CA2155320A1 - Substituted acetamide compound - Google Patents
Substituted acetamide compoundInfo
- Publication number
- CA2155320A1 CA2155320A1 CA 2155320 CA2155320A CA2155320A1 CA 2155320 A1 CA2155320 A1 CA 2155320A1 CA 2155320 CA2155320 CA 2155320 CA 2155320 A CA2155320 A CA 2155320A CA 2155320 A1 CA2155320 A1 CA 2155320A1
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- nmr
- ethyl
- mass
- hydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A compound having an anticholinergic activity represented by the following general formula (I):
(I) , wherein R1 and R2 are each aryl which may have suitable substituent, R3 is hydrogen, hydroxy or lower alkyl, R4 is a group represented by the following formula (i), (ii), (iii) or (iv):
, , or
(I) , wherein R1 and R2 are each aryl which may have suitable substituent, R3 is hydrogen, hydroxy or lower alkyl, R4 is a group represented by the following formula (i), (ii), (iii) or (iv):
, , or
Description
SPECIFICATION
Title of the Invention SU~STITUTED ACETAMIDE COMPOUND
Field of the Invention This invention relates to a novel substituted acetamide compound and a pharmaceutically acceptable salt thereof.
More particularly, it relates to a novel substituted-acetamide compound and a pharmaceutically acceptable salt thereof which have anticholinergic activity, and are useful for the treatment of dysuria such as pollakiuria, urinary incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfuction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis or the like; and for the treatment of convulsion and/or hypanakinesis in case of gastric ulcer, duodenal ulcer, gastro~ynsis, esophagospasm, gastritis, enteri-tis, irritable colon syndrome, enteralgia, cholecystitis, cholan-gitis, pylorospasm, pancreatitis, pai.n in case of pancreatitis, biliary dyskinesia, aftereffect after cholecystectomy, urinary calculus cystitis, dysmenorrhea, hidrosis, convulsion of urinary tract; and which are expected to be useful for the treatment of asthma, Parkinson disease, angina pectris or the like.
Title of the Invention SU~STITUTED ACETAMIDE COMPOUND
Field of the Invention This invention relates to a novel substituted acetamide compound and a pharmaceutically acceptable salt thereof.
More particularly, it relates to a novel substituted-acetamide compound and a pharmaceutically acceptable salt thereof which have anticholinergic activity, and are useful for the treatment of dysuria such as pollakiuria, urinary incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfuction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis or the like; and for the treatment of convulsion and/or hypanakinesis in case of gastric ulcer, duodenal ulcer, gastro~ynsis, esophagospasm, gastritis, enteri-tis, irritable colon syndrome, enteralgia, cholecystitis, cholan-gitis, pylorospasm, pancreatitis, pai.n in case of pancreatitis, biliary dyskinesia, aftereffect after cholecystectomy, urinary calculus cystitis, dysmenorrhea, hidrosis, convulsion of urinary tract; and which are expected to be useful for the treatment of asthma, Parkinson disease, angina pectris or the like.
2~320 Prior ~rt One object of this invention is to provide a novel sub-stituted acetamide compound and a pharmaceutically acceptable salt thereof which are useful for the treatment of aforesaid diseases.
Another object of this invention is to provide a pharma-ceutical preparation comprising, as an active ingredient, said substituted acetamide compound or a pharmaceutically acceptable salt thereof, which is useful as an agent for the treatment of aforesaid diseases.
Disclosure of the Invention The object substituted acetamide compound of this inven-tion is novel and can be represented by the following formula (I):
R' R 2 - C - ( A' ) m - C O N H - (A 2 ) n - R~ (I) Rs wherein R1 and R2 are each aryl which may have suitable sub-stituent, R3 is hydrogen, hydro~y or lower alkyl, R4 is a group represented by the following formula (i), (ii), (iii) and (iv):
2lss3~a .
~ N - R 5 ( i ) wherein R5 is hydrogen, methyl, ethyl, propyl, isopropyl or imino protective group, ~ (i') ~ N - R 5 wherein R6 is lower alkyl, N (iii) ~ N - R 7 ~iv) wherein R7 is hydrogen, lower alkyl or imino protective group, A1 and A2 are each lower alkylene, and m and n are each O or 1, provided that (a) R5 is not ethyl when R1 and R2 are both phenyl, R3 is hydro~y, A2 is methylene, m is O and n is 1, ~ ~15 ~ 3 2 ~
(b) R7 is not methyl when R1 and R2 are both phenyl, R3 is hydro~y, and m and n are both 0.
The object compound (I) may have (an) asymmetric carbon atom(s) and the stereo isomer caused by asymmetry is also includ-ed in the scope of the present invention.
For the preparation of the object compound (I), a start-ing compound which may be prepared according to the "Preparation"
e~emplarily illustrated later may be reacted according to the "E~ample" also e~emplarily illustrated later.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-to~ic mono or di salts and include an organic acid addition salt [e.g., formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzene-sulfonate, toluenesulfonate, etc.], an inorganic acid addition salt [e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.], a salt with an amino acid [e.g., arginine salt, aspartic acid salt, glutamic acid salt, etc.], metal salt such as alkali metal salt [e.g., sodium salt, potassi-um salt, etc.], alkaline earth metal salt [e.g., calcium salt, magnesium salt, etc.], ammonium salt, a salt with an organic base [e.g., trimcthyl amine salt, triethyl amine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzyl ethylenedia-mine salt, etc.], and the like.
In the above and subsequent descriptions of this specifi-cation, suitable of the various definitions are explained in ~ 21~2~
detail as follows:
The term "lower" is intended to mean 1 to 6 carbon atom(s), preferably to 1 to 4 carbon atom(s).
Suitable "aryl" in "aryl which may have suitable substit-uent" may include phenyl, naphthyl, pentalenyl, anthracenyl and the like.
"Suitable substituent" which may be substituted with the above "aryl" may include halogen (e.g., fluorine, chlorine, bromine, iodine), lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, he~yl, etc.), lower alkoxy (e.g., metho~y, etho~y, propo~y, isopropo~y, buto~y, t-buto~y, pentylo~y, he~ylo~y, etc.), and the like. A number of substituent substituted to aryl may be one or more than one, preferably one to three.
Accordingly, suitable "aryl which may have suitable substituent" may include phenyl which has one suitable substitu-ent selected from the group consisting of halogen, lower alkyl and lower alko~y, in which the preferred one may be phenyl which has halogen, phenyl which has (C1-C4)alkyl or phenyl which has (C1-C4)alkoxy, and the more preferred onc may be phenyl which has chlorine, phenyl which has fluorine, phenyl which has methyl or phenyl which has metho~y.
Suitable "lower alkyl" may include the straight and branched ones such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, he~yl or the like, in which the preferred one may be (C1-C4)alkyl, and the more preferred one may be methyl, ethyl, propyl, isopropyl, butyl or t-butyl. 21 ~32~
Suitable "imino-protective group" may include the conven-tional protective group such as substituted or unsubstituted ar (lower)alkyl (e.g., trityl, benzhydryl, benzyl, 4-metho~ybenzyl, etc.), dinitrophenyl, lower alko~y carbonyl(lower)alkenyl (e.g., 1-metho~ycarbonyl-1-propene-2-yl, etc.), aroyl(lower)alkenyl (e.g., 1-benzoyl-1-propene-2-yl, etc.), hydro~y ar(lower)alkyli-dine (e.g., 2-hydro~ybenzylidene, etc.), silyl compound such as tri(lower)alkylsilyl (e.g., trimethyl silyl, etc.), acyl as e~emplified as follows, and the like.
Suitable "acyl" may include aliphatic acyl group, aromat-ic acyl group, heterocyclic acyl group, and aliphatic acyl group wherein the aliphatic chain is substituted with aromatic group or heterocyclic group.
Suitable "aliphatic acyl group" may include saturated or unsaturated, acyclic or cyclic acyl such as carbamoyl, lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, varelyl, isovarelyl, pivaloyl, hexanoyl, etc.), lower alkane sulfonyl (e.g., mesyl, ethane sulfonyl, propane sulfonyl, etc.), lower alko~y carbonyl (e.g., metho~y carbonyl, etho~y carbonyl, propo~y carbonyl, buto~y carbonyl, tert-butoxy carbonyl, etc.), lower alkenoyl (e.g., acryloyl, methacryloyl, crotonoyl, etc.), (C3-C7)cycloalkane carbonyl (e.g., cyclohexane carbonyl, etc.), amidino, protected carbo~y carbonyl such as lower alko~alyl (e.g., metho~alyl, etho~alyl, tert-buto~alyl, etc.), and the like.
~1~5320 Suitable "aromatic acyl group" may include aroyl (e.g., benzoyl, toluoyl, ~yloyl, etc.), arene sulfonyl (e.g., benzene sulfonyl, tosyl, etc.), and the like.
Suitable "heterocyclic acyl group" may include heterocy-clic carbonyl (e.g., furoyl, thenoyl, nicotinoyl isonicotinoyl, thiazolyl carbonyl, thiadiazolyl carbonyl, tetrazolyl carbonyl, morpholino carbonyl, etc.), and the like.
Suitable "aliphatic acyl group wherein the aliphatic chain is substituted with aromatic group" may include ar (lower)alkanoyl such as phenyl(lower)alkanoyl (e.g., phenyl acetyl, phenyl propionyl, phenyl hexanoyl, etc.), ar (lower)alko~y carbonyl such as phenyl(lower)alkoxy carbonyl (e.g., benzyloxycarbonyl, phenetylo~y carbonyl, etc.), phenoxy (lower)alkanoyl (e.g., pheno~yacetyl, pheno~ypropionyl, etc.), and the like.
Suitable "aliphatic acyl group wherein the aliphatic chain substituted with heterocyclic group" may include thienyl acetyl, imidazolyl acetyl, furyl acetyl, tetrazolyl acetyl, thia-zolyl acetyl, thiadiazolyl acetyl, thienyl propionyl, thiadiazo-lyl propionyl, and the like.
