PH26646A - Benzazepine and benzothiazepine derivatives - Google Patents

Benzazepine and benzothiazepine derivatives Download PDF

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Publication number
PH26646A
PH26646A PH38739A PH38739A PH26646A PH 26646 A PH26646 A PH 26646A PH 38739 A PH38739 A PH 38739A PH 38739 A PH38739 A PH 38739A PH 26646 A PH26646 A PH 26646A
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Philippines
Prior art keywords
alkyl
solution
trifluoromethyl
methoxyphenyl
benzazepin
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PH38739A
Inventor
David Floyd
John Thomas Hunt
Spencer David Kimball
John Krapcho
Jagabandhu Das
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Squibb & Sons Inc
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Publication of PH26646A publication Critical patent/PH26646A/en

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Description

p LC WS 3 ‘o Vet ” . ’
Ce A
SE
. y pe . . : 1)
A
HA460
BENZAZEPINE DERIVATIVES
Brief Description of the Invention
Compounds having the formula RB (C5 ] Jf 3
R3 © 1, Ry 0 and the pharmaceutically acceptable salts thereof, have useful vasodilating activity. In formula I, and throughout the specification, the symbols are as defined below. } 1
Ry is -CH or -0-Y3; 2
R, 1s H-Y, ' H, ’ H-CH
H-Y, Yu- -Yg Hy)n ’ 6 17 Ye Y PN 6 7
H H——(CH,,) 2 2'n
Lp , _ N CH, =( Hy), Ye- H H,
Ye 7 or
Co tha ’
HA460 “Dw
H-Y,
H-C 5
Hy), i -Chz > 6
Ry and R, are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, diarylalkoxy, arylalkyl, cyano, hydroxy, alkanoyloxy,
I fluoro substituted alkoxy, fluoro substituted alkyl, (cycloalkyl )alkoxy, -NO,,, -NY, oY 10 -S(0) alkyl, -5(0) aryl, He or f 0-C-¥y37 nis 0, 1, 2 or 3; m is 0, 1 or 2; : Yy and Y, are each hydrogen or alkyl, Yy is ! 20 hydrogen and Y, is alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl, or Y, and Y, together with the carbon atom to which they are attached are cycloalkyl;
Yq is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl, or Hoa,
Y, and Yg are each independently hydrogen, alkyl, aryl or arylalkyl, provided that when both are present they are not both hydrogen, and provided further that when both are attached to the same carbon atom neither of them is hydrogen;
Ye and Y, are each independently hydrogen, : alkyl, cycloalkyl or arylalkyl or Ye and Y, together with the nitrogen atom to which they are
HA460 -3- attached are azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
Yq and Y, are each independently hydrogen, alkyl, aryl or heteroaryl, or Yq and Yq together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl or morpholinyl;
Yio and Yq are each independently hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl, or Hows,
Yio is hydroxy, alkoxy, aryloxy, amino, alkylamino or dialkylamino; and
Yi is alkyl, alkoxy or aryloxy.
Listed beiow are definitions of various
BE 15 terms used to describe the benzazepines of this invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
The terms "alkyl" and "alkoxy" refer to both straight and branched chain groups. Those groups having 1 to 10 carbon atoms are preferred.
The term "alkenyl" refers to both straight and branched chain groups. Those groups having 2 to 10 carbon atoms are preferred.
The term "aryl" refers to phenyl and sub- : stituted phenyl. Exemplary substituted phenyl groups are phenyl groups substituted with 1, 2 or 3 amino (-NH,), alkylamino, dialkylamino, nitro, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), alkylthio (of 1 to 4 carbon atoms), alkanoyloxy, carbamoyl, or carboxyl groups.
HA460 -4~
The term "alkanoyl" refers to groups having the formula ei. Those alkanoyl groups having 2 to 11 carbon atoms are preferred.
The term "heterocaryl" refers to an aromatic heterocyclic group having at least one heteroatom in the ring. Preferred groups are pyridinyl, pyrrolyl, imidazolyl, furyl, thienyl, or thiazolyl.
The term "cycloalkyl" refers to groups having 3, 4, 5, 6 or 7 carbon atoms.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The terms "fluoro substituted alkyl" and "fluoro substituted alkoxy" refer to alkyl and alkoxy groups (as described above) in which one or more hydrogens have been replaced by fluorine atoms.
Exemplary groups are trifluoromethyl, 2,2,2-tri- fluoroethyl, pentafluorcethyl, fluoromethoxy, difluoromethoxy, etc.
The compounds of formula I form acid-addition salts with inorganic and organic acids. These acid- addition salts frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble. The free base may then be obtained by neutralization, e.g., with a base such as sodium hydroxide. Any other salt may then be formed from the free base and the appropriate inorganic or organic acid. Illustrative are the hydrohalides, especially the hydrochloride and hydrobromide, sulfate, nitrate, phosphate, borate, acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, salicylate, methanesulfonate, benzene- sulfonate, toluenesulfonate and the like.
HA460 -5-
The carbon atoms in the 3 and 4-positions of the benzazepine nucleus of the compound of formula I are asymmetric carbons. The compounds of formula I, therefore, exist in enantiomeric and diastereo- meric forms and as racemic mixtures thereof. All are within the scope of this invention. It is believed that those compounds of formula I which have the d-cis configuration are the most potent and are therefore preferred.
Detailed Description of the Invention
The compounds of formula I and the pharmaceutically acceptable salts thereof are } useful as cardiovascular agents. These compounds act as vasodilators and are especially useful as" mth anti-hypertensive agents. BY the administration of a composition containing one (or a combination) of the compounds of this invention the blood pressure of a hypertensive mammalian (e.g., human) host is reduced. Daily doses of about 0.1 to 20mg. per kilogram of body weight per day, preferably about 0.5 to about 10mg. per kilogram per day, are appropriate to reduce blood pressure, and can be administered in single or divided doses. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intra- muscular, or intravenous routes can also be employed.
As a result of the vasodilating activity of the compounds of formula I, it is believed that such compounds in addition to being anti-hyper- tensives may also be useful as anti-arrhythmic agents, as anti-anginal agents, as anti-fibrilla- tory agents, as anti-asthmatic agents, as
HA460 -6~ anti-ischemic agents and in limiting myocardial infarction.
The compounds of this invention can also be formulated in combination with a diuretic or an angiotensin converting enzyme inhibitor. Suitable diuretics include the thiazide diuretics such as hydrochlorothiazide and bendroflumethiazide and suitable angiotensin converting enzyme inhibitors include captopril, zofenopril, fosinopril, enalapril, and lisinopril.
The compounds of formula I can be prepared from the corresponding compounds having the formula
IT 4
R3 1
B
The preparation of the racemic and nonracemic forms of the compounds of formula II is described in 4 ALD Lp
United States Patent app iédtich serial no:-52;360 filed May 21;-1987 for those compounds wherein 1
R; is i , and in United States patent 4,748,239, 2 . issued May 31, 1988 for those compounds wherein
Ry is -OH. Compounds of formula II wherein Ry is -0-Y, and Y, is other than hydrogen can be obtained by alkylation or acylation (using conventional techniques) of the corresponding compound of the formula 11 wherein Ry is ~-QH.
Treatment of a compound of formula II with an alkali metal hydride (e.g., sodium hydride) in
HA460 ~7- an inert solvent (e.g., dimethylformamide or dimethylsulfoxide) followed by reaction with a compound of the formula 111 R,-halogen yields the corresponding product of formula I.
Alternatively, a compound of formula I can be prepared by reacting a compound of formula II under phase transfer conditions in a mixture of water and dichloromethane or toluene in the presence of an appropriate base (e.g., barium hydroxide or sodium hydroxide) and catalyst (e.g., benzyl trimethylammonium chloride or tetra-n-butylammonium hydrogen sulfate).
Alternatively, the products of formula I wherein R, is -OH can be alkylated or acylated (using conventional techniques) to obtain those products of formula I wherein Ry is -0-Y, and
Yq is other than hydrogen.
An additional procedure for preparing the compounds of formula I wherein R, is
H-Y,
H, ‘ 6 Y, comprises treating a compound of formula II with an alkali metal hydride (e.g., sodium hydride) in - an inert solvent (e.g., dimethylformamide or dimethylsul foxide) followed by reaction with a compound of the formula [a
IV halogen-CH-C=N to obtain the corresponding compound having the formula
HA460 -8-
Vv R, > 3 1 bo, =N
Reduction of a compound of formula V using, for example, catalytic hydrogenation (e.g., rhodium on alumina) yields the corresponding product of formula I having the formula vi R,
R3 1
H-Y,
H,
NH,
Reductive amination of a compound of formula VI with the appropriate aldehyde or ketone using a chemical reducing agent (e.g., sodium - cyanoborohydride) yields the corresponding product of formula I having the formula
HA460 -9-
VII 4 3 R3 1
Cn-y
L 4 2
AN
Ye Y, ’ wherein at least one of Ye and Y, is other than hydrogen.
Alternatively, compounds of formula I wherein
R, is H-Y, fs . iN . 15 . . . H-Y, , Ten, ) oe . : eR es ea Pe anes A . / ' N—C¢ 5 2'n , 6 17 Yq
N bH——(CH,)
Te, or ,
H-—C 3 ay 1.
ZY, l can be prepared by first treating a compound of formula II with an alkali metal hydride (e.g., sodium hydride) in an inert organic solvent (e.g., © dimethyl formamide or dimethylsulfoxide) followed by reaction with the appropriate compound having the formula
VIII R_-halogen wherein R, is in ,
HA460 -10- !
Y -éu- —C He—C 4 2 H.) I H.)
H-C 2'’n , CH,= 2'’n , or - A
Yg- _c “2'n
The resultant compound has the formula
IX a
R3 Ry
Ry and can be reacted with ozone in an inert solvent (e.g., a halogenated hydrocarbon) followed by reduction (e.g., using a chemical reducing agent such as dimethylsulfide) to yield the corresponding compound having the formula
X 4
R3 1 i Ry wherein Ry is Yams Yam dn )
B—7C 3 or Ye- -CH-CH,- (CH, ) = H.
CH: Hy) py 5 ,
A compound of formula X can be treated with the appropriate amine having the formula
XI HNY Y.,
HA460 -11- in the presence of a reducing agent (e.g.., hydrogen using a catalyst such as palladium on carbon, or a chemical reducing agent such as sodium cyanoborohydride) to obtain the corresponding product of formula I. i It is also possible to obtain an intermediate of formula X wherein Ry is Yams
In ) : or Cc 2’n by reacting a compound of formula II with a ketone of the formula ’ alogen
XIIa tee or
XI11b halogen - HD"
Bl: 5 2'n’
Preferred compounds of this invention are those wherein R, and R, are different; Rg is located in the 6- or 7-position of the benzazepine nucleus and is halogen or trifluoromethyl; and Ry is located in the 4-position of the phenyl ring to which it is attached and is hydroxy, alkoxy, alkylthio, alkylamino, aryloxy or arylalkoxy.
Most preferred are compounds wherein Ry is - 6-trifluoromethyl and R, is methoxy.
The following examples are specific embodiments of this invention.
oo HA460 -12-~- i EXAMPLE 1 [1(trans),3a,40]-1-[2~(Dimethylamino)cyclohexyl]- 1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-methyl-6- (trifluoromethyl )-2H-1-benzazepin-2-one, monohydrochloride
To a suspension of 0.3g of sodium hydride (6.3mmol of a 50% oil dispersion) in 20ml of dry dimethyl formamide was added 2.0g of (cis)-1,3,4,5- tetrahydro-4-(4-methoxyphenyl)-3-methyl-6- trifluoromethyl )-2H-1-benzazepin-2~-one (5.73mmol) - in one portion as a solid. The solution was stirred for 45 minutes and then a solution of 1.599 (6.3mmol) of (trans)-l-iodo-2-(dimethyl- amino)cyclohexane in 12ml of dry dimethyl formamide was added dropwise over 15 minutes. The solution was stirred at room temperature for 20 minutes and then heated to 75°C for 70 minutes. An additional 0.159 of sodium hydride and 0.8g of (trans)-1- iodo-2~(dimethylamino)cyclohexane were added and heating was continued for an additional 30 minutes.
