7-4.5 (,?H,m,N-CH2CH2O)
4-37 (2H, ABq * J=I J H
z t C6-) [2) 5.62 (IH, wide s, OH) 5.73 (IH,,,C,-
H) 6.5-7.7 (13H, m, kr-H) Production Example 3 tcp instead of p-acetoxyphenylacetyl chloride
-Synthesized in the same manner as in Production Example 1 except that chlorophenylacetyl chloride was used.

Hydrochloride yield: 44% Melting point 2 173-175°C (methanol-ethyl ether) Elemental analysis: C24H24NOct-HCt-7H2
0 Chukin; C611,09H6,19N3.31 free base NMR spectrum (CDCts) δpprn: 2,
so-s,oo(6ferm, -0CH2CH2N NCH,CH!-@)-ct) 3.53~4.40(2H1m, -0CH2CH2N
) e, 6a ~ y, 4g (7JH+m+Ar-H
) Production Example 4 Ile' Synthesized in the same manner as Production Example 1 except that phenylacetyl chloride was used instead of p-acetoxyphenylacetyl chloride.

Hydrochloride yield: 85% Melting point 2 194-196.5°C (decomposition) (methanol-
Methyl ethyl ketone) Elemental analysis: C24H25No-HCt reduction η; C
75,87H6,90N3.69 actual measurement; C75,88
H6, I37 N3.56 Free base NMR spectrum (cDct3) δppm: 2.57
~． (,23(6H, m*nNCH2CH2O and"
:;N CH,,CH! φ) 3.53~4.33 (2H+m+ >NCH2CH2
0-) Production Example 5 Nophenyl-1,3,5,6-tetrahydro-5H-
Benz[]-]2rs-oxazosine oxalate 3.51
/ as the free base, to which was added 40 ml of dry trimethylformamide % NhHCOs 1-21 and p-
3 g of nitrophenethyl bromide was added and stirred at 100-105° C. for 6 hours under nitrogen atmosphere. Afterwards, the reaction mixture was poured into ice water and extracted with ether. The ether extract was washed with water, dried over N 112 SO4, filtered, and the ether was distilled off from the P solution. The obtained oil was purified by silica gel column chromatography (ether), then converted into a hydrochloride salt, dissolved in methanol goml, and subjected to catalytic reduction treatment by adding 5% Pd-CO,41/. For about 2 hours! After stirring for 1 hour, the catalyst was removed by filtration, and methanol was distilled off from the P solution. The resulting residue was extracted with aqueous ammonia and ether, and the ether layer was separated, washed with water, dried over Na2SO4, and the ether was distilled off to obtain an oil. The target compound is obtained by purifying this oil by silica gel column chromatography (ether). This was further converted into a hydrochloride salt, dissolved in methanol, and then an ether solution of hydrochloric acid was added to completely convert it into a dihydrochloride salt. If methyl ethyl ketone is added while methanol is distilled off, hydrochloride 2 is obtained.
．． 3 Ji' (63.9%) is obtained.

Hydrochloride melting point: 199-202°C (decomposition) (methanol-methyl ethyl ketone) Elemental analysis: C24H24N203.HCl-1-H2゜Elbow%: Crr6. a3H6, o4N6.4e actual measurement:
C66,13H6,23H6,37 free base NMR spectrum (cDC63) δppm: 2.5~
．． '3.25 (6H, m, NCHICH20an
dNCR2CH2()No2) 3.6-4.4 (2HIrn, NCH2CAl2O
)4.28 (,?H,ABq, J=12.6Hz
, Δ=58.7Hz.

Production Example 6 5-(p-aminophenethyl)-1-phenyluha J, 4.6-f) Rahydro 5H-benz(4)-2,5-oxazocine obtained by the method described in Production Example 52.
2J g (6.77 mmol) was dissolved in 100 ml of tetrahydrofuran and 3-(
Chlorformyl) ethyl acrylate 1.109 (6,v
y mmol) in 2 srnl of tetrahydrofuran to 3
The mixture was added in 0 minutes and stirred for an additional 30 minutes.