Above e~emplified acyl may be rurther substituted with carbo~y, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, he~yl, etc.), halogen (e.g., chlorine, bromine, iodine, fluorine), carbamoyl, lower alkanoyl (e.g., formyl, acetyl, propionyl, etc.), ar(lower)alkyl (e.g., benzyl, etc.), lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, 2 ~
butyl, tert-butyl, etc.), lower alkoxycarbonYl (e.g., methoxycar-bonyl, etho~ycarbonyl, tert-buto~ycarbonyl, etc.), ar(lower)alkylo~ycarbonyl (e.g., benzylo~ycarbonYl, etc.), ary-lo~ycarbonyl (e.g., phenyloxycarbonyl, etc.), carbo~y(lower)alkyl (e.g., carbo~ymethyl, carbo~yethyl, etc.), protected carbo~y(lower)alkyl (e.g., tert-buto~ycarbonylmethyl, etc.), or the like.
Suitable "lower alkylene" may include the straight and branced ones such as methylene, ethylene, trimethylene, tetra-methylene, 1,1-dimethylethylene, pentamethylene, he~amethylene, or the like, in which the preferred one may be (C1-C4)alkylene, and the more preferred one may be methylene and ethylene. In the object compound (I), direct chemical bond is formed without a lower alkylene when m and/or n is 0.
Each definition of the present invention is as described above with representatives thereof. The object compound (I) is constructed under the optimum assortment of each difinition e~-cepting the specific under-mentioned assortment.
(a) an assortment that both R1 and R2 are phenyl, R3 is hydro~y, A2 is methylene, m is 0, n is 1, and R5 is ethyl (b) an assortment that both of R1 and R2 are respectively phenyl, R3 is hydro~y, m and n are respectively O and R7 is methyl Most preferred difinition of the present invention in-cludes the following assortment, i.e., R1 and R2 are respectively phenyl or phenyl which has fluorine, R3 is hydrogen, hydro~y or 21~2~
.
methyl, m is 0 or 1, A1 is methylene, n is 0 or 1, A2 is methyl-ene or ethylene, R5 is hydrogen, methyl, ethyl, isopropyl, imino-protective group, R~ is ethyl, R7 is hygrogen, methyl, ethyl, isopropyl or imino-protective group.
Effect of the Invention The object compound (I) and a pharmaceutically acceptable salt thereof of this invention have anticholinergic activity and are useful for the treatment of dysuria or other diseases as mentioned before in human being and animals.
In the object compound (I) and a pharmaceutically accept-able salt thereof, side effect such as mydriasis or the llke is alleviated.
In order to illustrate the usefulness of the object compound (I), the pharmacological test data of the representative compound Or this invention is shown in the following.
Test 1 Test on Inhibltion of Urinary Bladder Contractions Induced by Water Filing in Rats [11 Test Method ----Male Sprague-Dawly rats, weighing 240-450 g, were anes-thetized with urethane 1.0 g/kg s.c. The bladder was e~posed through a midline incision in the abdomen for the recording of pressure within the bladder as follows; a balloon attached to one 21~532~
e~d of a stainless steel tube (O.D., 1.2 mm, 5 cm in length) was inserted into the bladder through a small incision in the bladder dome. The other end of the tube was connected to a pressure-transducer. The ureters were ligated and cut, and the prozimal cut end was cannulated with polyethylene tubing and the urine was led outside.
Ilyperactive urinary bladder (hyperactive contractions of the detrusor muscle) was induced by water filling of the bladder.
Therefore, the balloon in the bladder was filled with water of a volume which caused a resting pressure Or about 10 mmllg. Systemic blood pressure and heart rate were monitored from the common carotid artery.
When the contractile responses to water filling became constant, test compounds were administered intravenously.
[II] Test Compound The Compound (I): N-(1,2,3,6-tetrahydropyridin-4-yl)methyl-2-hydro~y-2,2-diphenylacetamide [III] Test Result The ED30 value (mg/kg) was as follows.
ED30 = 0.005 (mg/kg) The pharmaceutical composition of this invention (an agent for the prevention and/or the treatment of dysuria) can be used in the form of a pharmaceutical preparation, for ezample, in 21~532~
solid, semisolid or liquid form, which contains the object com-pound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admi~ture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, e~ternal (topical), oral or parenteral (including subcutaneous, intravenous and intramuscu-lar) administrations or insufflation or intravesica administra-tion. The active ingredient may be compounded, for e~ample, with the usual non-to~ic, pharmaceutically acceptable carrier for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosole, powders for insufflation, solutions, emul-sions, suspensions, and any other form suitable for use. ~nd, if necessary, in addition, au~iliary, stabilizing, thickening and coloring age~ts and perfumes may be used. The object compound (I) or a pharmaceutical acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to prod`uce the desired effect upon the process or condition of diseases.
For applying the composition to human being or animal, it is preferable to apply it by intravenous, intramuscular, pulmo-nary, or oral administration, or insufflation. While the dosage of therapeutically effective amount of the object compound (I) varies from and also depend~s upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 20 mg of the object com-pound (I) per kg weight of human being or animal, in the case of intramuscular administration, a daily dose of 0.1 - 20 mg of the =----~ 5 3~ D
object compound (I) per kg weight of human being or animal, in case of oral administration, a daily dose of 0.5 - 50 mg of the object compound (I) per kg weight of human being or animal is generally given for treating or preventing the aforesaid dis-eases.
The following Preparations and Examples are given for the purpose of illustrating this invention in more detail.
Preparation 1 Penzilic acid (5.00 g) and phosphorus pentachloride (9.4 g) were stirred at 100 C for 3.5 hours. ~fter cooling, the reaction mi~ture was partitioned between ice-water (50 ml) and diethyl ether (100 ml). The organic layer was separated, washed with brine, dried over magnesium sul~ate, and evaporated to give crude 2-chloro-2,2-diphenylacetyl chloride (6.16 g). A solution of 4-(aminomethyl)pyridine (1.97 g) in dry toluene (5 ml) was added dropwise to a solution of crude 2-chloro-2,2-diphenylacetyl chloride (6.16 g) in dry toluene (50 ml) at room temperature The reaction mi~ture was stirred at room temperature for 1 hour, diluted witll ethyl acetate (50 ml) and lN sodium hydro~ide solu-tion (50 ml). The organic layer was separated, washed with lN-sodium hydroxide solution (50 ml ~ 3), and evaporated to give crude N-(pyridine-4-yl)methyl-2-chloro-2,2-diphenylacetamide (9.06 g). ~ solution of the crude N-(pyridine-4-yl)methyl-2-chloro-2,2-diphenylacetamide (9.06 g) in lN hydrochloric acid 2155~2~
(50 ml) was stirred at 70C for 2 hours. A~ter cooling, the solu-tion was washed with diethyl ether (50 ml) and was made alkaline wlth 6N sodium hydro~ide solution. The precipitated powder was collected by filtration to give N-(pyridine-4-yl)methyl-2-hy-droxy-2,2-diphenylacetamide (6.37 g) as a colorless powder.
mp:148-151 ~
IR(Nujol) :3330, 1650, 1600, 760, 740, 690cm~' NMR(DMSO-d6,~) :4.33(2H, d, J=6.3Hz), 6.85(lH, s), 7.15-7.18(2H, m), 7.25-7.40(lOH, m), 8.42-8.45(2H, m), 8.84(1H, t, J=6.3Hz) MASS(m/z) :183, 105 Preparation 2 A solution of N-(p~ridine-4-yl)methyl-2-hydroxy-2,2-dipheny-lacetamide (80 g) and 4-metho~ybenzyl chloride (47.2 g) in N,N-dimethylformamide (120 ml) was stirred at 65 C for 1 hour. After cooling, the reaction mi~ture was diluted with acetone (500 ml) and diethyl ether (100 ml) and stirred under ice cooling for 20 minutes. The precipitated powder was collected by filtration to give 4-[(2-hydro~y-2,2-diphenylacetylamino)methyl]-1-(4-metho~y-benzyl)pyridinium chloride (107.57 g) as a colorless powder.
mp:205-208~
IR(Nujol) :3250, 3050, 1650, 1610, 750, 700cm~' NMR(DMSO-d~,~) :3.76(3H, s), 4.55(2H, d, J=5.9HZ), 5.72(2H, s), 6.99(2H, d, J=6.7Hz), 7.00(lH, s).
21553~
7.25-7.40(lOH, m), 7.53(ZH, d, J=6.7Hz), 7.87(ZH, d, J=6.7Hz), 9.13(2H, d, J=6.7Hz), 9.11(lH, t, J=5.9Hz) MASS(m/z) :183. 93 Preparation 3 ~ ~
A solution of 4-acetylaminomethylpyridine (7.00 g) and 4-metho~ybenzyl chloride (6.8 ml) in acetone (100 ml) was stirred for 4 hours under reflu~ and then for 30 minutes under ice cool-ing. The precipitated powder was collected by filtration and washed with acetone to give hygroscopic 4-acetylamino-methyl-1-(4-metho~ybenzyl)pyridinium chloride (10.88 g) which was used for next step reaction (Preparation 4) witllout further purification.
Preparation 4 To a solution of 4-acetylaminomethyl-1-(4-methoxybenzyl)pyridinium chloride (10.88 g) in methanol (200 ml) was added portionwise sodium borohydride (5.37 g) under ice cooling and the resulting solution was stirred at room tempera-ture for 13 hours. Water (10 ml) was added to the reaction solu-tion, and the solvent was distilled of r. Ethyl acetate and water were added to the residue, and the organic layer was separated, washed with brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chlomatogra-phy on silicagel with an eluent of a mi~ture of methylene chlo-2 1 ~ ~ 3 ~ ~
ride and methanol (15:1) to give 4-acetylaminomethyl-1-(4-met-hoxybenzyl)-1,2,3,6-tetrahydropyridine (7.27 g) as a pale yellow oil.
IR(film) : 3300, 1650, 1610, 760cm~l NMR(CDCl 9, ~ ) 1. 98(s, 3H), 2.10(br s, 2H), 2.56(t, J=5.7Hz, 2H), 2.95(br s, 2H), 3.52(s, 2H),
Another object of this invention is to provide a pharma-ceutical preparation comprising, as an active ingredient, said substituted acetamide compound or a pharmaceutically acceptable salt thereof, which is useful as an agent for the treatment of aforesaid diseases.
Disclosure of the Invention The object substituted acetamide compound of this inven-tion is novel and can be represented by the following formula (I):
R' R 2 - C - ( A' ) m - C O N H - (A 2 ) n - R~ (I) Rs wherein R1 and R2 are each aryl which may have suitable sub-stituent, R3 is hydrogen, hydro~y or lower alkyl, R4 is a group represented by the following formula (i), (ii), (iii) and (iv):
2lss3~a .