The solution was allowed to cool and the dimethyl- formamide was removed under vacuum. Water was added to the residue, the aqueous solution was extracted twice with ethyl acetate and the combined organic phases were washed with brine and dried : (magnesium sulfate) to afford 3.15g of a semi- solid. Chromatography on silica with 1% } triethylamine: 2% methanol:dichloromethane afforded 0.74g of the free base of the title compound as a white foamy solid. The free base was dissolved in ether and hydrogen chloride-saturated ether was : added to afford a white precipitate. The solution was evaporated and washed twice with ether to remove excess hydrogen chloride. The remaining
HA460 -13- white solid was recrystallized from isopropanol- isopropyl ether to afford 0.68g of the title compound, melting point >250°C.
Analysis calc'd. for C,,H3,ClF,N,0,-1.5H,0
C:62.51; H:6.77; N:5.40; Cl:6.83; F:10.99
Found: C:62.59; H:6.84; N:5.30; C1:6.70; F:10.99
Example 2 (cis)-1=[2~-(Dimethylamino)propyl]-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl)-3-methyl-6-(trifluoro- methyl )-2H-1-benzazepin-2-one, isomer A, monohydrochloride
A stirred solution of 3.0g (8.69 mol) of (cis)~-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3- methyl-6-(trifluoromethyl)-2H-1-benzazepin-2-one in 90ml of 2-butanone was treated with 1.7g (10.75mmol) of N,N-dimethyl-2-chloro-1-(methyl) ethylamine followed by 3.0g (2.17mmol) of pulverized potassium carbonate and heated to reflux. After approximately 2 days of heating, a significant amount of (cis)-1,3,4,5-tetrahydro-4- (4-methoxyphenyl )-3-methyl-6-(trifluoromethyl)-2H- cl 1-benzazepin-2-one was still present. An additional 1.2g of N,N-dimethyl-2-chloro-1-(methyl)ethyl- oC 25 amine and 2.2g of potassium carbonate wére added and heating was continued for an additional day.
After cooling, solids were filtered off, washed with 2-butanone, and the combined filtrates oo evaporated. The residue was shaken with 90ml of ethyl acetate and 30 ml of water, the layers separated, and the ethyl acetate layer washed with 30ml each of water and brine, dried (magnesium . sulfate), evaporated. The residue was taken up. in ether, the evaporation repeated, and the residue pump-dried to give 3.86g of solid. Following two
HA460 -14- crystallizations from isopropyl ether, there was obtained 1.05g of solid; melting point 154-157°C (s. 152°C). TLC: Major product, Re 0.51, minor product, Re 0.42 (90:10 dichloromethane-methanol);
Major product, Re 0.27; minor product, Rg 0.17 (30:70 acetone-hexane).
The above material was chromatographed on 40g of Baker silica gel, eluting with 30:70 . acetone-hexane, to give 0.6g of the single isomer as a colorless solid; melting point 159-161°C.
Analysis calc'd. for C,4H,gF3N,0,: " C,66.34; H,6.73; N,6.45
Found: C,66.50; H,7.02; N,6.32
The residue from the second isopropyl ether seat 15 crystallization and cuts from the above . =. . __ .. chromatography rich in isomer A were combined and chromatographed to give an additional 0.36g of identical material.
The 2 batches were combined (total, 0.92q), suspended in 25ml of methanol, treated with 0.45ml of 5 N ethanolic hydrogen chloride (solution obtained), and the solvent evaporated.
The syrupy residue was rubbed under ether, evaporated, and pump-dried. This process was repeated to yield 0.92g of the title colorless, non-hygroscopic, hydrochloride salt; melting point 101-104°C (foaming); sintering at 88°C.
TLC: Re 0.40 (40:60 acetone-hexane)
Re 0.25 (8:1:1 dichloromethane-methancol-acetic acid)
Analysis calc'd. for C,4HygF3N,0,-HC1:0.5 H,0:
C,60.05; H,6.51; N,5.84; Cl1,7.39
Found: C,59.93; H,6.87; N,6.04; Cl1,7.14
HA460 -15-
Example 3 (cis)-1-[2-(Dimethylamino)propyl]-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl)-3-methyl-6-(trifluoro- methyl )-2H-1-benzazepin-2-one, isomer B, monohydrochloride
The isopropyl ether mother liquors from the crystallization of the free base of Isomer A of : Example 2 were evaporated and the residual oil- pump dried to give 2.4g of a waxy residue. TLC (40:60 acetone-hexane) showed this material to be about a 40:60 mixture of isomer A and isomer B.
The mixture was chromatographed on Baker silica gel, eluting with 40:60 acetone-hexane, to give 0.49g of Isomer B base as a waxy solid.
TLC: R0.19 (40:60 acetone-hexane). A solution of the base (0.48g) in methanol was treated with 0.24ml of 5 N ethanolic hydrogen chloride and the solvent evaporated. The residue was rubbed under ether, evaporated, and pump-dried. This process was repeated to yield 0.50g of colorless, slightly hygroscopic, hydrochloride salt; melting point 83-86°C (foaming); sintering at 76°C.
TLC: Re 0.22 (40:60 acetone-hexane).
Analysis calc'd. for C,4H,gF3N,0,-HC1-0.5 H,0
C,60.05; H,6.51; N,5.84; C1,7.39
Found: C,60.30; H,7.00; N,5.62; Cl1,7.17
HA460 -16-
Example 4 (cis)-1-(2-Amino-l-methylethyl)-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl)-3-methyl-6-(trifluoro- methyl )-2H-1-benzazepin-2-one, isomer B, monohydrochloride
A) (cis)-1,3,4,5-Tetrahydro-4-(4-methoxyphenyl)- o,3-dimethyl-2-oxo-6-(trifluoromethyl)-1H- 1-benzazepine-l-acetonitrile, faster moving isomer ‘To a suspension of 0.22g of sodium hydride (5.37mmol of a 60% oil dispersion) in 15ml of dry dimethylformamide was added 1.509 (4.29mmol) of (cis)-3-methyl-4-(4-methoxyphenyl)-6-(tri- fluoromethyl)-2H-1-benzazepin-2-one. The solution was stirred for 15 minutes at room temperature, cooled at 0°C and 0.42ml (5.37 mmol) of 2-chloro- propionitrile was added neat. The solution was stirred at 0°C for 10 minutes, warmed to room temperature for 15 minutes and heated to 45°C for ! 20 90 minutes. An additional 50 mg of sodium hydride : and 0.15ml of chlciopropionitrile were added and the solution was stirred at 45°C for 20 minutes.
The reaction was quenched with 1M ammonium chloride and dimethylformamide was removed under : 25 high vacuum with gentle warming. The residue was partitioned between ether and 1M ammonium chloride and the organic layer was washed with brine, dried : (magnesium sulfate) and evaporated to afford a brown foamy solid which was combined with the crude product from a similar reaction performed on a 1.68mmol scale. The crude product consisted of the two diastereomers of the product, designated the faster-moving isomer (FMI, Re=0.74, 50% ethyl acetate/hexane) and the slower-moving isomer (SMI,
R.=0.66, 50% ethyl acetate/hexane). The solid was
HA460 -17- chromatographed on silica (60% ether/hexane) to afford 0.90g of clean FMI as a white solid. The chromatography also afforded 0.34g of nearly clean
SMI, which was dissolved in hot hexane containing 5% isopropyl ether and cooled to afford 0.29g of clean SMI as hexagonal prisms, melting point 166-168°C. Chromatography of the mixed fractions afforded an additional 0.44g of clean FMI (total 1.349) and 0.31g of SMI (total 0.60q).
B) (cis)-1-(2-Amino-l-methylethyl)-1,3,4,5-tetra- . hydro-4-(4-methoxyphenyl }-3-methyl-6-(tri- fluoromethyl)-2H-1-benzazepin-2-one, isomer B, monohydrochloride
A solution of 0.87g of (cis)-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl)-a,3-dimethyl-2-0x0-6- (trifluoromethyl )-1H-1-benzazepine-l-acetonitrile, faster moving isomer (2.16mmol) and 0.87g of 5% rhodium on alumina in 125ml of 1:1 methanol: - ammonia saturated methanol was hydrogerated under 50
Cl : 20 psi of hydrogen for 25 hours. The solution was filtered through Celite, the Celite was rinsed twice with methanol and the combined filtrates were evaporated. The semi-solid residue was taken up in dichloromethane, filtered through Celite and evaporated to afford 0.89g of white foamy solid.
To a solution of 0.34g of this material in ether was added hydrogen chloride saturated ether. The - solution, which became cloudy white, was evaporated and the residue was taken up in methanol and evaporated. The residue was taken up in 1ml of methanol, 20ml of ether was added followed by 20ml of hexane, and the solution was chilled. The white solid was filtered and dried to afford 0.30g of the title compound as a white solid, melting point 157-162°C (foaming).
HA460 -18-
Analysis calc'd. for C,,H,gClF3N,0,0.21H,0
C,59.15; H,5.96; N,6.27; C1,7.93; F,12.76
Found: C,59.15; H,6.10; N,6.04; Cl,7.84; F,12.78
Example 5
Co (cis)-1-[2-(Dimethylamino)-1-methylethyl]-1,3,4,-
Bh 5-tetrahydro-4-(4-methoxyphenyl)-3-methyl-6-(tri- fluoromethyl )-2H-1-benzazepin-2-one, isomer B, ! monohydrochloride
A solution of 0.62g of (cis)-l1-(2-amino-1- methylethyl)-1,3,4,5-tetrahydro-4-(4-methoxy- phenyl )-3-methyl-6-(trifluoromethyl)-2H-1-benzaze- pin-2-one, isomer B, monohydrochloride (1.52mmol; see Example 4) and 1.3ml of 37) aqueous formaldehyde in 10ml of acetonitrile was added in one portion with stirring to 0.31g of solid sodium cyanoborohydride and 0.16ml of acetic acid was then added. The solution was stirred at room temperature for 2 hours, an additional 0.16ml of acetic acid was added and the solution was stirred 30 minutes. Ether and 5% potassium carbonate were added, the mixture was partitioned, the organic layer was washed with brine, dried (magnesium sulfate) and evaporated to afford 0.84g of a thick 0il. Chromatography on silica with 2% methanol:1}% triethylamine:dichloromethane produced 0.30g of clean free base of the title compound. This . material was dissolved in ether, hydrogen chloride saturated ether was added, the white suspension was evaporated and the residue was twice dissolved in methanol and evaporated. Hot isopropyl ether was added to the glassy solid and hot methanol was added dropwise until the solid dissolved. The solution was filtered, hot isopropyl ether was added until cloudiness persisted and the solution
. : { -
HA460 -19- was cooled and refrigerated. The waxy precipitate was filtered and dried under vacuum to afford 220mg of the title compound as a white solid, melting point >220°C.
Analysis calc'd for C,,Hy,ClF3N,0,:0.60H,0:
C,59.84; H,6.53; N,5,81; C1,7.36; F,11.83
Found: C,59.84; H,6.52; N,5.76; C1,7.27; F,11.93
Example 6 (cis)-1-[2-(Dimethylamino)-1-methylethyl]-1,3,4,5~- tetrahydro-4-(4-methoxyphenyl)-3-methyl-6-(tri- fluoromethyl }-2H-1-benzazepin-2-one, isomer A, monohydrochloride
A) (cis)-1-(2-Amino-l-methylethyl)-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl )-3-methyl-6-(tri- fluoromethyl )-2H~-1l-benzazepine-2-one :
A solution of 0.60g of (cis)-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl)-«,3-dimethyl-2-0xo0-6- (trifluoromethyl)-1H~1-benzazepine-l-acetonitrile, slower moving isomer (1.49mmol) and 0.49g of 5% rhodium on alumina in 125ml of 1:1 methanol: ammonia saturated methanol was hydrogenated under 50 psi of hydrogen for 20 hours. The solution was filtered through Celite, the Celite was rinsed twice with methanol and the combined filtrates were evaporated. The semi-solid residue was taken up in dichloromethane, filtered through Celite and evaporated to afford 0.56g of the title compound as a white foamy solid.