After the reaction mixture was concentrated under reduced pressure, water was added, made basic with aqueous ammonia, extracted with CH2Ct2, washed with water, and
Drying with a 2 S O4, concentration under reduced pressure, and purification by short column chromatography on silica gel (ethyl ether) yields the target compound as a yellow oil (2.57%).
g (86,1%) is obtained.

If the hydrochloride salt is formed in methanol and recrystallized from methanol-methyl ethyl ketone, the melting point is 209-212°C (
decomposition) to form colorless prismatic crystals.

Free radical MS' spectrum El"/z: C84 (M"), 252 (base) CI (
1-Bu)”/z: 485 (M-11) High MSrrl/z: C3oH, N204 (M+)
Calculation; 4sn, xsex actual measurement + 484,239Q NMR spectrum (coct, ) δppm: 1.3
0 (,?H#t, J=7.77Hz, CH2CH
, ) x, e ~ s, 1 (6Hl m , C4-H2 and NCH2CH2Ar ): t-sx (JHl
dp y=1s-oH*+ca-H)4.24
C2HIqTJ=7.0Hz, l-CH2CH3)s
, e P-4,4 (2H, m, cs-) (2) 4.47
(IHld#J-=13.0Ht, C6-H)5
-80 (JHI s+ct-H)6-9~7-7
(15H2m #olefinic zolotone and Ar-H
) Hydrochloride elemental analysis: C3oH32N204. Hct calculation; C6
9,15H6,38N5.381715,1675 (
C=Q) Production Example 7 A sample was prepared in the same manner as Production Example 6 except that bromoacetyl chloride was used instead of ethyl 3-(chloroformyl)acrylate.

Hydrochloride yield: 9o, 6% Crystal form: Colorless prismatic crystal Melting point: 2oo~203°C (decomposed) (methanol-methyl ethyl ketone) Elemental analysis: C26H27BrN202・HCt calculation;
C60,53H5,47N5.43 actual measurement; C60,6
0H5, 50H5, 482600 (NH), Noro 90 (
C=0) NMR spectrum (DMSO-d6) δppm
:J, 2bes, eceH*m, C4-H2 and NCH
2CH2A r )4.27 ('H,s, -
CH2Br) 3.8-4.8 (3Hjrn, C, -H
2 and C6-H)s,o ~5.6(JH,m+c6-
H) 5.93 (I Hr a r C1-H)
7.0-7.8 (13H, m, kr-H) free base MS spectrum: EIrr/z; 4781480 (M+), 105 (base) CI (1-Bu)''/z; 479, 481 (
M+J) NMR spectrum (CDC13) δppm
:z, v ~s, o(e; Hrm*c4-H2 and NC
H,,CH2Ar)s,vg(IH,d,,r
=z, y, OHz, C6-H) 4.00 and 4.17
(2H* 2 g + -CH2Br)s, 4 to 5
．． s(2H*mr C5-H2)4.77 (I
H, dll=13.0H1,C6-H)5.80
(7H1s +C+H)6.8~7.7 (
13H, m, Ar-11) 7.9 to 8.4 (lH,
m, Nc=0. Disappeared by addition of D20) Production Example 8 Instead of ethyl 3-(chloroformyl)acrylate [3-
It was synthesized in the same manner as in Production Example 6 except that ethyl (chloroformyl)propionate was used.

Fumarate yield: 97.5% Crystal form: Colorless prismatic crystal Melting point -148~149°C (decomposed) (methanol-methyl ethyl ketone) Elemental analysis: C3oH34N204・C4H404・H2
0 calculation: C65,79H6,50N4.51 actual measurement;
C65,59H6,42N4.47IR spectrum
BI cm-1; ay 2500 (NH) L1720,1680 (C=0) free base MS spectrum: EI''/'z; 486 (M+), 252 (salt,
4= )CI(i-Bu)”/z ;4.!17(M+
7) High MSrr//z; C3oH34N204 (M
+) Calculation; 486,2517 Actual measurement; 486,2542 NMR quictor (cDct3) δppm: 1.25
(,?H,t,J=7.OH2,-CH2CH
5) 2.5-3.0 (IOHTm, C4-H2, NCH
2Cl2Ar and -CH2-) 3.82 (IH, d, J=13.OHz, C6
-H) 4.15 (2Htq, J=7.0
H1, -CH2CH3)s -y H4.4 (2Hp
m + c s - H2) 4.75 (7) (,
d, J=7J, (IJH1Ic6-H)5.80
(I H+ I, C+ -H)6.8~7-6(J
JH+m+Ar-H)7, J~7.8 (IH+
m t N C=(7+ D Disappeared by addition of 20) Production Example 9 5-(1)-aminophenethyl-1-phenyl-1,3,4,6-tetrahydro 5 H obtained by the method described in Production Example 5 -benz [r:] -]2. ．． 5-Oxazocine 100, P (2,79 mmol) in 2 oml of tetrahydro7ran under an argon atmosphere with maleic anhydride, 12,! 1 m4/(3.35 mmol) was added and refluxed for 1.5 hours. In the future, ethyl ether 3
oml and the resulting crystals J, 24F! (9y,
s%) was calculated as the number of households.