~ N - R 5 ( i ) wherein R5 is hydrogen, methyl, ethyl, propyl, isopropyl or imino protective group, ~ (i') ~ N - R 5 wherein R6 is lower alkyl, N (iii) ~ N - R 7 ~iv) wherein R7 is hydrogen, lower alkyl or imino protective group, A1 and A2 are each lower alkylene, and m and n are each O or 1, provided that (a) R5 is not ethyl when R1 and R2 are both phenyl, R3 is hydro~y, A2 is methylene, m is O and n is 1, ~ ~15 ~ 3 2 ~
(b) R7 is not methyl when R1 and R2 are both phenyl, R3 is hydro~y, and m and n are both 0.
The object compound (I) may have (an) asymmetric carbon atom(s) and the stereo isomer caused by asymmetry is also includ-ed in the scope of the present invention.
For the preparation of the object compound (I), a start-ing compound which may be prepared according to the "Preparation"
e~emplarily illustrated later may be reacted according to the "E~ample" also e~emplarily illustrated later.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-to~ic mono or di salts and include an organic acid addition salt [e.g., formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzene-sulfonate, toluenesulfonate, etc.], an inorganic acid addition salt [e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.], a salt with an amino acid [e.g., arginine salt, aspartic acid salt, glutamic acid salt, etc.], metal salt such as alkali metal salt [e.g., sodium salt, potassi-um salt, etc.], alkaline earth metal salt [e.g., calcium salt, magnesium salt, etc.], ammonium salt, a salt with an organic base [e.g., trimcthyl amine salt, triethyl amine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzyl ethylenedia-mine salt, etc.], and the like.
In the above and subsequent descriptions of this specifi-cation, suitable of the various definitions are explained in ~ 21~2~
detail as follows:
The term "lower" is intended to mean 1 to 6 carbon atom(s), preferably to 1 to 4 carbon atom(s).
Suitable "aryl" in "aryl which may have suitable substit-uent" may include phenyl, naphthyl, pentalenyl, anthracenyl and the like.
"Suitable substituent" which may be substituted with the above "aryl" may include halogen (e.g., fluorine, chlorine, bromine, iodine), lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, he~yl, etc.), lower alkoxy (e.g., metho~y, etho~y, propo~y, isopropo~y, buto~y, t-buto~y, pentylo~y, he~ylo~y, etc.), and the like. A number of substituent substituted to aryl may be one or more than one, preferably one to three.
Accordingly, suitable "aryl which may have suitable substituent" may include phenyl which has one suitable substitu-ent selected from the group consisting of halogen, lower alkyl and lower alko~y, in which the preferred one may be phenyl which has halogen, phenyl which has (C1-C4)alkyl or phenyl which has (C1-C4)alkoxy, and the more preferred onc may be phenyl which has chlorine, phenyl which has fluorine, phenyl which has methyl or phenyl which has metho~y.
Suitable "lower alkyl" may include the straight and branched ones such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, he~yl or the like, in which the preferred one may be (C1-C4)alkyl, and the more preferred one may be methyl, ethyl, propyl, isopropyl, butyl or t-butyl. 21 ~32~
Suitable "imino-protective group" may include the conven-tional protective group such as substituted or unsubstituted ar (lower)alkyl (e.g., trityl, benzhydryl, benzyl, 4-metho~ybenzyl, etc.), dinitrophenyl, lower alko~y carbonyl(lower)alkenyl (e.g., 1-metho~ycarbonyl-1-propene-2-yl, etc.), aroyl(lower)alkenyl (e.g., 1-benzoyl-1-propene-2-yl, etc.), hydro~y ar(lower)alkyli-dine (e.g., 2-hydro~ybenzylidene, etc.), silyl compound such as tri(lower)alkylsilyl (e.g., trimethyl silyl, etc.), acyl as e~emplified as follows, and the like.
Suitable "acyl" may include aliphatic acyl group, aromat-ic acyl group, heterocyclic acyl group, and aliphatic acyl group wherein the aliphatic chain is substituted with aromatic group or heterocyclic group.
Suitable "aliphatic acyl group" may include saturated or unsaturated, acyclic or cyclic acyl such as carbamoyl, lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, varelyl, isovarelyl, pivaloyl, hexanoyl, etc.), lower alkane sulfonyl (e.g., mesyl, ethane sulfonyl, propane sulfonyl, etc.), lower alko~y carbonyl (e.g., metho~y carbonyl, etho~y carbonyl, propo~y carbonyl, buto~y carbonyl, tert-butoxy carbonyl, etc.), lower alkenoyl (e.g., acryloyl, methacryloyl, crotonoyl, etc.), (C3-C7)cycloalkane carbonyl (e.g., cyclohexane carbonyl, etc.), amidino, protected carbo~y carbonyl such as lower alko~alyl (e.g., metho~alyl, etho~alyl, tert-buto~alyl, etc.), and the like.
~1~5320 Suitable "aromatic acyl group" may include aroyl (e.g., benzoyl, toluoyl, ~yloyl, etc.), arene sulfonyl (e.g., benzene sulfonyl, tosyl, etc.), and the like.
Suitable "heterocyclic acyl group" may include heterocy-clic carbonyl (e.g., furoyl, thenoyl, nicotinoyl isonicotinoyl, thiazolyl carbonyl, thiadiazolyl carbonyl, tetrazolyl carbonyl, morpholino carbonyl, etc.), and the like.
Suitable "aliphatic acyl group wherein the aliphatic chain is substituted with aromatic group" may include ar (lower)alkanoyl such as phenyl(lower)alkanoyl (e.g., phenyl acetyl, phenyl propionyl, phenyl hexanoyl, etc.), ar (lower)alko~y carbonyl such as phenyl(lower)alkoxy carbonyl (e.g., benzyloxycarbonyl, phenetylo~y carbonyl, etc.), phenoxy (lower)alkanoyl (e.g., pheno~yacetyl, pheno~ypropionyl, etc.), and the like.
Suitable "aliphatic acyl group wherein the aliphatic chain substituted with heterocyclic group" may include thienyl acetyl, imidazolyl acetyl, furyl acetyl, tetrazolyl acetyl, thia-zolyl acetyl, thiadiazolyl acetyl, thienyl propionyl, thiadiazo-lyl propionyl, and the like.
Above e~emplified acyl may be rurther substituted with carbo~y, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, he~yl, etc.), halogen (e.g., chlorine, bromine, iodine, fluorine), carbamoyl, lower alkanoyl (e.g., formyl, acetyl, propionyl, etc.), ar(lower)alkyl (e.g., benzyl, etc.), lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, 2 ~
butyl, tert-butyl, etc.), lower alkoxycarbonYl (e.g., methoxycar-bonyl, etho~ycarbonyl, tert-buto~ycarbonyl, etc.), ar(lower)alkylo~ycarbonyl (e.g., benzylo~ycarbonYl, etc.), ary-lo~ycarbonyl (e.g., phenyloxycarbonyl, etc.), carbo~y(lower)alkyl (e.g., carbo~ymethyl, carbo~yethyl, etc.), protected carbo~y(lower)alkyl (e.g., tert-buto~ycarbonylmethyl, etc.), or the like.
Suitable "lower alkylene" may include the straight and branced ones such as methylene, ethylene, trimethylene, tetra-methylene, 1,1-dimethylethylene, pentamethylene, he~amethylene, or the like, in which the preferred one may be (C1-C4)alkylene, and the more preferred one may be methylene and ethylene. In the object compound (I), direct chemical bond is formed without a lower alkylene when m and/or n is 0.
Each definition of the present invention is as described above with representatives thereof. The object compound (I) is constructed under the optimum assortment of each difinition e~-cepting the specific under-mentioned assortment.
(a) an assortment that both R1 and R2 are phenyl, R3 is hydro~y, A2 is methylene, m is 0, n is 1, and R5 is ethyl (b) an assortment that both of R1 and R2 are respectively phenyl, R3 is hydro~y, m and n are respectively O and R7 is methyl Most preferred difinition of the present invention in-cludes the following assortment, i.e., R1 and R2 are respectively phenyl or phenyl which has fluorine, R3 is hydrogen, hydro~y or 21~2~
.
methyl, m is 0 or 1, A1 is methylene, n is 0 or 1, A2 is methyl-ene or ethylene, R5 is hydrogen, methyl, ethyl, isopropyl, imino-protective group, R~ is ethyl, R7 is hygrogen, methyl, ethyl, isopropyl or imino-protective group.
Effect of the Invention The object compound (I) and a pharmaceutically acceptable salt thereof of this invention have anticholinergic activity and are useful for the treatment of dysuria or other diseases as mentioned before in human being and animals.
In the object compound (I) and a pharmaceutically accept-able salt thereof, side effect such as mydriasis or the llke is alleviated.
In order to illustrate the usefulness of the object compound (I), the pharmacological test data of the representative compound Or this invention is shown in the following.
Test 1 Test on Inhibltion of Urinary Bladder Contractions Induced by Water Filing in Rats [11 Test Method ----Male Sprague-Dawly rats, weighing 240-450 g, were anes-thetized with urethane 1.0 g/kg s.c. The bladder was e~posed through a midline incision in the abdomen for the recording of pressure within the bladder as follows; a balloon attached to one 21~532~
e~d of a stainless steel tube (O.D., 1.2 mm, 5 cm in length) was inserted into the bladder through a small incision in the bladder dome. The other end of the tube was connected to a pressure-transducer. The ureters were ligated and cut, and the prozimal cut end was cannulated with polyethylene tubing and the urine was led outside.
Ilyperactive urinary bladder (hyperactive contractions of the detrusor muscle) was induced by water filling of the bladder.
Therefore, the balloon in the bladder was filled with water of a volume which caused a resting pressure Or about 10 mmllg. Systemic blood pressure and heart rate were monitored from the common carotid artery.
When the contractile responses to water filling became constant, test compounds were administered intravenously.
[II] Test Compound The Compound (I): N-(1,2,3,6-tetrahydropyridin-4-yl)methyl-2-hydro~y-2,2-diphenylacetamide [III] Test Result The ED30 value (mg/kg) was as follows.