B) (cis)-1-[2-(Dimethylamino)-l-methylethyl]-1,3,- 4,5-tetrahydro-4-(4-methoxyphenyl )-3-methyl-6~ (trifluoromethyl )-2H-1-benzazepin-2-one, isomer A, monohydrochloride
A solution of 0.56g of crude (cis)-1-(2- amino-l-methylethyl)-1,3,4,5-tetrahydro-4-(4-~
Co Cp ;
HA460 -20-~ methoxyphenyl )-3~-methyl-6-(trifluoromethyl)-2H-1~ benzazepin-2-one (1.38mmol) in 10ml of acetonitrile containing 1.2ml of 37% aqueous formaldehyde was added with stirring to 0.28g of solid sodium cyanoborohydride (4.44mmol) and 0.145ml of acetic acid was then added. The solution was stirred for 2 hours, an additional 0.145ml of acetic acid was added and the solution was stirred for 30 minutes. The reaction was partitioned between ether and 10% aqueous potassium carbonate and the organic layer was washed with brine, dried (magnesium sulfate) and evaporated to afford 0.70g of oil. This material was flash chromatographed on silica (1% methanol/ 0.5% triethylamine/dichloromethane) to afford 0.32g of clean free base of the title compound as a white foamy solid. This material was dissolved in ether and hydrogen chloride saturated ether was added to produce a white precipitate. The ether : 20 was evaporated, the solid was dissolved in methanol and the solution was evaporated. The solid was again dissolved in methanol and the solution was filtered through Celite and evaporated. The solid was dissolved in 2ml of warm methanol, hot isopropyl ether was added until incipient cloudiness, the solution was cooled and the solid collected by filtration to afford . 0.27g of the title compound as a white crystalline solid, melting point >220°C.
Analysis calc'd. for C,4H3(CLF3N, 0, -HC1:
C,61.20; H,6.42; N,5.95; c1,7.53; F,12.10; : Found: C,61.15; H,6.52; N,5.88; C1,7.71; F,11.78
. Cs .
HA460 -21-
Example 7 [3R-[1(R*),30,40]}]-3-(Acetyloxy)-1,3,4,5-tetra- hydro~4-(4-methoxyphenyl)-1-{(l-methyl-2-pyr- rolidinyl )methyl]-6-(trifluoromethyl)-2H-1-ben- zazepin-2-one, monohydrochloride
A) (R)-(-)-N-(t-Butoxycarbonyl)-2-pyrrolidine- methanol
A solution of (R)-(-)-2-pyrrolidinemethanol (5.0g, S0mmol) in dry dichloromethane (125ml) at 0°C was treated dropwise with a solution of di-t-butyl dicarbonate (13g, 59.5mmol) in 50ml of dichloromethane over a period of 15 minutes.
Immediate evolution of carbon dioxide gas - occurred. The cooling bath was removed and the
EI 15 mixture was stirred at room temperature for an additional 6 hours. The reaction mixture was then concentrated under reduced pressure to obtain the title compound as a light yellow viscous oil (13g). The crude material was used in the next reaction without further purification.
B) (R)-(-)-N-Methyl-2-pyrrolidinemethanol
Lithium aluminum hydride (7.6g, 200mmol) was added in small portions to dry tetrahydrofuran (200ml) cooled to 0-5°C. A solution of (R)-(-)-N- (t-butoxycarbonyl)-2-pyrrolidinemethanol (13g crude, ~50mmol) in dry tetrahydrofuran (100ml) was then added dropwise with vigorous stirring over a period of 45 minutes. After 30 minutes at 0°C : room temperature, the reaction mixture was heated to reflux for 16 hours. The reaction mixture was then cooled to 0°C and the excess hydride was destroyed by a slow addition of saturated aqueous sodium sulfate. Addition was continued until all the inorganic salts were precipitated as a white granular solid. The mixture was diluted with
HA460 -22- ethyl acetate (500ml), dried (magnesium sulfate), filtered and concentrated to give the title compound as a colorless oil (5.79). The crude product was used without purification in the next reaction
C) (R)-2-(Chloromethyl)-1-methylpyrrolidine, hydrochloride
To a solution of (R)-(-)-N-methyl-2- pyrrolidinemethanol (2.0g, 17.4mmol) in chloroform (18ml) at 0°C was added dropwise thionyl chloride (0.74g, 52.1mmol). The reaction mixture was ; heated to reflux for 2 hours, and then cooled to
Co room temperature and concentrated at reduced pressure. The residue was recrystallized from acetone-ether to yield the title compound as a pale yellow solid (1.149).
D) {3(R)-[1(R*),3a,4a]]-1-[(1-Methyl-2-pyr- rolidinyl)methyl]-3-(hydroxy)-1,3,4,5-tetra- hydro-4- (4-methoxyphenyl)-6-(trifluoromethyl)- 2H-1-benzazepin-2-one sodium hydride (0.19g, 8.lmmol) was added to a solution of (3R-cis)-3-hydroxy-4-(4-methoxy- phenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one (1.05g, 3.0mmol) in dry dimethyl formamide (30ml).
The mixture was stirred at room temperature for 1 : hour whereupon (R)-2-(chloromethyl)-1-methyl- pyrrolidine, hydrochloride (0.789, 4.5mmol) was - added and the mixture was heated to 80°C for 1 hour.
The reaction mixture was then cooled and quenched with saturated aqueous potassium bicarbonate and extracted with ethyl acetate (three times). The combined extracts were washed with 10% aqueous lithium chloride, dried (magnesium sulfate) and concentrated. The crude yellow liquid was chromatographed on a silica gel column and
HA460 -23- eluted with 1-3% methanol in dichloromethane to give the title compound as a viscous liquid (0.249).
E) [3R-{1(R*),3a,4a]]-3-{(Acetyloxy)-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl)-1-({(1-methyl-2-pyr- rolidinyl)methyl]-6-(trifluoromethyl)-2H-1- benzazepin-2-one, monohydrochloride
A solution of [3(R)-[1(R*),3a,4a]]}=-1-[(1- methyl-2-pyrrolidinyl )methyl}-3-(hydroxy)-1,3,4,5- tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)- 2H-1-benzazepin-2-one (0.24g, 0.54mmol), acetic anhydride (0.27g, 2.68mmol) and 4-dimethylamino- pyridine (0.07g, 1.07mmol) in dry dichloromethane (6ml) was stirred at room temperature for 60 hours.
The reaction mixture was then absorbed onto silica gel (60-200mesh), poured onto a silica gel column and eluted with 1-3% methanol in dichloromethane to give the free base of the title compound. The viscous oil was dissolved in ether and treated with a saturated etheral hydrogen chloride solution.
The white precipitate was recrystallized from toluene-hexane to yield the title compound as a white solid (0.23g), melting point 158-162°C. [x]p=+126.8° (C=3.7, methanol). .
Analysis calc'd. for C,gH30F3CIN,0,-1.0H,0:
C,57.31; H,5.92; N,5.14; F,10.46; Cl1,6.51
Found: C,57.63; H,5.68; N,5.23; F,10.21; Cl,6.34
Example 8 [3R-{1(S*),3a,40]]-3-(Acetyloxy)-1-[2-(dimethyl-~ amino )-3-phenylpropyl]-1,3,4,5-tetrahydro-4-(4- methoxyphenyl)-6-(trifluoromethyl)-2H-1-benza- zepin-2-one, monohydrochloride
A) (S)-2-(Dimethylamino)-3-phenyl-l-propanol
To a solution of (S)-2-amino-3-phenyl-1- propanol (6.0g, 4.0mmol) and 37% aqueous
HA460 -24- formaldehyde (20ml) in acetonitrile (200ml) was added with stirring sodium cyanoborohydride (4.0gq, 64mmol) in small portions. The mixture was stirred for 30 minutes whereupon glacial acetic acid was added dropwise to the solution until it tested neutral to pH paper. The mixture was’ ' stirred at room temperature for 2 hours with occasional addition of glacial acetic acid to maintain a neutral pH. The reaction mixture was then concentrated and the residual oil was diluted with 2N potassium hydroxide (250ml). It was extracted with ethyl acetate three times and the combined extracts washed with 1N potassium hydroxide and extracted with 1N aqueous hydrochloric acid three times. The acid extracts were combined, neutralized with solid potassium hydroxide and extracted with ethyl acetate three times. The extracts were combined, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound as a viscous oil (6.489).
B) (S)-1-Chloro-2-(dimethylamino)-3-phenylpropane, hydrochloride
To (S)-2-(Dimethylamino)-3-phenyl-1l-propanol (3.0g, 16.7mmol) in chloroform (20ml) at 0°C was added dropwise thionyl chloride (5.97g, 50.2mmol).
The reaction mixture was heated to reflux for 2 hours and then evaporated to dryness under reduced pressure. The residue was recrystallized from acetone-ether to give the title compound as an off white solid (2.38g, melting point 167.5-168.5°C). c) [3(R)-[1(S*),3a,4a])]-1-[2-(Dimethylamino)-3- phenylpropyl]-3-(hydroxy)-1,3,4,5~tetrahydro- 4-(4-methoxyphenyl)-6-trifluoromethyl)-2H-1- benzazepin-2-one
HA460 ~25-
Sodium hydride (0.22g, 9.0mmol) was added to a solution of (3R-cis)-3-hydroxy-4-(4-methoxy- phenyl )-6-(trifluoromethyl)-2H-1-benzazepin-2-one (1.05g, 3.0mmol) in dry dimethylformamide (30ml).
The mixture was stirred at room temperature for 1 hour whereupon (S)-1-Chloro-2-(dimethylamino)-3- phenylpropane, hydrochloride (0.89g, 4.5mmol) was added and the mixture was heated to 85°C for 2 hours. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate three times. The combined extracts were washed with 10% aqueous lithium chloride three times; brine, and dried over anhydrous magnesium sulfate. After concentration, the crude product was chromatographed on a silica gel column and eluted with 10-30% ethyl acetate-hexane to yield the title compound as a white foam (1.16g).
D) [3R-[1(S*),3a,4a]]-3-(Acetyloxy)-1-[2-(di- methylamino)-3-phenylpropyl]-1,3,4,5-tetra- ‘ 20 hydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)- : 2H-1-benzazepin-2-one, monohydrochloride
A solution of {3(R)-[1(S*),3a,4a]]-1-[2~ (dimethylamino)-3-phenylpropyl]-3-(hydroxy)-1,3,4,
S5-tetrahydro-4-(4-methoxyphenyl)-6-trifluoro- methyl )-2H-1-benzazepin-2-one (1.16g, 2.26mmol}, acetic anhydride (1.16g, 11.32mmol) and 4-dimethyl- aminopyridine (0.559, 4.53mmol) in dry dichloro- methane (25ml) was stirred at room temperature for 16 hours. The reaction mixture was absorbed onto silica gel (60-200mesh), poured onto a silica gel column and eluted with 5-25% ethyl acetate-hexane to obtain the free base of the title compound as a white foam. The free base was dissolved in ether and excess hydrogen chloride ether solution was added to give the title compound as a white solid
HA460 -26~ (0.96g), melting point 144-147°C. [«]p=+52.4° (C=3.3, methanol).