Add 2028 ml of AC and Na0 to this crystal under an argon stream.
Aes 6om9 (6,sa mmol) and 2
The mixture was refluxed for several hours.

The reaction mixture was concentrated under reduced pressure, neutralized with Na HCOs solution, extracted with CH2C42, washed with water, dried over Na2SO4, further concentrated under reduced pressure, and separated and purified by column chromatography (silica gel 20F!, ethyl ether). and Rr=o, ;z (silica gel, ethyl ether) compound 1.00,? (81.8%) was obtained. If this is added to a solution of fumaric acid in methyl ethyl ketone and crystallized, a fumarate salt can be obtained.

Fumarate yield: ljl, 8% Crystal form: pale yellow prismatic crystals Melting point 2186 to 187°C (decomposition) Elemental analysis: C28H26N20.・C4H404 calculation;
C69, 30H5, 45N5.05 actual measurement; C69,
15H5, 44N5.082550 (NH), 1710
(C=0) Free base MS spectrum: EIn/z; 438 (M+), 252 (base) CI (1
-Bu)”/z;439(M+1)”IMS
”/Z; C28H26N20 s@1 calculation; 438.
1944 Actual measurement; 438.1967 NMR quictor (CDC63) δppm:,? ,7
HeJ, (7(6H, m, C4-H2 and NCH2CH
2Ar)3.83 (IH, d, J=13.0
H1, C6-H) 3.6-4.4 (2H2mlC3-H
2) 4.80 (IH2d 1l=13-OHz
, C6-H) 5-82 (I Hrs , C+ -H)
6.80 (2H,,olefinic groton)6
, to IJ 7-5 (13H, m, Ar-H) Production Example 10 1-Phenyl-1,3,4,6-tetrahydro-5H-benz[)-2,5-oxazosine 1. 79.9 (7,50 mmol) and 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,
3-dioxolane 2.42 Ji' (9,90 mmol) and NaHCOs 1 , I J g (13,5
A mixture of 30 ml of dimethylformamide and 30 ml of dimethylformamide was stirred at 100° C. for 7 hours.

The reaction mixture was concentrated under reduced pressure, 1θornl of water was added, and C
H2Ct2 extracted, washed with water, dried with Na2SO4,
It was further concentrated under reduced pressure to obtain 4.0 g of a brown oil.

Dissolved in methanol SO ml, aN-1iC18
ml, stirred at room temperature for 4 hours, concentrated under reduced pressure, and crystallized from methanol/methyl ethyl ketone.
7.9 J g (ss, ty%) of the hydrochloride of the target compound was obtained, and when recrystallized from ethanol, the melting point was 192-19.
Colorless prismatic crystals at 4° C. (min M) are obtained.