ED30 = 0.005 (mg/kg) The pharmaceutical composition of this invention (an agent for the prevention and/or the treatment of dysuria) can be used in the form of a pharmaceutical preparation, for ezample, in 21~532~
solid, semisolid or liquid form, which contains the object com-pound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admi~ture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, e~ternal (topical), oral or parenteral (including subcutaneous, intravenous and intramuscu-lar) administrations or insufflation or intravesica administra-tion. The active ingredient may be compounded, for e~ample, with the usual non-to~ic, pharmaceutically acceptable carrier for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosole, powders for insufflation, solutions, emul-sions, suspensions, and any other form suitable for use. ~nd, if necessary, in addition, au~iliary, stabilizing, thickening and coloring age~ts and perfumes may be used. The object compound (I) or a pharmaceutical acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to prod`uce the desired effect upon the process or condition of diseases.
For applying the composition to human being or animal, it is preferable to apply it by intravenous, intramuscular, pulmo-nary, or oral administration, or insufflation. While the dosage of therapeutically effective amount of the object compound (I) varies from and also depend~s upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 20 mg of the object com-pound (I) per kg weight of human being or animal, in the case of intramuscular administration, a daily dose of 0.1 - 20 mg of the =----~ 5 3~ D
object compound (I) per kg weight of human being or animal, in case of oral administration, a daily dose of 0.5 - 50 mg of the object compound (I) per kg weight of human being or animal is generally given for treating or preventing the aforesaid dis-eases.
The following Preparations and Examples are given for the purpose of illustrating this invention in more detail.
Preparation 1 Penzilic acid (5.00 g) and phosphorus pentachloride (9.4 g) were stirred at 100 C for 3.5 hours. ~fter cooling, the reaction mi~ture was partitioned between ice-water (50 ml) and diethyl ether (100 ml). The organic layer was separated, washed with brine, dried over magnesium sul~ate, and evaporated to give crude 2-chloro-2,2-diphenylacetyl chloride (6.16 g). A solution of 4-(aminomethyl)pyridine (1.97 g) in dry toluene (5 ml) was added dropwise to a solution of crude 2-chloro-2,2-diphenylacetyl chloride (6.16 g) in dry toluene (50 ml) at room temperature The reaction mi~ture was stirred at room temperature for 1 hour, diluted witll ethyl acetate (50 ml) and lN sodium hydro~ide solu-tion (50 ml). The organic layer was separated, washed with lN-sodium hydroxide solution (50 ml ~ 3), and evaporated to give crude N-(pyridine-4-yl)methyl-2-chloro-2,2-diphenylacetamide (9.06 g). ~ solution of the crude N-(pyridine-4-yl)methyl-2-chloro-2,2-diphenylacetamide (9.06 g) in lN hydrochloric acid 2155~2~
(50 ml) was stirred at 70C for 2 hours. A~ter cooling, the solu-tion was washed with diethyl ether (50 ml) and was made alkaline wlth 6N sodium hydro~ide solution. The precipitated powder was collected by filtration to give N-(pyridine-4-yl)methyl-2-hy-droxy-2,2-diphenylacetamide (6.37 g) as a colorless powder.
mp:148-151 ~
IR(Nujol) :3330, 1650, 1600, 760, 740, 690cm~' NMR(DMSO-d6,~) :4.33(2H, d, J=6.3Hz), 6.85(lH, s), 7.15-7.18(2H, m), 7.25-7.40(lOH, m), 8.42-8.45(2H, m), 8.84(1H, t, J=6.3Hz) MASS(m/z) :183, 105 Preparation 2 A solution of N-(p~ridine-4-yl)methyl-2-hydroxy-2,2-dipheny-lacetamide (80 g) and 4-metho~ybenzyl chloride (47.2 g) in N,N-dimethylformamide (120 ml) was stirred at 65 C for 1 hour. After cooling, the reaction mi~ture was diluted with acetone (500 ml) and diethyl ether (100 ml) and stirred under ice cooling for 20 minutes. The precipitated powder was collected by filtration to give 4-[(2-hydro~y-2,2-diphenylacetylamino)methyl]-1-(4-metho~y-benzyl)pyridinium chloride (107.57 g) as a colorless powder.
mp:205-208~
IR(Nujol) :3250, 3050, 1650, 1610, 750, 700cm~' NMR(DMSO-d~,~) :3.76(3H, s), 4.55(2H, d, J=5.9HZ), 5.72(2H, s), 6.99(2H, d, J=6.7Hz), 7.00(lH, s).
21553~
7.25-7.40(lOH, m), 7.53(ZH, d, J=6.7Hz), 7.87(ZH, d, J=6.7Hz), 9.13(2H, d, J=6.7Hz), 9.11(lH, t, J=5.9Hz) MASS(m/z) :183. 93 Preparation 3 ~ ~
A solution of 4-acetylaminomethylpyridine (7.00 g) and 4-metho~ybenzyl chloride (6.8 ml) in acetone (100 ml) was stirred for 4 hours under reflu~ and then for 30 minutes under ice cool-ing. The precipitated powder was collected by filtration and washed with acetone to give hygroscopic 4-acetylamino-methyl-1-(4-metho~ybenzyl)pyridinium chloride (10.88 g) which was used for next step reaction (Preparation 4) witllout further purification.
Preparation 4 To a solution of 4-acetylaminomethyl-1-(4-methoxybenzyl)pyridinium chloride (10.88 g) in methanol (200 ml) was added portionwise sodium borohydride (5.37 g) under ice cooling and the resulting solution was stirred at room tempera-ture for 13 hours. Water (10 ml) was added to the reaction solu-tion, and the solvent was distilled of r. Ethyl acetate and water were added to the residue, and the organic layer was separated, washed with brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chlomatogra-phy on silicagel with an eluent of a mi~ture of methylene chlo-2 1 ~ ~ 3 ~ ~
ride and methanol (15:1) to give 4-acetylaminomethyl-1-(4-met-hoxybenzyl)-1,2,3,6-tetrahydropyridine (7.27 g) as a pale yellow oil.
IR(film) : 3300, 1650, 1610, 760cm~l NMR(CDCl 9, ~ ) 1. 98(s, 3H), 2.10(br s, 2H), 2.56(t, J=5.7Hz, 2H), 2.95(br s, 2H), 3.52(s, 2H),
3.76(s, 2H), 3.80(s, 3H), 5.53(t, J=1.5Hz, lH), 5.95(br s, lH), 6.80-6.90(m, 2H), 7.20-7.30(m, 2H) MASS(m/z) : 274(M~), 215, 121 Preparation 5 .
4-Acetylaminomethyl-1-propylpyridinium iodide was ob-tained by reacting 4-acetylmethylpyridine as a raw material, in a similar manner to that o~ Preparation 3.
mp: 135-137 ~ (washed with acetone) IR(Nujol) : 3250, 1670, 1640, 760, 750 cm~' NMR(DMS0-d6, ~) : 0.87(t. J=7.3Hz, 3H), 1.65-2.00(m, 2H), 1.97(s, 3H), 4.45-4.55(m, 4H), 7.96(d, J=6.8Hz, 2H) 8.67(t, J=5.8Hz, lH), 8.98(d, J=6.8Hz, 2H) MASS(m/z) : 193(MI), 149, 107 Preparation 6 4-~cetylaminomethyl-1-propyl-1,2,3,6-tetrahydropyridine w~s obtained by reacting the compound obtained in Preparation 5 as a raw material, in a similar manner to that Or Preparation 4.
~15~2~
IR(film) : 3300, 3050, 1650,750cm~' NMR(CDClJ, ~) : O.91(t, J=7.3Hz, 3H), 1.58(t, quartet, J=7.3Hz, J=5.7Hz, 2H), l.99(s, 3H), 2.23(br s, 2H), 2.30-2.40(m, 2H), 2.56(t, J=5.7Hz, 2H) 2.95(d, J=1.6Hz, 2H), 3.79(d, J=5.4Hz, 2H),
mp: 135-137 ~ (washed with acetone) IR(Nujol) : 3250, 1670, 1640, 760, 750 cm~' NMR(DMS0-d6, ~) : 0.87(t. J=7.3Hz, 3H), 1.65-2.00(m, 2H), 1.97(s, 3H), 4.45-4.55(m, 4H), 7.96(d, J=6.8Hz, 2H) 8.67(t, J=5.8Hz, lH), 8.98(d, J=6.8Hz, 2H) MASS(m/z) : 193(MI), 149, 107 Preparation 6 4-~cetylaminomethyl-1-propyl-1,2,3,6-tetrahydropyridine w~s obtained by reacting the compound obtained in Preparation 5 as a raw material, in a similar manner to that Or Preparation 4.
~15~2~
IR(film) : 3300, 3050, 1650,750cm~' NMR(CDClJ, ~) : O.91(t, J=7.3Hz, 3H), 1.58(t, quartet, J=7.3Hz, J=5.7Hz, 2H), l.99(s, 3H), 2.23(br s, 2H), 2.30-2.40(m, 2H), 2.56(t, J=5.7Hz, 2H) 2.95(d, J=1.6Hz, 2H), 3.79(d, J=5.4Hz, 2H),
5.54-5.57(m, lH), 5.66(br s, lH) MASS(m/z) : 196(MI), 167, 96 Preparation 7 3-Acetylamino-1-ethyl-1,2,3,6-tetrahydropyridine was ob-tained as an oil by reacting 3-acetylaminomethyl-1-ethylpyridini-um iodide as a raw material, in a similar manner to that of Preparation 4.
bp 150 ~ /0.08mmHg (kugelrohr) IR(film) : 3270, 1640, 1540cm~' NMR(CDClJ, ~) : 1.15(3H, t, J=7Hz, CHa), 1.99(3H, s, COCHs), 2.19(2H, m, NCH2CH2CH=), 2.49(2H, quartet, J=7Hz, NCHzCH9), 2.52(2H, t, J=611z, CH2CHzN), Z.72(2H, d, J=2.5Hz, NCH2C=), 3.78(2H, d, J=5.5Hz, CHzN), 5.65(lH, m, HC=), 5.8(1H, m, NH) MASS(m/z) : 182(MI), 123, llO(b~se), 108 Preparation 8 4-Acetylaminomethyl-1-benzyl-1,2,3,6-tetrahydropyridine ~1~532~
.
was obtained via 4-acetylaminomethyl-l-benzyl-pyridinium bromide by reacting ~-acetylamino-methYlpYridine and benzyl bromide as raw materials, in a similar manner to those of rreparations 3 and 4.