Analysis calc'd. for C43,H34CLlF3N,0,-0.76H,0:
Cc,61.56; H,5.92; N,4.63; C1,5.86; F,9.42
Found: C,61.60; H,6.00; N,4.59; C1,5.93; F,9.23
Example 9 [3R-[1(R*),3a,4a]]-3-(Acetyloxy)-1-[2-(dimethyl- amino )-3-phenylpropyl]-1,3,4,5-tetrahydro-4-(4- methoxyphenyl )-6-(trifluoromethyl)-2H-1-benz~- azepin-2-one, monohydrochloride
A) (R)=-(+)-2-(Dimethylamino)-3-phenyl-1-propanol
To a solution of (R)-(+)-2-amino-3-phenyl-1- propanol (6g, 40mmol) and 37% aqueous formaldehyde (20ml) in acetonitrile (200ml) was added with stirring sodium cyanoborohydride (4.0g, 64mmol) in small portions. The mixture was stirred for 30 minutes whereupon glacial acetic acid was added dropwise to the solution until it tested neutral ; 20 to pH paper. The mixture was stirred at room temperature for 2 hours with occasional addition of glacial acetic acid to maintain a neutral pH.
The reaction mixture was then concentrated and the residual oil was diluted with 2N (potassium hydroxide (250ml). It was extracted with ethyl : acetate three times and the combined extracts - washed with 1N potassium hydroxide and extracted - with 1N hydrochloric acid three times. The acid extracts were combined, neutralized with solid potassium hydroxide and extracted with ethyl acetate three times. The extracts were combined, dried over anhydrous magnesium sulfate and y concentrated to obtain the title compound as a viscous oil (6.23g).
HA460 -27-
B) (R)-1-Chloro-2-(dimethylamino)-3-phenylpropane, hydrochloride
To (R)-(+)-2-(dimethylamino)-3-phenyl-1- propanol (3.0g, 16.7mmol) in chloroform (20ml) at 0°C was added dropwise thionyl chloride (6.0g, 50.2mmol). The reaction mixture was heated to reflux for 2 hours whereupon it was evaporated to dryness under reduced pressure. The residue was recrystallized from acetone-ether to give the title compound as an off white solid (2.27g, oo melting point 170-171.5°C).
Cc) [3(R)-[1(R*),3a,4a)]-1-[2-(Dimethylamino)~3- phenylpropyl]-3-(hydroxy)-1,3,4,5-tetrahydro- 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1- benzazepin-2-one
Sodium hydride (0.13g, 5.4mmol) was added to a solution of (3R-cis)-3-hydroxy-4-(4-methoxy- phenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one (0.70g, 2.0mmol) in dry dimethylformamide (200ml).
The mixture was stirred at room temperature for 1 hour whereupon (R)-1-chloro-2-(dimethylamino)-3- phenylpropane, hydrochloride (0.60g, 3.0mmol) was added and the mixture was heated to 80°C for 2.5 hours. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate three times. The combined extracts were washed with 10% aqueous lithium chloride three times; brine; . filtered, dried over anhydrous magnesium sulfate and concentrated. The crude product was chromatographed on a silica gel column and eluted with 20-50% ethyl acetate-hexane to yield the title compound as a white foam (0.60q).
HA460 -28-
D) [3R-[1(R*),3a,4a]]-3-(Acetyloxy)-1-[2~-(di- methylamino)-3-phenylpropyl]-1,3,4,5-tetra- hydro-4- (4-methoxyphenyl)-6-(trifluoromethyl)- 2H-1-benzazepin-2-one, monohydrochloride
A solution of [3(R)-[1(R*),3a,4a]]-1-[2- (dimethylamino)-3-phenylpropyl]-3-(hydroxy)-1,3, 4,5-tetrahydro-4-(4-methoxyphenyl)-6-(trifluoro- methyl )-2H-1-benzazepin-2-one (1.0gq, 1.95mmol), oo acetic anhydride (1.0g, 9.8mmol) and 4-dimethyl- aminopyridine (0.48g, 3.90mmol) in dry dichloromethane (20ml) was stirred at room temperature for 14 hours. The reaction mixture was absorbed onto silica gel (60-200mesh), poured oo onto a silica gel column and eluted with 5-25% ethyl acetate-hexane to obtain the free base as a white foam. The free base was dissolved in ether and excess hydrogen chloride-ether solution was added to give the title compound as a white solid (0.61 g), melting point 146-150°C. («]p=+137.3° (C=3.0, methanol).
Analysis calc'd. for Cy,H34CLF3N,0,:0.56-Hy0:
C,61.93; H,5.89; N,4.66; C1,5.90; F,9.48
Found: C,62.02; H,6.21; N,4.67; cl1,5.83; F,9.33
Example 10 . (3R-cis)-1-[2-(Dimethylamino)-2-methylpropylj-1.3, 4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6- . (trifluoromethyl )-2H-1-benzazepin-2-one, monohydrochloride
The following preparation is run under argon.
A stirred solution of (3R-cis)-3-hydroxy-4- (4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benza- zepin-2-one (2.59: 7.12mmol) in 75ml of dimethyl formamide was treated with 0.3g (7.5mmol) of 60% sodium hydride and stirred for 1 hour. To
HA460 -29- this solution was added a dried toluene solution of 1-chloro-2-(dimethylamino)-2-methylpropane (released from 3.75g (21.8mmol) of the hydrochloride salt with potassium carbonate into toluene) and the mixture was heated in an oil btah at 71-78°C (both temp.) for 1.25 hours. After cooling, the bulk of dimethylformamide was removed on a rotary evaporator at 0.2mm. and the residue was shaken with 125ml of ethyl acetate and 50ml of water. The layers were separated and the organic phase was washed with water (twice, 50ml), brine (25ml) dried (magnesium sulfate), and evaporated.
The solid residue was suspended in ether, the evaporation repeated, and the solid pump dried; weight 3.33g. This was combined with 0.64g of product from an earlier run by dissolving in ether, filtering to clarify, and evaporating. , The solid residue (3.949) was shaken with 60ml of ethyl acetate and 40ml of water containing 17ml of
IN hydrochloric acid. The layers were separated and the organic phase extracted with 40ml of water.
The combined aqueous phases were washed with ether (wash discarded), layered over with 40ml of ethyl acetate, 19ml of N sodium hydroxide was added, the } 25 mixture shaken and separated. The aqueous phase was extracted with ethyl acetate (two times 30ml), the combined ethyl acetate layers were washed with . brine (20ml), dried (magnesium sulfate), and evaporated finally at 0.2mm to give 3.66g of solid. Following crystallization from 25ml of hot isopropanol the colorless material (free base of the title compound) weighed 2.36g, melting point 157-159°C (sintering at 155°C).
HA460 -30-
Analysis calc'd. for C,4HygF3N,04
C,63.98; H,6.49; N,6.22; F,12.65:
Found: C,64.17; H,6.53; N,6.08; F,12.93
The base (2.349) in 50ml of ethyl acetate was treated with 1.2ml of 5N ethanolic hydrogen chloride and the solvent evaporated finally at 0.2mm. The almost solid residue was rubbed under ethyl ether and the evaporation repeated to give after pump drying, 2.67g of the title compound as a colorless solid; melting point 90-93°C (foaming), sintering g2°cC. [«]p=+114° (C=1.0, methanol).
Analysis calc'd. for C,4H,gF3N,04-HC1-0.5H,0: c,58.12; H,6.30; N,5.64; Cl1,7.15
Found: C,58.06; H,6.53; N,5.37; C1,7.00
Example 11 (3R-cis)-1-[2-(Dimethylamino)-1-phenylethyl]-1,- 3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 6-(trifluoromethyl)-2H-1-benzazepin-2-one, isomer A, monohydrochloride
A toluene solution of N,N-dimethyl-2-chloro- 2-phenylethylamine was prepared by partitioning 3.59g of the hydrochloride salt (16.3mmol) between 15m1 of toluene and 100ml of aqueous sodium bicarbonate. The aqueous phase was washed with an , additional 10ml of toluene and the combined organic phases were dried (magnesium sulfate) and filtered. , To a stirred suspension of 0.75g of sodium hydride (15.6mmol of a 50% oil dispersion) in 30ml of dry dimethyl formamide was added 5.0g of (3R-cis)-3- hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)- . 2H-1-benzazepin-2-one (14.2mmol) in one portion as v. a solid. The solution was stirred for 1 hour at room temperature, heated to 70°C and the toluene solution of N,N-dimethyl-2-chloro-2-phenylethyl-
HA460 -31- amine was added dropwise over 2 hours. A solution of 1g of the above hydrochloride salt (4.Smmol) and 0.51g of potassium t-butoxide (4.5mmol) was stirred in 5ml of dimethylformamide for 2 minutes and added to the alkylation reaction. The resulting solution was stirred at 70°C for an additional 2.25 hours and quenched with aqueous sodium bicarbonate. Solvents were removed under high vacuum with gentle warming. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate, the organic phase was washed with brine, dried (magnesium sulfate), filtered and evaporated to afford a light yellow foamy gum.
The crude product was dissolved in 25ml of ether, seeded with (3R-cis)-3-hydroxy-4-(4-methoxy- phenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one and chilled to afford (after filtration) 0.25g of recovered (3R-cis)-3-hydroxy-4-(4-methoxyphenyl)- 6-(trifluoromethyl)-2H-1-benzazepin-2-one.
Evaporation of the mother liquor provided 7.23g of foamy solid which was chromatographed on silica (2% methanol/0.5% triethylamine/dichloromethane) to : yield 1.90g of clean FMI (faster-moving isomer) as a light yellow foamy solid. A solution of 0.41g of clean FMI was dissolved in ether and treated with hydrogen chloride-saturated ether. The white solid was filtered, rinsed twice with ether and air-dried to produce 0.41g of white solid. This material was dissolved in 2ml of isopropanol/éml isopropyl ether with warming and the solution was filtered of a small amount of insoluble material.
The filtrate was treated with hexane and the resulting white solid was collected by filtration and dried to afford 0.39g of the title compound,
HA460 -32- melting point 136-142°C. [x],=+146.2° (c=1, methanol).
Analysis calc'd. for C,gH,,C1F3N,04-0.52moles H,O: c,61.77; H,5.75; N,5.14; Cl,6.51; F,10.47
Found: C,61.77; H,6.02; N,5.26; C1,6.46; F,10.63
Example 12 (3R-cis)-1-[2-(Dimethylamino)-1-phenylethyl]-1,3, 4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-one, isomer B, ! monohydrochloride
No pure SMI (slower-moving isomer)- containing fractions were obtained from the chromatography of (3R-cis)-1-[2-(dimethylamino)-1- "15 phenylethyl]-1,3,4,5-tetrahydro-3-hydroxy-4-(4- methoxyphenyl)-6-(trifluoromethyl)-2H-1-benza- zepin-2-one, isomer A, monohydrochloride.
Fractions containing SMI (contaminated with FMI and (3R-cis)-3-hydroxy-4- (4-methoxyphenyl)-6-(tri- a. 20 fluoromethyl)-2H-1-benzazepin-2-one) were pooled and evaporated to afford 3.40g of crude SMI. This material was rechromatographed on silica (2% methanol /0.5% triethylamine/dichloromethane) to yield 0.81g of SMI, containing trace amounts of - FMI and a significant amount of (3R-cis)-3- . hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)- 2H-1-benzazepin-2-one. This material was - chromatographed on six preparative thin layer chromatography plates (5% methanol/dichloro- methane), the major band was excised, extracted twice with 5% methanol/1% triethylamine/dichloro- . methane and the combined extracts evaporated and chased three times with carbon tetrachloride to afford 0.41g of clean free base of the title compound. This material was dissolved in ether,
- .
HA460 -33- filtered through Celite to remove cloudiness and hydrogen chloride saturated ether was added. The resulting white solid was filtered, rinsed twice with ether and air-dried to afford 0.42g of the title compound as a white solid, melting point 165-171°C. [«x],=+221.8° (C=1, methanol).