Hydrochloride elemental analysis: C26H26FN02・HC1 calculation: C7
0,911H6,19N3.18 actual measurement; C70,75
H6, 15N3.192600 (NH), 1680 (C
=0) Free base MS square: E I ”/z: 403 (M) + 194
(Base) CI (1-Bu) rr//z: 404 (M-
z )"I Ms"/ Z t C26H2bF NO
2(M) Calculation; 403.1947 Actual measurement; 403.1972 NMR spectrum (CDC43) δppm: 1.8~
3.2 (8H1m, C4H2 and -CH2-)J ・7
0 (I H! d r J = I J , OHz
, C6-H)s, 7-4.4(2Hl m r c
s-H2) 4.70 (IHld, J-13,0H
2, C6-H) 5.78 (jH181c, -H
)6,s to77-4(11Hr+kr-H)y,s
~8.1 (2H+rlC2,6-H) Pharmacological Test Example The compounds (hydrochloride) obtained in Production Examples 1.3.4 and 5 were selected as compounds according to the present invention, and a known analgesic was selected as a control substance. Select a certain nefopam, analgesic effect,
The results of tests for acute toxicity and edematability are shown in the table below, and it can be concluded that the compound according to the present invention has approximately the same effect as nefopam, which is considered a non-narcotic analgesic. It can be seen that it has a wide safety margin and therefore satisfies the current requirements as an analgesic.

Continuation of page 1 0 shots bright rattan material Kyoto City, Sakyo-ku, Shikagaya Shimo-Miyanomae-cho -2 0 shots Akira Suenaga Kunitachi City Nishi 1-15-20

Claims (7)

[Claims] (1) Formula (wherein R is a phenethyl group, or a substituted phenethyl group having a hydroxy group, halogen atom, nitro group, amine group, amide group, or imido group in the aromatic ring, or p-fluoropenzoyl group) A novel 1-phenyl-2,5-benzoxazosine derivative represented by (meaning all bil groups) or a pharmacologically acceptable salt thereof. (2) In the presence of a reducing agent, 1-phenyl-1,3,5,6-titrahydro-5H-benz[f:] -]2,5-oxazoxy expressed by the formula (wherein X is a halogen atom, and R7 means an aqueous system, a halodane atom, or an acetoxy group), and in this case, when R1 is an acetoxy group and is reacted with a compound of 2), a reaction product is produced. A patent characterized by decomposing a corresponding part of a substance and further converting the resulting reaction product into a pharmacologically acceptable salt (wherein R2 represents a hydrogen atom, a halogen atom, or a hydroxy group). new 1-7 enyl 2 indicated by
, a method for producing a 5-benzoxazosine derivative or a salt thereof. (3) 1-phenyl-1,3,5,6-tetrahydro-5H-benz[f]-2,,s-oxazosine represented by the formula (wherein X means a halogen atom) A novel 1-phenyl-2,5-benz compound represented by the formula, characterized in that the obtained reaction product is converted into a pharmacologically acceptable salt as required by reacting the compound with the represented compound. A method for producing an oxazosin derivative or a salt thereof. (4) Represented by the formula 1-7enyl-1.3,5.6-tetrahydro-5H-benz[f]-2,5-oxazocinto (wherein X means a halogen atom) A novel compound represented by the formula: - A method for producing a phenyl-2,5-benzoxazosine derivative or a salt thereof. (5) Formula K is expressed as 1-phenyl-1,3,5,6-titrahy-1'0-5H-benz[f]-2,5-oxazocinto formula (Xli means halokene atom in the formula). The compound represented by the formula obtained is reacted with a compound represented by the formula R3C0X (V) (
In the formula, X means a halodane atom, I9,3 means a lower alkyl group or a lower alkenyl group), and then the obtained reaction product is pharmacologically approved as necessary. A novel salt represented by the formula (wherein R3 has the above-mentioned meaning), characterized in that
A method for producing a DI-phenyl-2,5-benzoxazosine derivative or a salt thereof. (6) A compound represented by the 1-phenyl-1,3+5.6-tetrahydro-5H-benz[t]-2,s-oxazocinto formula (wherein X means a halodane atom) and , the resulting compound represented by the formula is subjected to catalytic reduction, the resulting compound represented by the formula is reacted with maleic anhydride, and then the reaction product is converted into a pharmacologically acceptable salt as required. A novel 1-phenyl-2 represented by the formula
, a method for producing a 5-benzoxazosine derivative or a salt thereof. (7) Represented by the formula 1-7enyl-1.3.5.6-tetrahydro-5H-benz(f) -2,5-oxazocinto (wherein X means a halodane atom) A novel 1-7enyl-2,5-penzoxazocine represented by the formula, characterized in that the reaction product is reacted with a compound, and then, if necessary, the reaction product is converted into a pharmacologically acceptable salt. Process for producing derivatives or their salts.