IR(Film):3250, 1650, 740, 700cm~' NMR(CDC13,~) :1.98(s, 3H), 2.00-2.15(m, 2H), 2.15-2.35(m, 2H), 2.97(br s, 2H), 3.45(s, 2H), 3.95-4.00(m, 2H), 5.53(br s, lH), 5.84(br s, lH), 7.20-7.40(m, 5H) MASS(m/z) :244(M+), 185, 172 Preparation 9 A solution of 4-acetylaminomethyl-l-(4-metho~ybenzyl)-l,2,3,6-tetrahydropyridine (5.00 g) and 6N aqueous solution of sodium hydro~ide (16 ml) in methanol (32 ml) was refluxed for 23 hours, and then the solvent was evaporated. Ethyl acetate and lN
sodium hydro~ide aqueous solution were added to the residue. The organic layer was separated, washed with brine, dried over magne-sium sulfate, and the solvent was evaporated. The residue was subjected to column chromatographY on silicagel with an eluent of a mixture of methylene chloride and methanol (lO:l - 2:1) to give 4-aminomethyl-l-(4-metho~ybenzyl)-l,2,3,6-tetrahydropyridine (2.31 g) as an oil.
IR(film):3370, 1610, 760, 730cm~
~532~
NMR(CDCl 3, ~ ) 1. 84(br s, 2H), 2.13(br s, 2H), 2.57(t, J=5.8Hz, 2H), 2.99(br s, 2H), 3.20(br s, 2H), 3.53(s, 2H),3.80(s, 3H), 5.53-5.57(m, lH),
bp 150 ~ /0.08mmHg (kugelrohr) IR(film) : 3270, 1640, 1540cm~' NMR(CDClJ, ~) : 1.15(3H, t, J=7Hz, CHa), 1.99(3H, s, COCHs), 2.19(2H, m, NCH2CH2CH=), 2.49(2H, quartet, J=7Hz, NCHzCH9), 2.52(2H, t, J=611z, CH2CHzN), Z.72(2H, d, J=2.5Hz, NCH2C=), 3.78(2H, d, J=5.5Hz, CHzN), 5.65(lH, m, HC=), 5.8(1H, m, NH) MASS(m/z) : 182(MI), 123, llO(b~se), 108 Preparation 8 4-Acetylaminomethyl-1-benzyl-1,2,3,6-tetrahydropyridine ~1~532~
.
was obtained via 4-acetylaminomethyl-l-benzyl-pyridinium bromide by reacting ~-acetylamino-methYlpYridine and benzyl bromide as raw materials, in a similar manner to those of rreparations 3 and 4.
IR(Film):3250, 1650, 740, 700cm~' NMR(CDC13,~) :1.98(s, 3H), 2.00-2.15(m, 2H), 2.15-2.35(m, 2H), 2.97(br s, 2H), 3.45(s, 2H), 3.95-4.00(m, 2H), 5.53(br s, lH), 5.84(br s, lH), 7.20-7.40(m, 5H) MASS(m/z) :244(M+), 185, 172 Preparation 9 A solution of 4-acetylaminomethyl-l-(4-metho~ybenzyl)-l,2,3,6-tetrahydropyridine (5.00 g) and 6N aqueous solution of sodium hydro~ide (16 ml) in methanol (32 ml) was refluxed for 23 hours, and then the solvent was evaporated. Ethyl acetate and lN
sodium hydro~ide aqueous solution were added to the residue. The organic layer was separated, washed with brine, dried over magne-sium sulfate, and the solvent was evaporated. The residue was subjected to column chromatographY on silicagel with an eluent of a mixture of methylene chloride and methanol (lO:l - 2:1) to give 4-aminomethyl-l-(4-metho~ybenzyl)-l,2,3,6-tetrahydropyridine (2.31 g) as an oil.
IR(film):3370, 1610, 760, 730cm~
~532~
NMR(CDCl 3, ~ ) 1. 84(br s, 2H), 2.13(br s, 2H), 2.57(t, J=5.8Hz, 2H), 2.99(br s, 2H), 3.20(br s, 2H), 3.53(s, 2H),3.80(s, 3H), 5.53-5.57(m, lH),
6.80-6.90(m, 2H), 7.20-7.30(m, 2H) MASS(m/z) : 232(M~), 202, 121 Preparation 10 4-Aminomethyl-1-propyl-1,2,3,6-tetrahydropyridine was obtained by reacting 4-acetylaminomethyl-1-propyl-1,2,3,6-tetrahydropyridine as a raw material, in a similar manner to that of Preparation 9.
bp: 140-150 C/lOmmHg (Kugelrohr) IR(Film) : 3270, 1600cm~' NMR(CDCl~, ~) : 0.92(t, J=7.3Hz, 3H), 1.10-1.70(br s, 2H), 1.55(t, quartet, J=7.3Hz, J=5.7Hz, 2H), 2.14(d, J=1.6Hz, 2H), 2.30-2.40(m, 2H), 2.57(t, J=5.7Hz, 2H), 2.96-3.00(m, 2H), 3.10(s, 2H), 5.53-5.57(m, lH) MASS(m/z) : 154(M'), 125, 96 Preparation 11 4-Aminomethyl-1-benzyl-1,2,3,6-tetrahydropyridine was obtained by reacting 4-acetylaminomcthyl-1-benzyl-1,2,3,6-tetrahydropyridine as a raw material, in a similar manner to that of Preparation 9.
IR(Film) : 3370, 3270, 1600, 740, 700cm~' 1~
~ 21~5320 NMR(CDC13, ~) : 1.61(s, 211), 2.13(br s, 2H), 2.58(t, J=5.8Hz, 2H), 2.95-3.05(m, 2H), 3.20(br s, 2H) 3.59(s, 2H), 5.50-5.55(m, lH), 7.20-7.37(m, 5H) MASS(m/z) : 202 (Mf), 172, 97 I'reparation 12 3-Aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine was obtained by reacting 3-acetylaminomethyl-1-ethyl-1,2,3,6-tetrahy-dropyridine as a raw material, in a similar manner to that of Preparation 9.
bp: 100-105 ~ /8.5mmHg (Kugelrohr) IR(Nujol) : 3450, 3370, 3280, 3200cm~' NMR(CDCl~ 1.14(3H, t, J=7Hz, CH3), 1.61(2H, s, NH2), 2.21(2H, m, CH2CH2CH=), 2.47(2H, quartet, J=7Hz, NCH2CH~), 2.49(2H, t, J=6Hz, NCH2CH2CH=), 2.93(2H, m, CH2N), 3.20(2H, m, CHzN), 5.62(1H, m, CH=) MS(m/z) : 140(M~), 123(base), 110, 108 Preparation 13 Acetic anhydride (17.5 ml) was added to a stirred solu-tion of 3-aminomethylpyridine (10.0 g) in acetic acid (30 ml) at room temperature. The resulting mi~ture was stirred at room temperature for 30 minutes and concentrated in vacuo to afford 3-acetylaminomethylpyridine as a crude oil, which was converted 21~32~
to 3-acetylaminomcthyl-1-ethylpyridinium iodide by reacting with ethyl iodide in a similar manner to that of Preparation 3, and then crystallized from a mi~ture o~ n-he~ane and ethyl acetate to g~ve pale yellow crystals.
mp: 110-111 C
IR(Nujol) : 34Z0, 3260, 1640cm~' NMR(DMS0-d~ 1.54(3H, t, J=7.5Hz, CH3), 1.93(3H, s, COCH3), 4.44(2H, d, J=6Hz, CH2NCO), 4.64(2H, quartet, J=7.5Hz, NCH2CH~), 8.12(1H, t, J=7.5Hz, pyridinium H), 8.43(lH, d, J=7.5Hz, pyridinium H), 8.59(lH, t, J=6Hz, NH), 9.0(2H, m, pyridinium H) MASS(m/z) : 135, 107 Preparation 14 A mi~ture of ethyl 3,3-diphenyl-2-propenoate (4.28 g) in 3N-sodium hydroxide aqueous solution (28 ml) and ethanol (50 ml) was allowed to stand overnight at room temperature and stirred at 50Cfor 2 hours. Ethyl acetate and brine were added to the mi~-ture and the resulting solution was acidified with concentratcd hydrochloric acid. The organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated in vacuo to give 3,3-diphenyl-2-propenoic acid.
mp: 158-161 C (washed with ethyl acetate) 2~ ~32~
.
IR(Nujol) :1690, 1660, 1610, 720,700cm~' NMR(CDC1~ 6.32(s, lH), 7.10-7.40(m, 10H) MASS (m/z) : 224(M~), 179, 165 Examlllc 1 To a solution of 4-[(2-hydro~y-2,2-diphenylacetylamino)methyl]-l-(4-methoxybenzyl)pyridinium chlo-ride (lOO g) in methanol (800 ml) was added portionwise sodium borohydride (32.7 g) at lO - 20 C in a nitrogen atomosphere. The resulting solution was stirred at room temperature for l hour, and then the mixture was evaporated. Ethyl acetate (l Q ) and water (500 ml) were added to the residue, and the organic layer was separated, washed with water (500 ml), brine (500 ml), dried over magnesium sulfate, and evaporated to give N-[l-(4-metho~ybenzyl)-l,2,3,6-tetrahydropyridin-4-yl]methyl-2-hydro~y-2,2-diphenylacetamide as crude oil. A mi~ture of the crude oil and l-chloroethyl chloroformate (25 ml) in methylene chloride (700 ml) was refluxed for l hour. Methanol (350 ml) was added to the mi~ture. The solution was reflu~ed for 30 minutes, and the solvent was evaporated. The residue was treated with 4N-hydrogen chloride in ethyl acetate, crystallized and recrystallized from cthanol to give N-(l,2,3,6-tctrahydropyridin-4-Yl)-mcthyl-2-hydroxy-2,2-diphenylacetamide hydrochloride as colorless crystals (4l.64).
mp:222-224 ~
IR(Nujol) :3350, 1650, 750, 730, 690cm~' 21~320 NMR(DMS0-d6, ~) : 2.15(2H, br s), 3.10(2H, t, J=5.9Hz), 3.34(2H, br s), 3.70(2H, d, J=5.5Hz), 5.41(lH, br s), 6.82(1H, s), 7.20-7.45(10H, m), 8.34(1H, t, J=5.5Hz), 9.15(2H, br s) MASS(m/z) : 322(M~), 183, 95 Example 2 2-Hydroxy-2,2-diphenyl-N-[(1,2,3,6-tetrahydro-4-pyridyl)methyl]acetamide (1.00 g) was hydrogenated over 10 %
palladium on carbon in methanol. After the catalyst was removed by filtration, the filtrate was evaporated in vacuo and recrys-tallized from ethanol to give 2-hydro~y-2,2-diphenyl-N-[(piperi-dine-4-yl)methyl]acetamide hydrochloride (0.35 g)-mp: 251-253 ~
IR(Nujol) : 3360, 2470, 1650, 1600, 750, 730, 700cm~' NMR(DMS0-d6, ~) : 1.10-1.40(m, 2H), 1.50-1.80(m, 3H), 2.65-2.90(m, 2H), 2.90-3.10(m, 2H), 3.10-3.30(m, 2H), 6.75(s, lH), 7.20-7.45(m, lOH), 8.28(br s, lH), 8.69(br s, 2H) MASS(m/z) : 324(M~), 183, 105 Elemental analysis: C20H24N202-HCl Calculated value: C 66.56, H 6.98, N 7.76 Actual value: C 67.04, H 7.09, N 7.76 Example 3 21~320 .