Analysis calc'd. for C,gH3gN,03C1F 5: 0.49H,0:
C,61.84; H,5.74; N,5.15; Cl1,6.51; F,10.48
Found: C,61.84; H,5.81; N,5.07; Cl,6.12; F,10.18
Example 13 [3R-[1(S*),3a,4a]]-3-(Acetyloxy)-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl- methyl )-6-(trifluoromethyl)-2H-1-benzazepin-2- one, monohydrochloride
A) N-(Benzyloxycarbonyl)-2-pyrrolidinemethanol
Powdered anhydrous potassium carbonate (41g, 297mmol) was added with stirring to a solution of (S)-2-pyrrolidinemethanol (6g, 59.32mmol) in acetone (120ml). The mixture was cooled to 0°C and benzyl chloroformate (16.94ml, 118.6mmol) was added dropwise. After 40 minutes, the reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, dried (magnesium sulfate) and concentrated. The crude oil was chromatographed on a silica gel column and eluted with 25% ethyl acetate in hexane to obtain the title compound 2 (12.22g) as a pale yellow oil.
B) (S)-1-(Benzyloxycarbonyl)-2-(bromomethyl)- pyrrolidine
Triphenyl phosphine (4.46g, 17mmol) and carbon tetrabromide (5.64g, 17mmol) were added to
HA460 -34-~ a solution of N-(Benzyloxycarbonyl)-2-pyrrolidine- methanol (2g, 8.5mmol) in ether (100ml). The mixture was stirred at room temperature for 19 hours, cooled and the precipitated solids were filtered off. The residual solids were washed
Co with hexane. The filtrate was concentrated and bo purified by chromatography on a silica gel . column. Elution with 10-20% ethyl acetate in . hexane afforded the title compound (2.1lg), as a ol 10 colorless oil. : C) [3(R)-[1(S*),3a,4a]]-1-[(Benzyloxycarbonyl-2- pyrrolidinyl )methyl]-3-hydroxy-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)- 2H-1-benzazepin-2-one (3R-cis)-3-Hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl )-2H-1-benzazepin-2-one {(0.84g, 2.3mmol) was added to a suspension of sodium hydride (0.066g, 2.7mmol) in dimethyl formamide } (23ml). After 1 hour at room temperature, (S)-1- (benzyloxycarbonyl)-2-(bromomethyl)pyrrolidine (0.97g, 3.4mmol) was added. The reaction mixture was heated at 65°C for 2.5 hours and then additional amounts of sodium hydride (0.028g, 1.14mmol) and (S)-1-(Benzyloxycarbonyl)-2-(bromomethyl)pyrrole (0.33g, 1.14mmol) were added. After an additional . 1 hour at 65°C the mixture was cooled and then diluted with water and extracted with ethyl : acetate three times. The ethyl acetate extracts were combined, washed with 109 aqueous lithium chloride, dried (magnesium sulfate) and concentrated. The crude residue was i chromatographed on a silica gel column and eluted with 20-40% ethyl acetate in hexane to obtain the title compound (0.89).
HA460 -35~-
D) [3(R)=-[1(S*),30,4a]]-3-Acetoxy-1-[(1l-benzyl- oxycarbonyl-2-pyrrolidinyl)methyl]-1,3,4,5- tetrahydro-4-(4-methoxyphenyl)-6-(trifluoro- methyl )-2H-1-benzazepin-2-one
N,N-Dimethylaminopyridine (0.45g, 3.7mmol) was added to a solution of [3(R)-[1(S*),3a,4a]]-1- [ (benzyloxycarbonyl-2-pyrrolidinyl )methyl]-3- hydroxy-1,3,4,5-tetrahydro-4-(4-methoxyphenyl }-6- (trifluoromethyl)-2H-1-benzazepin-2-one (1.1l4g, 1.85mmol) and acetic anhydride (0.87ml, 9.24mmol) in dichloromethane (20ml). The mixture was stirred at room temperature for 4 days, absorbed into silica gel (60mesh) and flash chromatography on a silica gel column. Elution with 10-40% ethyl
Co 15 acetate in hexane afforded the title compound DE (0.68g) as a viscous oil.
E) [3R-[1(S*}),30,4a]]-3~(Acetyloxy)-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl- methyl )-6~-(trifluoromethyl )-2H-1-benzazepin-2- one, monohydrochloride
Ammonium formate (0.23g, 3.64mmol) was added in one portion to a suspension of 10% palladium on charcoal (0.05g) and [3(R)-[1(S*),3a,4a]]-3- acetoxy-1-{(l-benzyloxycarbonyl-2-pyrrolidinyl)- ~methyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6- (trifluoromethyl )-2H-1-benzazepin-2-one (0.48qg, 0.73mmol) in methanol (10ml). The mixture was heated under reflux for 30 minutes, whereupon it was cooled and filtered through Celite. The residual solids were washed with ethyl acetate.
The filtrate was concentrated to obtain a white foam, which was dissolved in ether and treated with excess etheral hydrogen chloride solution.
The solution was concentrated and crystallized from toluene/hexane to obtain the title compound
HA460 -36- (0.325g) as an off-white solid, melting point 217-219°C. [x],=+78.7° (C=3.0, methanol).
Analysis calc'd. for C,gHy7F3N,0, -HC1:0.29H,0: c,58.06; H,5.37; N,5.42, Cl1,6.86; F,11.02
Found: C,58.37; H,5.57; N,5.54; Cl1,7.05; F,10.58
Example 14 [3R-[1(S*),3¢,4a]]-3-(Acetyloxy)-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl)-1-[(1l-methyl-2-pyr- rolidinyl)methyl]-6-(trifluoromethyl)-2H-1-ben- zazepin-2-one, monohydrochloride
A) (S)-(+)-N-(t-Butyloxycarbonyl)-2-pyrrolidine- methanol
A solution of (S)-(+)-2-pyrrolidinemethanol (10g, 100mmol) in dry dichloromethane (250ml) was treated dropwise at 0-5°C with a solution of di- t-butyl dicarbonate (26g, 119mmol) in 100ml of dichloromethane over a period of 30 minutes.
After 6 hours at room temperature, the reaction mixture was concentrated to obtain the title compound (23.5g) as a viscous oil.
B) (S)-(+)-N-Methyl-2-pyrrolidinemethanol
A solution of (S)-(+)-N-(t-butyloxy- carbonyl)-2-pyrrolidinemethanol (17.5g crude, 87mmol) in dry tetrahydrofuran (100ml) was added dropwise at 0-5°C to a suspension of lithium aluminum hydride (1l1.4g, 300mmol). The mixture . was heated under reflux for 16 hours. It was then cooled in an ice-water bath and excess hydride was destroyed by dropwise addition of saturated sodium sulfate solution. The mixture was diluted with ethyl acetate and filtered through anhydrous ¥ magnesium sulfate. The residual solid was washed thoroughly with ethyl acetate. The combined filtrate was concentrated under reduced pressure
HA460 -37- to obtain a yellow oil, which was distilled to obtain the title compound, boiling point 97°C/50mm. Hg.
C) (S)-2-(Chloromethyl)-1-methylpyrrolidine
Thionyl chloride (3.28ml, 45mmol) was added dropwise to a solution of (S)~(+)-N-methyl-2-pyr- rolidinemethanol (1.73g, 15mmol) in chloroform (15ml) at 0-5°C. The mixture was heated under reflux for 2 hours and was then concentrated. The crude residue was crystallized from acetone/ether to obtain the title compound (1.48g) as a hydrochloride salt.
D) [3(R)-[1(S*),30,4a]]-1-[(1-Methyl-2-pyr- rolidinyl )methyl ]-3-hydroxy-1,3,4,5-tetra- hydro-4-(4-methoxyphenyl)-6-(trifluoro- methyl )-2H-1-benzazepin-2-one (3R-cis)-3-Hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl )-2H-1-benzazepin-2-one (0.7qg, 2mmol) was added to a suspension of sodium hydride (0.13g, 5.4mmol) in dimethyl formamide (20ml). The mixture was stirred at room temperature for 1 hour, cooled at 0°C and the hydrochloride salt of (S)-2-(chloromethyl)~1-methylpyrrolidine (0.52q, 3mmol) was added. After stirring for 1 hour at room temperature, additional sodium hydride (0.012g, 0.5mmol) was added. The mixture was stirred for an additional 3 hours and was then diluted with water. It was then extracted with ethyl acetate and the ethyl acetate extract was washed with 10% aqueous lithium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The crude residue was - chromatographed on a silica gel column and eluted with 2-5% methanol in dichloromethane to obtain the title compound (0.659) as a white foam.
HA460 -38~
E) [3R-[1(S*),30,4a]]-3-(Acetyloxy)-1,3,4,5~- tetrahydro-4-(4-methoxyphenyl)-1-[(1-methyl-2- pyrrolidinyl)methyl]-6-(trifluoromethyl)-2H-1- benzazepin-2-one, monohydrochloride
N,N-Dimethylaminopyridine (0.41g, 3.34mmol) was added to a solution of [3(R)-[1(S*),3a,4a]]-1- [ (1-methyl-2-pyrrolidinyl)methyl]-3-hydroxy-1,3,4, 5-tetrahydro-4-(4-methoxyphenyl)-6-(trifluoro- methyl )-2H-1-benzazepin-2-one (0.75g, 1.67mmol) and acetic anhydride (0.79ml, 8.4mmol) in dichloromethane (18ml). The mixture was stirred at room temperture for 24 hours. It was absorbed onto coarse silica gel and flash chromatographed on a silica gel column using 2-3% methanol in dichloromethane as eluents to obtain the title compound as its free base. The free base was dissolved in ether and was then treated with excess etheral hydrogen chloride solution. An additional 20ml of ether was added and the precipitated salt was decanted off and dried in vacuo at 70°C to obtain the title compound
Lo (0.536g) as a white solid, melting point 151-154°C. («],=+80.0° {(C=3.0, methanol).
Analysis calc'd for C,gHygF3N,0, *HC1-0.63H,0:
Cc,58.00; H,5.85; N,5.20; Cl,6.59; F,10.59
Found: C,57.74; H,5.56; N,4.93; cl,7.01; F,10.16 . Example 15 [3R-[1(R*),30,4a]]-1,3,4,5-Tetrahydro-3-hydroxy-4- (4-methoxyphenyl)-1-(2-pyrrolidinylmethyl)-6-(tri- fluoromethyl)-2H-1-benzazepin-2-one, monohydro- chloride
A) (R)-N- (Benzyloxycarbonyl)-2-pyrrolidine- methanol
HA460 -39-
Benzyl chloroformate (6ml, 39.5mmol) was added dropwise at 0°C to a suspension of powdered anhydrous potassium carbonate (13.7g, 99mmol) and (R)-2-pyrrolidinemethanol (2g, 19.8mmol) in acetone (100ml). After 1 hour, the reaction mixture was diluted with water and ethyl acetate.
The organic layer was separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic extracts were dried (magnesium sulfate), filtered and concentrated. The crude 0il was chromatographed on a silica gel column and eluted with 20-60% ethyl acetate in hexane to obtain the title compound (4.57g).
B) (R)-1-(Benzyloxycarbonyl)-2-(bromomethyl)- pyrrolidine
A solution of (R)-N-(benzyloxycarbonyl)-2- pyrrolidinemethanol (4.55g, 19.3mmol), triphenyl phosphine (10.2g, 38.7mmol) and carbon tetrabromide (12.8g, 38.7mmol) in ether (200ml) was stirred at room temperature overnight. The reaction mixture was diluted with hexane and filtered. The filtrate was concentrated and the residue was chromatographed on a silica gel column. Elution with 5-10% ethyl acetate in hexane afforded the title compound (3.59g) as a colorless solid.