2-llydro~y-N~ methylpipcridinc-4-yl)mcthyll-2,2-diphe-nylacetamide hydrochloride was obtained by reacting N-[(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)methyll-2-hydroxy-2,2-diphenylacetamide as a raw material, in a similar manner to that of Example 2.
mp:237-239 ~
IR(Nujol) :3430, 3150, 1670, 790, 770, 710, 700cm~' NMR(DMS0-d6,~) :1.20-1.50(m, lH), 1.60-1.80(m, 2H), 2.20-3.20 (m, 8H), 2.68(s, 3H), 6.73(s, lH),
bp: 140-150 C/lOmmHg (Kugelrohr) IR(Film) : 3270, 1600cm~' NMR(CDCl~, ~) : 0.92(t, J=7.3Hz, 3H), 1.10-1.70(br s, 2H), 1.55(t, quartet, J=7.3Hz, J=5.7Hz, 2H), 2.14(d, J=1.6Hz, 2H), 2.30-2.40(m, 2H), 2.57(t, J=5.7Hz, 2H), 2.96-3.00(m, 2H), 3.10(s, 2H), 5.53-5.57(m, lH) MASS(m/z) : 154(M'), 125, 96 Preparation 11 4-Aminomethyl-1-benzyl-1,2,3,6-tetrahydropyridine was obtained by reacting 4-acetylaminomcthyl-1-benzyl-1,2,3,6-tetrahydropyridine as a raw material, in a similar manner to that of Preparation 9.
IR(Film) : 3370, 3270, 1600, 740, 700cm~' 1~
~ 21~5320 NMR(CDC13, ~) : 1.61(s, 211), 2.13(br s, 2H), 2.58(t, J=5.8Hz, 2H), 2.95-3.05(m, 2H), 3.20(br s, 2H) 3.59(s, 2H), 5.50-5.55(m, lH), 7.20-7.37(m, 5H) MASS(m/z) : 202 (Mf), 172, 97 I'reparation 12 3-Aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine was obtained by reacting 3-acetylaminomethyl-1-ethyl-1,2,3,6-tetrahy-dropyridine as a raw material, in a similar manner to that of Preparation 9.
bp: 100-105 ~ /8.5mmHg (Kugelrohr) IR(Nujol) : 3450, 3370, 3280, 3200cm~' NMR(CDCl~ 1.14(3H, t, J=7Hz, CH3), 1.61(2H, s, NH2), 2.21(2H, m, CH2CH2CH=), 2.47(2H, quartet, J=7Hz, NCH2CH~), 2.49(2H, t, J=6Hz, NCH2CH2CH=), 2.93(2H, m, CH2N), 3.20(2H, m, CHzN), 5.62(1H, m, CH=) MS(m/z) : 140(M~), 123(base), 110, 108 Preparation 13 Acetic anhydride (17.5 ml) was added to a stirred solu-tion of 3-aminomethylpyridine (10.0 g) in acetic acid (30 ml) at room temperature. The resulting mi~ture was stirred at room temperature for 30 minutes and concentrated in vacuo to afford 3-acetylaminomethylpyridine as a crude oil, which was converted 21~32~
to 3-acetylaminomcthyl-1-ethylpyridinium iodide by reacting with ethyl iodide in a similar manner to that of Preparation 3, and then crystallized from a mi~ture o~ n-he~ane and ethyl acetate to g~ve pale yellow crystals.
mp: 110-111 C
IR(Nujol) : 34Z0, 3260, 1640cm~' NMR(DMS0-d~ 1.54(3H, t, J=7.5Hz, CH3), 1.93(3H, s, COCH3), 4.44(2H, d, J=6Hz, CH2NCO), 4.64(2H, quartet, J=7.5Hz, NCH2CH~), 8.12(1H, t, J=7.5Hz, pyridinium H), 8.43(lH, d, J=7.5Hz, pyridinium H), 8.59(lH, t, J=6Hz, NH), 9.0(2H, m, pyridinium H) MASS(m/z) : 135, 107 Preparation 14 A mi~ture of ethyl 3,3-diphenyl-2-propenoate (4.28 g) in 3N-sodium hydroxide aqueous solution (28 ml) and ethanol (50 ml) was allowed to stand overnight at room temperature and stirred at 50Cfor 2 hours. Ethyl acetate and brine were added to the mi~-ture and the resulting solution was acidified with concentratcd hydrochloric acid. The organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated in vacuo to give 3,3-diphenyl-2-propenoic acid.
mp: 158-161 C (washed with ethyl acetate) 2~ ~32~
.
IR(Nujol) :1690, 1660, 1610, 720,700cm~' NMR(CDC1~ 6.32(s, lH), 7.10-7.40(m, 10H) MASS (m/z) : 224(M~), 179, 165 Examlllc 1 To a solution of 4-[(2-hydro~y-2,2-diphenylacetylamino)methyl]-l-(4-methoxybenzyl)pyridinium chlo-ride (lOO g) in methanol (800 ml) was added portionwise sodium borohydride (32.7 g) at lO - 20 C in a nitrogen atomosphere. The resulting solution was stirred at room temperature for l hour, and then the mixture was evaporated. Ethyl acetate (l Q ) and water (500 ml) were added to the residue, and the organic layer was separated, washed with water (500 ml), brine (500 ml), dried over magnesium sulfate, and evaporated to give N-[l-(4-metho~ybenzyl)-l,2,3,6-tetrahydropyridin-4-yl]methyl-2-hydro~y-2,2-diphenylacetamide as crude oil. A mi~ture of the crude oil and l-chloroethyl chloroformate (25 ml) in methylene chloride (700 ml) was refluxed for l hour. Methanol (350 ml) was added to the mi~ture. The solution was reflu~ed for 30 minutes, and the solvent was evaporated. The residue was treated with 4N-hydrogen chloride in ethyl acetate, crystallized and recrystallized from cthanol to give N-(l,2,3,6-tctrahydropyridin-4-Yl)-mcthyl-2-hydroxy-2,2-diphenylacetamide hydrochloride as colorless crystals (4l.64).
mp:222-224 ~
IR(Nujol) :3350, 1650, 750, 730, 690cm~' 21~320 NMR(DMS0-d6, ~) : 2.15(2H, br s), 3.10(2H, t, J=5.9Hz), 3.34(2H, br s), 3.70(2H, d, J=5.5Hz), 5.41(lH, br s), 6.82(1H, s), 7.20-7.45(10H, m), 8.34(1H, t, J=5.5Hz), 9.15(2H, br s) MASS(m/z) : 322(M~), 183, 95 Example 2 2-Hydroxy-2,2-diphenyl-N-[(1,2,3,6-tetrahydro-4-pyridyl)methyl]acetamide (1.00 g) was hydrogenated over 10 %
palladium on carbon in methanol. After the catalyst was removed by filtration, the filtrate was evaporated in vacuo and recrys-tallized from ethanol to give 2-hydro~y-2,2-diphenyl-N-[(piperi-dine-4-yl)methyl]acetamide hydrochloride (0.35 g)-mp: 251-253 ~
IR(Nujol) : 3360, 2470, 1650, 1600, 750, 730, 700cm~' NMR(DMS0-d6, ~) : 1.10-1.40(m, 2H), 1.50-1.80(m, 3H), 2.65-2.90(m, 2H), 2.90-3.10(m, 2H), 3.10-3.30(m, 2H), 6.75(s, lH), 7.20-7.45(m, lOH), 8.28(br s, lH), 8.69(br s, 2H) MASS(m/z) : 324(M~), 183, 105 Elemental analysis: C20H24N202-HCl Calculated value: C 66.56, H 6.98, N 7.76 Actual value: C 67.04, H 7.09, N 7.76 Example 3 21~320 .
2-llydro~y-N~ methylpipcridinc-4-yl)mcthyll-2,2-diphe-nylacetamide hydrochloride was obtained by reacting N-[(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)methyll-2-hydroxy-2,2-diphenylacetamide as a raw material, in a similar manner to that of Example 2.
mp:237-239 ~
IR(Nujol) :3430, 3150, 1670, 790, 770, 710, 700cm~' NMR(DMS0-d6,~) :1.20-1.50(m, lH), 1.60-1.80(m, 2H), 2.20-3.20 (m, 8H), 2.68(s, 3H), 6.73(s, lH),
7.20-7.35 (m, lOH), 8.30(br s, lH), 9.70-9.90(br s, lH) MASS(m/z) :338(M+), 183, lO~
Elemental analysis: C2lH26N202 HCl Calculated value: C 67.28, H 7.26, N 7.47 Actual value: C 67.64, H 7.56, N 7.53 E~ample 4 A solution of 2,2-diphenyl-2-hydro~y-N-[[1-(4-metho~ybenzyl)-1,2,3,6-tetraphydropyridine-4-yl]methyl]acetamide (1.03 g) and benzyl chloroformate (0.437 g) in 1,2-dichloro-ethane (lO ml) was stirred at room temperature for 4 hours, diLuted with water, and cxtractcd wlth mcthylcnc chloride. Thc extract was dried over magnesium sulfate, evaporated in vacuo, and chromatographed over silica gel usin~ methylene chloride-methanol as an eluent to afford N-[(1-benzylo~ycarbonyl-1,2,3,6-tetrahydropyridine-4-yl)methyl]-2,2-diphenyl-2-llydro:~y-acetamide 2~ 5~ 32 ~
.