C) [3(R)-[1(R*),30,4a]]-1-((1-Benzyloxycarbonyl- 2-pyrrolidinyl )methyl)-3-hydroxy-1,3,4,5- tetrahydro-4-(4-methoxyphenyl )-6~trifluoro- methyl )-2H-1~-benzazepin-2-one (3R~cis)-3-Hydroxy=-4-(4-methoxyphenyl)-6- (trifluoromethyl )-2H-1-benzazepin-2-one (2.46q, 7mmol) was added to a suspension of sodium hydride (0.25g, 10.5mmol) in dimethylformamide (70ml}).
The mixture was stirred at room temperature for 1
HA460 -40- hour and (R)-1-(benzyloxycarbonyl)-2-(bromo- methyl )pyrrolidine (3g, 10.5mmol) was added. The reaction mixture was heated at 80°C for 4 hours and additional methanol (0.08g, 3.5mmol) was ' 5 added. After an additional 2 hours at 80°C, the mixture was cooled and quenched with water. It was extracted with ethyl acetate three times.
Combined extracts were washed with 10% aqueous lithium chloride solution, dried (magnesium sulfate) and concentrated. The crude residue was chromatographed on a silica gel column and eluted with 1% methanol in dichloromethane to obtain the title compound (4.329), contaminated with unreacted (3R-cis)-3-hydroxy-4-(4-methoxyphenyl)- 6-(trifluoromethyl)-2H-1-benzazepin-2-one.
D) [3R-[1(R*),30,40]1}-1,3,4,5-Tetrahydro-3- hydroxy-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl- methyl)-6-(trifluoromethyl)~2H-1-benzazepin-2- one, monchydrochloride
Ammonium formate (1.8g, 28.3mmol) was added in one portion to a suspension of 10% palladium on charcoal (1g) and [3(R)-[1(R*),3a,4a]]-1-[(1- benzyloxycarbonyl-2-pyrrolidinyl)methyl}-3- ’ hydroxy-1,3, 4, 5-tetrahydro-4-(4-methoxyphenyl)-6- trifluoromethyl )-2H-1-benzazepin-2-one (3.59, 5.66mmol) in methanol (60ml). The mixture was heated under reflux for 1.5 hours, cooled and
To . filtered through Celite. The residual solid was } washed with chloroform. Combined filtrates were concentrated and the residue was chromatographed on a silica gel column. Elution with 3-10% methanol in dichloromethane afforded the free base of the title compound. The free base was, dissolved in ether and treated with excess etheral hydrogen chloride solution. Concentration under
HA460 -4]1-~ reduced pressure and finally in vacuo afforded the title compound (0.21g) as a white solid, melting point 147-151°C. fe]p=t108.5° (C=2.6, methanol).
Analysis calc'd for C,3H,5F3N,04-HC1-1.0H,0:
C,56.50; H,5.77; N,5.73; C1,7.25; F,11.66
Found: C,56.76; H,5.74; N,5.50; C1,7.12; F,11.36
Example 16 (3(R)-[1(S*),3a,40]]-1,3,4,5-tetrahydro-3-hydroxy- 4-(4-methoxyphenyl)-1-(2-pyrrolidinylmethyl)-6- (trifluoromethyl )-2H-1-benzazepin-2-one, monohydrochloride
A) [3(R)-[1(S*),3a,4a]]-1-[(1-Benzyloxycarbonyl- 2-pyrrolidinyl)methyl]-3-hydroxy-1,3,4,5~ tetrahydro-4-(4-methoxyphenyl)-6-(trifluoro- methyl )-2H-1-benzazepin-2-one (3R-cis)-3-Hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-one (1.41lg, 4mmol) was added to a suspension of sodium hydride (0.199, 4.8mmol) in dimethylformamide (40ml).
After 1 hour, (S)-1-(benzyloxycarbonyl)-2- (bromomethyl )pyrrolidine (1.7g, 6émmol) was added and the mixture was heated to 80°C for 1.5 hours.
Additional sodium hydride (0.05g, 2mmol) and (3R- ~~ c¢is)=-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoro- methyl )-2H~1-benzazepin-2-one (0.57g, 2mmol) were added. The reaction mixture was heated for an additional 2 hours, cooled and quenched by the addition of water. It was extracted with ethyl acetate three times. Combined ethyl acetate extracts were washed with 10% aqueous lithium chloride solution, dried (magnesium sulfate) and concentrated. The crude residue was
BE chromatographed on a silica gel column and eluted
HA460 -42- with 30-50% ethyl acetate in hexane to afford the title compound (1.12g) as a white foam.
B) [3(R)-[1(S*),3a,4a]]-1,3,4,5-tetrahydro=-3- hydroxy-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl- methyl )-6- (trifluoromethyl )-2H-1-benzazepin-2- one, monohydrochloride ]
Ammonium formate (0.57g, 9.1lmmol) was added to a suspension of 10% palladium on charcoal (0.34g) and [(3(R)~[1(S*),3a,4a]]-1-[(1l-benzyloxy- carbonyl-2-pyrrolidinyl)methyl]}-3-hydroxy-1,3,4,5- tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl) -2H-1-benzazepin-2-one (1.12g, 1.82mmol) in methanol (40ml). The mixture was heated under reflux for 30 minutes, cooled and filtered through anhydrous magnesium sulfate. Residual solid was washed with ethyl acetate. Combined filtrate was concentrated and was then chromatographed on a silica gel column. Elution with 2-5% methanol in ethyl acetate followed by 10% methanol in dichloromethane to afford the free base of the title compound (0.72g). The free base was dissolved in ethyl acetate and treated with excess ethereal hydrogen chloride solution, concentrated ' and dried in vacuo at 70°C to yield the title compound (0.64g), melting point 159-163°C. [«]p=+71.3° (C=1.0, methanol).
Analysis calc'd. for C,4H,gF3N,04 HCL: 0.5H,0: ‘ c,57.56; H,5.67; N,5.84; C1,7.39; F,11.88
Found: C,57.34; H,5.84; N,5.62; cl,7.31; F,12.17
Example 17 (3R-cis)-3-(Acetyloxy)-1-[2-(dimethylamino)-2- methylpropyll]-1,3,4,5-tetrahydro-4-(4-methoxy- phenyl J-6-(trifluoromethyl)-2H-1-benzazepin-2- one, monohydrochloride
HA460 ~-43-
A stirred solution of 1.99 (3.9mmol) of (3R-cis)-1-[2-(dimethylamino)-2-methylpropyl]-1,- 3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl )-2H-1-benzazepin-2-one, monohydrochloride (see Example 10) was heated in 50ml of acetic anhydride heated in an oil bath at 110-124°C (bath temperature). Acetylation was comparatively slow and approximately 4.25 hours of heating was necessary before the starting material was no longer seen by TLC. Concurrently, a high
Re by-product gradually formed during the heating.
After cooling, the bulk of acetic anhydride was removed on a rotary evaporator at 0.2mm and the residual oil (3.6g) was taken up in 10ml of ethyl wr 15 acetate. Since no crystallization occurred, the . ethyl acetate was evaporated and the oil rubbed under ether to give a solid. Most of the ether was decanted and the material was rubbed under fresh ether and cooled overnight.
The colorless solid which had become gelatinous was filtered under argon, washed with ether (hygroscopic), and dried in vacuo. Once free of solvent the solid was no longer hygroscopic and could be exposed to the atmosphere; weight 1.239; melting point 88-91°C (bubbles); sintering at 81°C. [x]p=+104° (C=1.0, methanol).
Analysis calc'd. for C,gH41N,0, HCL -H,O:
C,57.09; H,6.26; N,5.12; C1,6.48
Found: C,57.46; H,6.46; N,4.84; C1,6.33
Example 18 (3R-cis)-1-[1-[(Dimethylamino)methyl ]propyl]-1,3, 4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl )-2H-1-benzazepin-2-one, isomer B monohydrochloride
HA460 -44- :
A) (3R-cis)-3-(t-Butyldimethylsiloxy)-4-(4-
Ce methoxyphenyl)-6-(trifluoromethyl)-2H-1- benzazepin-2-one :
To a stirred solution of 10g of (3R-cis)-3- hydroxy-4- (4-methoxyphenyl)-6-(trifluoromethyl)- 2H-1-benzazepin-2-one (28.5mmol) and 4.85g of imidazole (71.2mmol) in 10ml of dry dimethyl formamide at 35°C was added 5.10g of t-butyldimethylsilyl chloride. The solution was
Co 10 stirred at 35°C overnight, cooled to room . : temperature and partitioned between ether and . water. The organic phase was washed with water and brine, dried (magnesium sulfate) and evaporated to afford 14.2g of the title compound as an amorphous solid, melting point 114-116°C.
B) (3R-cis)-3-(t-Butyldimethylsiloxy)-1-[1- [ (cyano )methyl]propyl]-4-(4-methoxyphenyl)- 6- (trifluoromethyl )-2H-1-benzazepin-2-one
To a stirred suspension of 0.54g of sodium hydride (11.2mmol of a 50% oil dispersion) in 10ml of dry dimethylformamide was added 4g of (3R-cis)- 3-(t-butyldimethylsiloxy)-4-(4-methoxyphenyl)-6- (trifluoromethyl )-2H-1-benzazepin-2-one (8.6mmol) in one portion as a solid. The solution vas stirred 30 minutes, 1.33g of 2-chlorobutyronitrile '(12.9mmol) was added neat and the solution was heated to 75°C for 1 hour. An additional 0.15g of sodium hydride and 0.3g of 2-chlorobutyronitrile were added and the solution was heated at 75°C for 45 minutes. The solution was quenched with 1M ammonium chloride and dimethylformamide was removed under vacuum with gentle warming. The residue was partitioned between ether and 1M ammonium chloride, the organic phase vas washed with water and brine, dried (magnesium sulfate)
HA460 -45- and evaporated to afford 4.68g of brown gum. Thin- layer chromatography (50% ether/hexane) indicated a 3:2 mixture of the diastereomers of the product, the faster-moving isomer (Rg=0.63) and the slower- moving isomer (Rg=0.56). Flash chromatography on silica (30% ether/hexane) afforded 1.10g of the title compound, the faster-moving isomer, as a white solid, melting point S54-57°C.
C) (3R-cis)-1-[1-[(Amino)methyl]propyl]-3-(t- butyldimethylsiloxy)-~-4-(4-methoxyphenyl)-6- (trifluoromethyl )-2H-1-benzazepin-2-one
A solution of 1.10g of (3R-cis)-3-(t- butyldimethylsiloxy)-1-[1-[(cyano)methyl}propyl]- 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1- benzazepin-2-one (2.06mmol) and 0.27g of rhodium _ Ce on alumina in 100ml of ammonia-saturated methanol was hydrogenated at 50psi for 6 hours. An additional 0.10g of rhodium on alumina was added, the solution was resaturated with ammonia and the solution was hydrogenated at 50psi for an additional 2 hours. The solution was filtered through Celite, the Celite rinsed twice with methanol and the combined filtrates were evaporated to afford 1.17g of foamy solid. Flash chromatography on silica (2% methanol/0.5% triethylamine/dichloromethane) afforded 0.70g of the title compound as a gum.
D) (3R-cis)-1-[1-[(Dimethylamino)methyl]propyl]- 3-(t-butyldimethylsiloxy)-4-(4-methoxyphenyl)- 6-(trifluoromethyl)-2H-1-benzazepin-2-one
To 0.26g of solid sodium cyanoborohydride (4.2mmol) at 0°C was added in portions with stirring a solution of 0.70g of (3R-cis)-1-[1- [(amino)methyl]propyl]-3-(t-butyldimethylsiloxy)- 4-(4-methoxyphenyl)-6~(trifluoromethyl)-2H-1-
HA460 -36= benzazepin-2-one (1.30mmol) and 1.2ml of 37% aqueous formaldehyde in 10ml of acetonitrile followed by 0.14ml of neat acetic acid. The ice bath was removed, the solution was stirred for 2 hours, another 0.05ml of acetic acid was added and the solution was stirred for 30 minutes. The solution was partitioned between ether and 10% aqueous potassium carbonate, the ether layer was washed with brine, dried (magnesium sulfate) and evaporated to afford 0.91g of thick oil. Flash chromatography on silica (1% methanol/0.2% triethylamine/dichloromethane) afforded 0.49g of the title compound as a clear gum.