(0.797 g) as an oil.
IR(film) : 3390, 1690, 1670cm~' NMR(CDCl~, ~) : 1.99(2H, br s, =CCH2CH2N), 3.52(2H, t, J=5.5Hz,CH2CH2NCOO), 3.76(lH, s, OH), 3.90(4H, m, =CHCH2NCOO and CONCHz), 5.13(2H, s, OCH2), 5.37(lH, br s, =CH), 6.49(lH, m, CONH), 7.3-7.5(15H, m, aromatic H) MASS(m/z) : 183, 105, 91, 77 Example 5 A mi~ture of N-[[1-(4-metho~ybenzyl)-1,2,3,6-tetrahydro-pyridine-4-yl]methyl]-2,2-diphenyl-2-hydroxy acetamide (2.77 g) and 1-chloroethyl chloroformate (0.75 ml) in 1,2-dichloroethane (55 ml) was reflu~ed for 30 minutes. Methanol (50 ml) was added to the mixture, and the solutlon was refluxed for 1 hour and evaporated. The residue was purified by column chromatography on silica gel with a mi~ture Or dichloromethane and methanol (10:1), methanol, and then a mi~ture of methanol and 28 % ammonia water (10:1), successively, as an eluent. The eluate was evaporated.
Thc residue was treated with 4N-hydrogen chloride in ethyl ace-tate, crystallized, and recrystallized from methanol and ethyl acetate to give N-[Ll,2,3,~-tetrahYdropYridine-4-yl]methyl]-2~2-diphenyl-2-1lydroxy acetamide hydrochloride as colorless crystals (1.33 g).
mp:223-224 ~
IR(Nujol) :3350, 1650, 750, 730, 690cm~' 2 1 5 !~
NMR(DMSO-d6, ~) : Z.15(br s, 21I), 3.10(t, J=5.91~z, 2H), 3.34(br s, 2H), 3.70(d, J=5.5Hz, 2H), 5.41(br s, lH), 6.82(s, lH), 7.20-7.45(m, lOH), 8.34(t, J=5.5HZ, lH), 9.15(br s, 2H) MASS(m/z) 322(M~), 183, 95 Example 6 A solution of N-[ll-benzyloxycarbonyl-1,2,3,6-tetrahy-dropyridine-4-yl]methyl]-2,2-diphenyl-2-llydroxyacetamide (186 mg) in 25 % hydrogen bromide-acetic acid solution (1.86 ml) was stirred for 30 minutes under ice cooling and for 3 hours at room temperature, and then evaporated in vacuo. The residue was partitioned between diisopropyl ether and water. The aqueous layer was separated, basified with lN sodium hydro~ide solution, and e~tracted with methylene chloride. The methylene chloride layer was washed with brine, dried over magnesium sul~ate, evapo-rated in vacuo. The residue was purified by column chromatography on silica gel using methylene chloride-methanol as an eluent to afford 2,2-diphenyl-2-hydro~y-N-[(1,2,3,6-tetrahydropyridine-4-yl)methyl]acetamide (85 mg) as a colorless powder, which was recrystallized with ethanol.
mp: 151-153 C
Elemental analysis:
Calculated value: C 74.51, H 6.88, N 8.69 Actual value: C 74.59, H 7.08, N 8.74 IR(Nujol) : 3380, 3300, 1670cm~' 21~5320 NMR(CDCls, ~) : 1.95(2H, m, =CCH2CHzNII), 2.85(2H, t, J=5.5Hz, CH2CH2NH), 3.23(2H, br s, =CHCH2NH), 3.35(2H, br, =NH and OH), 3.84(2H, d, J=5.5Hz, CONHCH2), 5.44(lH, br s, =CH), 6.70(lH, t, J=5.5Hz, CONH), 7.25-7.5(10H, m, aromatic H) MASS(m/z) : 322(M~), 183(base), 105(base), 96(base) Example 7 To a solution of N-[(1,2,3,6-tetrahydropyridin-4-yl)methyl~-2,2-diphenyl-2-hydro~y acetamide (6.00 g) in methanol (60 ml) was added a solution of methanol (20 ml) at room tempera-ture. The resulting solution was evaporated in vacuo and the residue was crystallized and recrystallized from ethanol to give N-1(1,2,3,6-tetrahydropyridine-4-yl)methyl]-2,2-diphenyl-2-hydro~yacetamide methanesulfonate as colorless crystals (6.66 g).
mp: 195-197 ~
IR(Nujol) : 3400, 1670, 1590, 780, 750, 740, 700cm~' NMR(DMSO-d6, ~) : 2.14(br s, 2H), 2.31(s, 3H), 3.14(t, J=6.lHz, 2H), 3.51(br s, 2H), 3.71(d, J=6.lHz, 2H), 5.40(br s, lH), 6.81(s, lH), 7.20-7.41(m, lOH), 8.36(t, J=6.lHz, lH),
Elemental analysis: C2lH26N202 HCl Calculated value: C 67.28, H 7.26, N 7.47 Actual value: C 67.64, H 7.56, N 7.53 E~ample 4 A solution of 2,2-diphenyl-2-hydro~y-N-[[1-(4-metho~ybenzyl)-1,2,3,6-tetraphydropyridine-4-yl]methyl]acetamide (1.03 g) and benzyl chloroformate (0.437 g) in 1,2-dichloro-ethane (lO ml) was stirred at room temperature for 4 hours, diLuted with water, and cxtractcd wlth mcthylcnc chloride. Thc extract was dried over magnesium sulfate, evaporated in vacuo, and chromatographed over silica gel usin~ methylene chloride-methanol as an eluent to afford N-[(1-benzylo~ycarbonyl-1,2,3,6-tetrahydropyridine-4-yl)methyl]-2,2-diphenyl-2-llydro:~y-acetamide 2~ 5~ 32 ~
.
(0.797 g) as an oil.
IR(film) : 3390, 1690, 1670cm~' NMR(CDCl~, ~) : 1.99(2H, br s, =CCH2CH2N), 3.52(2H, t, J=5.5Hz,CH2CH2NCOO), 3.76(lH, s, OH), 3.90(4H, m, =CHCH2NCOO and CONCHz), 5.13(2H, s, OCH2), 5.37(lH, br s, =CH), 6.49(lH, m, CONH), 7.3-7.5(15H, m, aromatic H) MASS(m/z) : 183, 105, 91, 77 Example 5 A mi~ture of N-[[1-(4-metho~ybenzyl)-1,2,3,6-tetrahydro-pyridine-4-yl]methyl]-2,2-diphenyl-2-hydroxy acetamide (2.77 g) and 1-chloroethyl chloroformate (0.75 ml) in 1,2-dichloroethane (55 ml) was reflu~ed for 30 minutes. Methanol (50 ml) was added to the mixture, and the solutlon was refluxed for 1 hour and evaporated. The residue was purified by column chromatography on silica gel with a mi~ture Or dichloromethane and methanol (10:1), methanol, and then a mi~ture of methanol and 28 % ammonia water (10:1), successively, as an eluent. The eluate was evaporated.
Thc residue was treated with 4N-hydrogen chloride in ethyl ace-tate, crystallized, and recrystallized from methanol and ethyl acetate to give N-[Ll,2,3,~-tetrahYdropYridine-4-yl]methyl]-2~2-diphenyl-2-1lydroxy acetamide hydrochloride as colorless crystals (1.33 g).
mp:223-224 ~
IR(Nujol) :3350, 1650, 750, 730, 690cm~' 2 1 5 !~
NMR(DMSO-d6, ~) : Z.15(br s, 21I), 3.10(t, J=5.91~z, 2H), 3.34(br s, 2H), 3.70(d, J=5.5Hz, 2H), 5.41(br s, lH), 6.82(s, lH), 7.20-7.45(m, lOH), 8.34(t, J=5.5HZ, lH), 9.15(br s, 2H) MASS(m/z) 322(M~), 183, 95 Example 6 A solution of N-[ll-benzyloxycarbonyl-1,2,3,6-tetrahy-dropyridine-4-yl]methyl]-2,2-diphenyl-2-llydroxyacetamide (186 mg) in 25 % hydrogen bromide-acetic acid solution (1.86 ml) was stirred for 30 minutes under ice cooling and for 3 hours at room temperature, and then evaporated in vacuo. The residue was partitioned between diisopropyl ether and water. The aqueous layer was separated, basified with lN sodium hydro~ide solution, and e~tracted with methylene chloride. The methylene chloride layer was washed with brine, dried over magnesium sul~ate, evapo-rated in vacuo. The residue was purified by column chromatography on silica gel using methylene chloride-methanol as an eluent to afford 2,2-diphenyl-2-hydro~y-N-[(1,2,3,6-tetrahydropyridine-4-yl)methyl]acetamide (85 mg) as a colorless powder, which was recrystallized with ethanol.
mp: 151-153 C
Elemental analysis:
Calculated value: C 74.51, H 6.88, N 8.69 Actual value: C 74.59, H 7.08, N 8.74 IR(Nujol) : 3380, 3300, 1670cm~' 21~5320 NMR(CDCls, ~) : 1.95(2H, m, =CCH2CHzNII), 2.85(2H, t, J=5.5Hz, CH2CH2NH), 3.23(2H, br s, =CHCH2NH), 3.35(2H, br, =NH and OH), 3.84(2H, d, J=5.5Hz, CONHCH2), 5.44(lH, br s, =CH), 6.70(lH, t, J=5.5Hz, CONH), 7.25-7.5(10H, m, aromatic H) MASS(m/z) : 322(M~), 183(base), 105(base), 96(base) Example 7 To a solution of N-[(1,2,3,6-tetrahydropyridin-4-yl)methyl~-2,2-diphenyl-2-hydro~y acetamide (6.00 g) in methanol (60 ml) was added a solution of methanol (20 ml) at room tempera-ture. The resulting solution was evaporated in vacuo and the residue was crystallized and recrystallized from ethanol to give N-1(1,2,3,6-tetrahydropyridine-4-yl)methyl]-2,2-diphenyl-2-hydro~yacetamide methanesulfonate as colorless crystals (6.66 g).
mp: 195-197 ~
IR(Nujol) : 3400, 1670, 1590, 780, 750, 740, 700cm~' NMR(DMSO-d6, ~) : 2.14(br s, 2H), 2.31(s, 3H), 3.14(t, J=6.lHz, 2H), 3.51(br s, 2H), 3.71(d, J=6.lHz, 2H), 5.40(br s, lH), 6.81(s, lH), 7.20-7.41(m, lOH), 8.36(t, J=6.lHz, lH),
8.65(br s, 2H) MASS(m/z) : 323(M~l) Elemental analysis: C20H22N202-CH~SOlH
21~32~
.