E) (3R-cis)-1-[1-[(Dimethylamino)methyl]propyl]-1,- 3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)- 6- (trifluoromethyl )-2H-1-benzazepin-2-one, isomer B, monohydrochloride
To a solution of 0.49g of (3R-cis)-1-[1- [(dimethylamino)methyl]propyl]-3-(t-butyldimethyl- siloxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)- 2H-1-benzazepin-2-one (0.87mmol) in 10ml of dry dimethyl formamide was added 0.55g of tetrabutylammonium fluoride trihydrate (1.74mmol) in one portion as a solid. The solution was stirred for 20 minutes, partitioned between ether and water and the organic layer was washed with brine, dried (magnesium sulfate) and evaporated to afford 0.49g of semi-solid. Preparative thin layer chromatography (3 plates, 5% methanol /dichloromethane) afforded 0.35g of the free base of the title compound as a white crystalline solid. The free base was suspended in : ether, ethyl acetate was added until dissolution oo and hydrogen chloride saturated ether was added.
The resulting white solid was quickly collected by
HA460 -47- filtration, washed with ether and dried under vacuum to afford 0.24g of the title compound as a : white solid, melting point 144-148°C, [«]=+89.6° (C=1, methanol).
Analysis calc'd. for C,4H3(ClF3N, 04-1. 06H,0:
C,56.96; H,6.38; N,5.45; F,11.11; Cl1,7.24;
Found: C,56.96; H,6.40; N,5.54; F,11.26; C1,7.00.
Example 19 (3R-cis)-1-[1-((Dimethylamino)methyl]propyl]-1,3,- 4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6- (trifluoromethyl )-2H-1-benzazepin-2-one, isomer A, monohydrochloride
A) (3R-cis)-3-(t-Butyldimethylsiloxy)-1-{1- [(cyano)methyl]lpropyl]-4-(4-methoxyphenyl)-6- (trifluoromethyl )-2H-1-benzazepin-2-one
No clean slower-moving isomer (SMI) was obtained from the chromatography of the nitrile mixture described for (3R-cis)-1-[1-(dimethyl- amino )methyl ]propyl]-1,3,4,5-tetrahydro-3-hydroxy- 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1- benzazepin-2-one, monohydrochloride (see Example 18). Fractions containing SMI were pooled and evaporated to afford 1.91g of solid. This material was flash chromatographed on silica (25% ~~ ether/hexane) to afford 1.21g of the nearly clean
SMI of the title compound as a white solid.
B) (3R-cis)-1-[1-[(Amino)methyl}jpropyl]-3-(t- butyldimethylsiloxy)-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-one
A solution of 1.21g of (3R-cis)-3-(t-butyl- dimethylsiloxy)-1-[1-[(cyano)methyl]propyl]-4-(4- methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzaze- pin-2-one (2.27mmol) and 0.30g of 5% rhodium on alumina in 75ml of ammonia-saturated methanol was hydrogenated at 50psi for 5 hours. The solution
HA460 : -48- was filtered through Celite, the Celite rinsed twice with methanol and the combined filtrates were evaporated to afford 1.36g of crude title compound as a clear gum.
Cc) (3R-cis)-1-[1-(Dimethylamino)methyl]propyl]- 3-(t-butyldimethylsiloxy)-4-(4-methoxyphenyl)- 6-(trifluoromethyl)-2H-1-benzazepin-2-one
To 0.46g of solid sodium cyanoborohydride (7.26mmol) at 0°C was added in portions with stirring a solution of 1.36g of (3R-cis)-1-[1- [ (amino )methyl]propyl]-3-(t-butyldimethylsiloxy)- 4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1- benzazepin-2-one (2.27mmol) and 2.1ml of 37% aqueous formaldehyde in 20ml of acetonitrile followed by 0.3ml of neat acetic acid. The ice bath was removed, the solution was stirred for 2 hours, another 0.15ml of acetic acid was added and the solution was stirred for 2 hours. The solution was partitioned between ether and 10% aqueous potassium carbonate, the ether layer was washed with 10% aqueous potassium carbonate and brine, dried (magnesium sulfate) and evaporated to afford 1.31g of a clear gum. Flash chromatography on silica (1% methanol/0.5% triethylamine /dichloromethane) afforded 1.02g of a white foamy solid containing crude title compound. This material was chromatographed on 6 preparative thin layer plates (25% ethyl acetate/hexane) and the band with Rg=0.52 was . 30 excised and extracted with 5% methanol/ dichloromethane. The extract was filtered and the filtrate evaporated to afford 0.44g of the title compound as a light tan gum. %
HA460 -49-
D) (3R-cis)-1-[1-[(Dimethylamino)methyl]propyl]- 1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxy- phenyl )-6-(trifluoromethyl)-2H~1-benzazepin- 2-one, isomer A, monohydrochloride
To a solution of 0.44g of (3R-cis)-1-[1- [ (dimethylamino)methyl]propyl]-3-(t-butyldimethyl- siloxy)-4-(4-methoxyphenyl)-6-(trifluoromethyl)- 2H-1-benzazepin-2-one (0.78mmol) in 10ml of dry dimethyl formamide was added 0.49g of tetrabutyl- ammonium fluoride trihydrate (1.56mmol) in one portion as a solid. The solution was stirred for 25 minutes, partitioned between ether and water and the organic layer was washed with brine, dried (magnesium sulfate) and evaporated to afford 0.45g of tan gum. Preparative thin layer chromatography (3 plates, 2% methanol/dichloro- methane) afforded 0.36g of the free base of the title compound as a white crystalline solid. The free base was dissolved in ether, the solution was filtered through Celite and hydrogen chloride saturated ether was added to the filtrate. The resulting white solid was collected by filtration, washed twice with ether and dried under vacuum to afford 0.35g of the title compound as a white solid, melting point 126-131°C, [«},=+106.8° (C=1, methanol).
Analysis calc'd. for C,4H3(ClF4N,04-0.78H,0: c,57.54; H,6.35; N,5.59; C1,7.08; F,11.38;
Found: C,57.54; H,6.39; N,5.64; Cl1,6.96; F,11.09.
HA460 -50-
Example 20 (3R-cis)-1,3,4,5-Tetrahydro-3-hydroxy-4-(4-methoxy- phenyl )-1-{1-methyl-2-(methylamino)ethylj-6-(tri- fluoromethyl)-2H-1-benzazepin-2-one, isomer B monohydrochloride
A) (3R-cis)-3-(t-Butyldimethylsiloxy)-1-(1l-cyano- ethyl )-4-(4-methoxyphenyl)-6-(trifluoro- methyl )-2H-1~-benzazepin-2-one
Co To a stirred solution of (3R-cis)-3-(t- butyldimethylsiloxy)-4-(4-methoxyphenyl)-6-(tri- fluoromethyl)-2H-1-benzazepin-2-one (4g, 8.60mmol; see Example 18) in dry dimethylformamide (40ml) was added sodium hydride as a 60% oil dispersion (380mg, 9.50mmol). The solution was stirred at room temperature for 30 minutes and 2-chloro- propionitrile (0.68ml, 8.66mmol) was added neat.
The solution was heated to 50°C for 1 hour, an additional 0.02g of sodium hydride and 0.07ml of 2-chloropropionitrile were added and the reaction was heated at 50°C for 3 hours. The solution was cooled to room temperature, concentrated in vacuo to remove dimethylformamide and the brown residue was partitioned between ethyl acetate and water.
The organic phase was washed with water and brine, dried (magnesium sulfate) and evaporated and the residue was applied to a column of silica gel.
Elution with 5% ethyl acetate:hexanes afforded 1.76g of the faster-moving isomer, of the title compound, and 1.0g of the slower-moving isomer
B) (3R-cis)-1-[1-[(Amino)methyl]ethyl]-3-(t- butyldimethylsiloxy)-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-one
A solution of (3R-cis)-3-(t-butyldimethyl- siloxy)-1-(1l-cyanoethyl)-4-(4-methoxyphenyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-one (0.8g,
HA460 ~51- 1.5mmol) in methanol (100ml) was saturated with gaseous ammonia at 0°C for 5 minutes and 5% rhodium on alumina (0.2g) was added. The solution was hydrogenated at 45psi for 1.5 hours, additional catalyst (100mg) was added and the solution was hydrogenated at 55psi for an additional 1 hour. The mixture was filtered through a pad of Celite, which was rinsed with methanol. The combined filtrates were evaporated to afford 0.75g of the title compound.
C) (3R-cis)-1-[1-[(Trifluoroacetylamino)methyl]- ethyl]-3-(t-butyldimethylsiloxy)-4-(4-methoxy- : phenyl )-6-(trifluoromethyl)-2H-1-benzazepin-2- one
To a solution of (3R-cis)-1-[1-[(amino)- methyl ]ethyl]-3-(t-butyldimethylsiloxy)-4-(4= B methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzaze- pin-2-one (0.76g, 1.46mmol) and pyridine (0.37ml, 4.66mmol) in dichloromethane (10ml) was added a solution of trifluoroacetic anhydride (0.41ml, 2.91mmol) in 5ml of dichloromethane over 2 minutes and the solution was stirred at room temperature overnight. Additional pyridine (0.37ml, 4.66mmole) and trifluoroacetic anhydride (0.41ml) in 5ml dichloromethane were added and the solution was stirred for 20 minutes. The solution was extracted with water and brine, dried (magnesium sulfate) and evaporated to afford 0.77g of the title compound as a red oil.
D) (3R-cis)-1-[1-{((Trifluoroacetyl)methylamino)- methyl ]ethyl]-3-(t-butyldimethylsiloxy)-4-(4- methoxyphenyl)-6-(trifluoromethyl-2H-1~ benzazepin-2-one
To a solution of (3R-cis)-1-[1-[(tri- fluoroacetylamino)methyl]ethyl]-3-(t-butyldi-
HA460 -52- methylsiloxy)-4-(4-methoxyphenyl)-6-(trifluoro- methyl )-2H-1-benzazepin-2-one (570mg, 0.94mmole) in dry dimethylformamide (5ml) was added sodium hydride as a 60% oil dispersion (44.9mg, 1l.12mmole).
The solution was stirred for 30 minutes at room temperature, methyl iodide (0.07ml, 1.12mmol) was added and the solution was stirred at room temperature for 2 hours. The solution was partitioned between ethyl acetate and water, the organic phase was washed with water and brine, dried (magnesium sulfate) and evaporated to afford 450mg of the title compound as a red oil.
E) (3R-cis)-1-[1-[(Methylamino)methyl]ethyl}-3- (t-butyldimethylsiloxy)=-4-(4-methoxyphenyl)- 6- (trifluoromethyl )-2H-1-benzazepin-2-one
A mixture of (3R-cis)-1-[1-[((trifluoro- acetyl )methylamino)methyl]ethyl]-3-(t-butyldi- methylsiloxy)-4-(4-methoxyphenyl)-6-(trifluoro- methyl )-2H-1-benzazepin-2-one (450mg, 0.72mmole) and sodium carbonate (0.5g, 4.72mmole) in methanol (20ml) was refluxed overnight. The reaction was cooled to room temperature and evaporated and the residue was partitioned between dichloromethane and water. The organic phase was washed with oo 25 water and brine, dried (magnesium sulfate) and evaporated. The residue was applied to 3 preparative silica gel plates which were eluted with 5% methanol:dichloromethane. The product bands were cut and extracted with 5% methanol: dichloromethane:0.5% triethylamine. The mixture was filtered through a pad of Celite and the pad was rinsed with dichloromethane. The combined . filtrates were evaporated and the residue was chased with toluene to afford 230mg of the title compound as a yellow oil.
/ ; HA460 -53- / /
F) (3Regis)-1,3,4, 5-Tetranlaro-3-hydrosy-4-(4- methoxyphenyl)-1-[1l-methyl-2-(methylamino)- ethyl]-6-(trifluoromethyl)-2H-1-benzazepin-2- one, isomer B monohydrochloride
To a solution of (3R-cis)-1-[1-[(methyl- amino)methyl]ethyl]-3-(t-butyldimethylsiloxy)-4- (4-methoxyphenyl)-6- (trifluoromethyl )-2H-1- benzazepin-2-one (1.2g, 2.24mmol) in dry tetrahydrofuran (50ml) was added tetrabutyl- ammonium fluoride trihydrate (1.06g, 3.36mmol).
The solution was stirred overnight, evaporated and the residue was partitioned between dichloromethane and water. The organic phase was washed with water and brine, dried (magnesium sulfate) and evaporated to afford 0.86g of a yellow oil. The residue was applied to 4 preparative silica gel plates, which were eluted with 10% methanol:dichloromethane.
Product bands were cut and extracted with 15% methanol:dichloromethane:0.5% triethylamine. The compound was dissolved in ether and a solution of hydrogen chloride saturated ether was added to afford a white solid which was filtered and rinsed with ether to afford 320mg of pure title compound, melting point 178-180°C, [x]p=+63.9° (C=1, ethanol).
Analysis calc'd for C, Hy5F3N,04+HC1-0.98H,0:
C,55.45; H,5.90; N,5.73; Cl1,7.94; F,11.61;
Found: C,55.45; H,5.91; N,5.88; Cl1,7.44; F,11.96,

Claims (1)

  1. HA460 Jz =54- ! what Is Claimed Is: co Le
    1. A compound having the formula SE No te 4 > eh No R3 Ry 2 or a pharmaceutically acceptable salt thereof, . 1 wherein Ry is -CH or -0-Y3; 2 R, 1s H-Y, ’ H, ' H-C > H-Y¢ Yu- -Yg CH,), , N H-CH 6 7 Ye 17 IN 6 7 oo 20 H H—( H ) ) _2 —cH,— H, 2'n ~~ _ ’ _ CH, ( Hy) Ye H, 6 7 or 6 H-Y, EE H-C > Hy), ; 1° 5 . 6 Ry and R, are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, diarylalkoxy, arylalkyl, cyano, hydroxy. alkanoyloxy,
    HA460 -55- oll, fluoro substituted alkoxy, fluoro substituted alkyl, (cycloalkyl)alkoxy, -NO,, “NY 0¥11 -S(0) alkyl, -5(0) aryl, 4. or oll, nis 0, 1, 2 or 3; m is 0, 1 or 2;
    Yy and Y, are each hydrogen or alkyl, Y, is hydrogen and Y, is alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl, or Y, and Y, together with the carbon atom to which they are attached are cycloalkyl;
    - 15 Y, is hydrogen, alkyl, alkanoyl, alkenyl, = arylcarbonyl, heterocarylcarbonyl, or Howe, v,, Y, and Ye are each independently hydrogen, alkyl, aryl or arylalkyl, provided that when both are present they are not both hydrogen, and provided further that when both are attached to the same carbon atom neither of them is hydrogen;
    Ye and Y, are each independently hydrogen, alkyl, cycloalkyl or arylalkyl or Ye and Y,
    together with the nitrogen atom to which they are attached are azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
    Yq and Yq are each independently hydrogen, alkyl, aryl or heteroaryl, or Yg and Yq together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl or morpholinyl;
    Yio and Yq are each independently hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl,
    or Haw,
    i 4 EN .- . Coo-u u = - ST Ty ursI3yM 1 wield UIs SOUepIOSO® UT punoduwod ¥ "9. i ! Ly 9 Sz-3-7% ; Cay s1 Cy ureasym oo 1 wre) YITH SOUBPIODOE UT punodwod ¥ * °§. 0c L 9 Sx-E . : Y;-m sT ’y uiaISYM . 1 WIETD YATA 0URpPIODDE UT punoduos ¥ °P } -E3-0- ST Ty ursIs ys " : 1 wield Ulta 2OUepICODE UT punocduod ¥ CE
    : . : : z . . ’ or Ii st Ty utsIays SL 1 weld ITH aauepicode ul punoduod ¥ "Z + 1AT0ZzeTY} pue TAUITY)Y f1Aang t{ATOoZRpTIWT t1AToxa4d ¢[AUTIPTIAd Jo BUllsSISUOD » dnoxd oy) woIj psioI(ss ST TAxe0Islsoy yoIys tulad SY} UT WO3BOIIISY SUO 3seas] Iv Butavy dnol? Ot oTT24003938Y DTjeWOLE ue sT [AIv0III8Y - pue fswojle uogIes , 03 § Butavy © dnoad oTT940 8 0} sI9Fsd TAN TBOTO4D - oo oo : (sdnodd 1AXOqIED Jo TAoweyIed t AXOTAOUBN TY tguuly uogled py ol} 1 g Jo OTYITEYTR “smole uoqauo p 03 1 Fo LXO)IN 'sSWOIV uogled § ©} 1 Jo TANT t [AYyswoIoNn1I TIL C1AXOIPAY : tusBuey ‘o0I3TU toutTweTA{IeTIp foufue TANT ¢ (CHN . -) vuywe g 10 Zz ‘1 Yin peinyTisgns ATreuctido - qq - . : i
    * Pe HA460 ~57~
    7. A compound in accordance with Claim 1 wherein R, is H, a 2 I 2. Hy-(CHy)p > 6 V7
    8. A compound in accordance with Claim 1 wherein R, is H——( Hy) Ye - H H,
    ! . 6
    "9. A compound in accordance with Claim 1 wherein R, is H-Y, H-C > Hy), . N-CHz Ye
    10. A compound in accordance with Claim 1 wherein R, is halogen or trifluoromethyl, R, is located in the 4-position of the phenyl ring to which it is attached, and R, is hydroxy, alkoxy, alkylamino, aryloxy, or arylalkoxy. . 11. A compound in accordance with Claim 1 wherein R, is 4-methoxy.
    12. A compound in accordance with Claim 1 wherein R, is halogen or trifluoromethyl.
    HA460 -58-
    13. The compound in accordance with Claim 1, [3R-[1(S*),3a,40]]-3-(acetyloxy)-1,3,4,5-tetra- bro hydro-4-(4-methoxyphenyl)-1-(2-pyrrolidinyl- methyl )-6-(trifluoromethyl)-2H-1-benzazepin-2- one or a pharmaceutically acceptable salt thereof...
    14. The compound in accordance with Claim 1, ut [3(R)-[1(S*),3a,40]}]-1,3,4,5-tetrahydro-3-hydroxy- - 4-(4-methoxyphenyl)-1-(2-pyrrolidinylmethyl)-6- (trifluoromethyl)-2H-1-benzazepin-2-one, or a pharmaceutically acceptable salt thereof.
    15. A method of treating a host having a disease susceptible to treatment with a vasodilator which comprises administering to said host an effective amount of a compound having the formula 4 Ry 1 2 or a pharmaceutically acceptable salt thereof, Ta wherein Ry 1s T or -0-Y,i 2 i H~-Y H Ley Cc R, 1s -~ a ’ ¢ 2 ’ = H-Y, Yu- -Ye Hy), ’ 2 \ TE 6 7 6 7 \ 6 7
    ~ | eee me smn eee rm 1 en HA460 -59- H, Sr H,), _Z—CH,- CH, Hy-(CHy)y Ab 6 7 or : 5 Ye bes, H-C en, ; } 6 Ry and R, are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy; arylalkoxy,- - diarylalkoxy, arylalkyl, cyano, hydroxy, alkanoyloxy,
    colle, fluoro substituted alkoxy, fluoro substituted alkyl, (cycloalkyl )alkoxy, -NO,,, “NY, 0¥94 -s(0) alkyl, -s(0) aryl, i. or f -0-C-Y, 41 : nis 0, 1, 2 or 3; mis 0, 1 or 2; Yy and Y, are each hydrogen or alkyl, Y, is - hydrogen and Y, is alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl, or Y, and Y, together with the carbon atom to which they are attached are cycloalkyl; Yq is hydrogen, alkyl, alkanoyl, alkenyl,
    no arylcarbonyl, heteroarylcarbonyl, or Dor x, Y, and Ye are each independently hydrogen, alkyl, aryl or arylalkyl, provided that when both i": »{rare;)present they are not both hydrogen, and
    Po buw ‘swojg uoqaey 4 v3 ¢ Sutavy dnoas TTA wv oy SdeJea 144 1voroiy - ‘sdnoas T4xoqaey 0¢ JO TAowegaws ‘AxoTAouuy Ty ‘smojy Uoqaes 4 ©) 1 JO Ooty TAY Tw ‘swojye uoqaes 4 03 1 Jo -AxoxqTw ‘swoje - Uoqaes » <3 1 30 14y te TIRy3amatony ray ' I &xoapay ‘UsBoruy ‘oa3tu fOuTWe LAY urp ‘outwe TAT “(HN -) outwe ¢ gq 2 ‘1 Yitm beinyrisqus £1Teuorydo G2 TLusyd Cl sIsjea ITed TLaw °y3 - : fswoqe , uoqaes yp 03 2g Yay T4udyre Puy 1437% - fswoqy uogaes 01 o3 1 SAVY TANTE Butputour Swasy ayy bue 1iy7e - Oz ‘souvysur Yses ug UTadaym “&Axo01k1e 10 AxoyTe "TATe ST ET, pue ‘ouTWe Ay Te Tp Xo ouTwe Tle ‘outure ‘AxotLze ‘AxoxTe ‘Axoxpiy ST eT, : ar} To gp 0 ‘TAuoqresTArRcrsyay !TAuoqrestiye ‘TAoueyTe ‘1&1 ‘usboxpiy AT3uspusdspur yses sie ny pue 01, ‘TAutToydrow Io TAutprasdrd "TAUTPTTOTIAq sxe P3yse33e aye Kama U92TUs 03 woqe usbor3ru M1 y31AM 01 9 Isy3shHog 6x pue gx I0 ‘TAaR019q0y 30 1&ze ‘1Xyq1e ‘usboapiy 4T3uspusdspur yses sie 62 pue 8x ol : ‘TAuTtoydrow zo : ‘TAutpTasdrd ‘TAutprro11Xd ‘TAurprysze oIx® Paysejqe oo 3Ie fain 42Tys o3 moe usboryry 73 y31aA ISy3esoy s
    - . } Ly pue °x T° 1&qTeri1e 10 TAjTROT5AS ‘T&XTe ‘usboxpiy AT3uspusdspuy yses sxe Ly pue Sx . ? ‘usboxpiy ST way zo ISI TSU woje uoqies sues . : 82 P3yoe3ze arp Y3IQq usys lem I9y3ang PSptacad . ’ =09- } Qo¥vH oo : » BAD ORIGINAL . : : . i ‘
    wool HA460 -6]1- BENZAZEP INE DERIVATIVES Abstract of the Disclosure vasodilating activity is exhibited by compounds having the formula 4 R3 1 2 wherein R, is H-Y, , H, , H-C H-Y¢ Y,- ~Yg Hop oo H-C 5 Ye 7 6 7 6 7 H H—(CH,) ! 2 . 2'n [eer CH, ,
    CH.,- (CH,) _ J AN 2 2'n Ye H H, . Ye 7 or Ye bv, H-CH3 CH,), - h-c 5 ,
    Ye .
PH38739A 1988-06-20 1989-06-02 Benzazepine and benzothiazepine derivatives PH26646A (en)

Applications Claiming Priority (1)

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US20852188A 1988-06-20 1988-06-20

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PH26646A true PH26646A (en) 1992-09-04

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MX16514A (en) 1994-03-31
ZA894315B (en) 1990-02-28

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