Calculated value: C 60.27, H 6.26, N 6.69, S 7.66 Actual value: C 60.32, H 6.32, N 6.62 , S 7.86 Example 8 ~ mixture Or N~ etho~ycarbonylpiperidine-4-yl)-2,2-diphenylacetamide (4.00 g) and potassium hydro~lde (2.0 g) in methyl cellosolve (30 ml) was refluxed for 3.5 hours. Ethyl acetate (100 ml) and water (300 ml) were added to the mi~ture and resulting solution was separated. The aqueous layer was e~tracted wlth ethyl acetate (100 ml x 3). The combined organic layers were evaporated in vacuo and treated with 4N hydrogen chloride in ethyl acetate to give N-(piperidine-4-yl)-2.2,-diphenylacetamide hydrochloride.
mp: 233-235 ~ (washed with ethyl acetate) IR(Nujol) : 3500, 3300, 1630, 740, 720cm~' NMR(DMS0-d6, ~) : 1.45 1.75(m, 2H), 1.75-2.00(m, 2H), 2.80-3.10(m, 2H), 3.10-3.25(m, 2H), 3.70-3.95(m, lH) 4.97(s, lH), 7.10-7.40(m, lOH), 8.59(d, J=7.4Hz, lH), 8.86(br s, 2H) MASS(m/z) : 294(M+), 229, 167, 127 Elemental analysis: C,DH22NzO HCl Calculated value: C 65.41, H 7.22, N 8.03 Actual value: C 65.67, H 7.32, N 8.12 Example 9 21~i~3,?0 .
2-llydroxy-N-(pipcridinc-4-yl)-2~2-diphenylacetamidc hydro-chloride was obtained by reacting N-(l-etho~ycarbonylpiperidin-4-yl)-2-hydroxY-2~2-diphenylacetamide as a raw material, in a similar manner to that of E~ample 8.
mp: 193-195 C (washed with acetone) IR(Nujol) : 3300, 2700, 2600, 2470, 1660, 770, 750, 730, 700 cm-' NMR(DMS0-d6, ~) : 1.60~2.00(m, 4H), 2.75-3.05(m, 2H), 3.05-3.30(m, 2H), 3.75-4.00(m, lH), 6.77(s, lH), 7.20-7.95(m, lOH), 8.15(d, J=7.7Hz, lH), 8.94(br s, lH), 9.10(br s, lH) MASS(m/z) : (no M~) , 183, 105 ~lemental analysis: C ,9H22N202~HCl Calculated value: C 64.67, H 6.76, N 7.94, Cl 10.05 Actual value: C 64.79, H 6.93, N 7.92, Cl 9.98 E~ample 10 A solution of N-(pyridine-4-yl)methyl-2-hydro~y-2~2-dipheny-lacetamide (2.00 g) and methyl iodide (1.6 ml) in acetone (100 ml) was refluxed for 3 hours and evaporated to give 1-meth-yl-4-L(2-hydro~y-2,2-dipllenylacc~ylamino)-mctllyl]pyridinium iodide as a crude oil. The oil was dissolved in methanol (50 ml), and sodium borohydride (0.95 g) was added to the solution. The resulting mi~ture was stirred for 1 hour at room temperature, and then evaporated. The residue was partitioned between ethyl ace-215~3,~
.
tate and lN sodiu~ llydro~ide solution. The organic layer wasFeparated, washed with water, brine, dried over magnesium sul-rate, and evaporated. The residue was treated with 4N-hydrogen chloride in ethyl acetate, crystallized and recrystallized from 2-propanol and methanol to give N-(1-methyl-1,2,3,6-tetrahydrop-yridine-4-yl)methyl-2-hydro~y-2,2-diphenylacetamide (0.41 g).
mp: 173-174 C
IR(Nujol) : 3340, 3200, 2550, 1660, 770, 750, 720, 700cm~' NMR(DMSO-dfi, ~) : 2.00-2.50(2H, m), 2.80-3.90(4H, m), 2.73(3H, s), 3.72(2H, d, J=6.lHz), 5.38(1H, s), 6.82(1H, s), 7.20-7.40(10H, m), 8.37(1H, t, J=6.lHz) 10.77(lH, br s) MASS(m/z) : 336(M~), 183, 109 E~ample 11 N-(1-ethylpyridinio-4-yl)methyl-2-hydroxy-2,2-diphenyla-cetamide iodide was obtained by reacting N-(pyridine-4-yl)methyl-2-hydroxy-2,2-diphenylacetamide and methyl iodide as raw materials, in a similar manner to that Or Example 10.
mp: 123-124 ~
IR(Nujol) : 3350, 1650, 780, 740, 720, 700cm~' NMR(DMSO-dfi, ~) : 1.52(t, J=7.2Hz, 3H), 4.57(q, J=7.2Nz, 2H) 4.60(d, J=6.OHz, 2H), 7.00(s, lH), 7.20-7.50(m, lOH), 7.85(d, J=6.6Hz, 2H), 9.01(d, J=6.6Hz, 2H), ~1~532~
.
21~32~
.
Calculated value: C 60.27, H 6.26, N 6.69, S 7.66 Actual value: C 60.32, H 6.32, N 6.62 , S 7.86 Example 8 ~ mixture Or N~ etho~ycarbonylpiperidine-4-yl)-2,2-diphenylacetamide (4.00 g) and potassium hydro~lde (2.0 g) in methyl cellosolve (30 ml) was refluxed for 3.5 hours. Ethyl acetate (100 ml) and water (300 ml) were added to the mi~ture and resulting solution was separated. The aqueous layer was e~tracted wlth ethyl acetate (100 ml x 3). The combined organic layers were evaporated in vacuo and treated with 4N hydrogen chloride in ethyl acetate to give N-(piperidine-4-yl)-2.2,-diphenylacetamide hydrochloride.
mp: 233-235 ~ (washed with ethyl acetate) IR(Nujol) : 3500, 3300, 1630, 740, 720cm~' NMR(DMS0-d6, ~) : 1.45 1.75(m, 2H), 1.75-2.00(m, 2H), 2.80-3.10(m, 2H), 3.10-3.25(m, 2H), 3.70-3.95(m, lH) 4.97(s, lH), 7.10-7.40(m, lOH), 8.59(d, J=7.4Hz, lH), 8.86(br s, 2H) MASS(m/z) : 294(M+), 229, 167, 127 Elemental analysis: C,DH22NzO HCl Calculated value: C 65.41, H 7.22, N 8.03 Actual value: C 65.67, H 7.32, N 8.12 Example 9 21~i~3,?0 .
2-llydroxy-N-(pipcridinc-4-yl)-2~2-diphenylacetamidc hydro-chloride was obtained by reacting N-(l-etho~ycarbonylpiperidin-4-yl)-2-hydroxY-2~2-diphenylacetamide as a raw material, in a similar manner to that of E~ample 8.
mp: 193-195 C (washed with acetone) IR(Nujol) : 3300, 2700, 2600, 2470, 1660, 770, 750, 730, 700 cm-' NMR(DMS0-d6, ~) : 1.60~2.00(m, 4H), 2.75-3.05(m, 2H), 3.05-3.30(m, 2H), 3.75-4.00(m, lH), 6.77(s, lH), 7.20-7.95(m, lOH), 8.15(d, J=7.7Hz, lH), 8.94(br s, lH), 9.10(br s, lH) MASS(m/z) : (no M~) , 183, 105 ~lemental analysis: C ,9H22N202~HCl Calculated value: C 64.67, H 6.76, N 7.94, Cl 10.05 Actual value: C 64.79, H 6.93, N 7.92, Cl 9.98 E~ample 10 A solution of N-(pyridine-4-yl)methyl-2-hydro~y-2~2-dipheny-lacetamide (2.00 g) and methyl iodide (1.6 ml) in acetone (100 ml) was refluxed for 3 hours and evaporated to give 1-meth-yl-4-L(2-hydro~y-2,2-dipllenylacc~ylamino)-mctllyl]pyridinium iodide as a crude oil. The oil was dissolved in methanol (50 ml), and sodium borohydride (0.95 g) was added to the solution. The resulting mi~ture was stirred for 1 hour at room temperature, and then evaporated. The residue was partitioned between ethyl ace-215~3,~
.
tate and lN sodiu~ llydro~ide solution. The organic layer wasFeparated, washed with water, brine, dried over magnesium sul-rate, and evaporated. The residue was treated with 4N-hydrogen chloride in ethyl acetate, crystallized and recrystallized from 2-propanol and methanol to give N-(1-methyl-1,2,3,6-tetrahydrop-yridine-4-yl)methyl-2-hydro~y-2,2-diphenylacetamide (0.41 g).
mp: 173-174 C
IR(Nujol) : 3340, 3200, 2550, 1660, 770, 750, 720, 700cm~' NMR(DMSO-dfi, ~) : 2.00-2.50(2H, m), 2.80-3.90(4H, m), 2.73(3H, s), 3.72(2H, d, J=6.lHz), 5.38(1H, s), 6.82(1H, s), 7.20-7.40(10H, m), 8.37(1H, t, J=6.lHz) 10.77(lH, br s) MASS(m/z) : 336(M~), 183, 109 E~ample 11 N-(1-ethylpyridinio-4-yl)methyl-2-hydroxy-2,2-diphenyla-cetamide iodide was obtained by reacting N-(pyridine-4-yl)methyl-2-hydroxy-2,2-diphenylacetamide and methyl iodide as raw materials, in a similar manner to that Or Example 10.
mp: 123-124 ~
IR(Nujol) : 3350, 1650, 780, 740, 720, 700cm~' NMR(DMSO-dfi, ~) : 1.52(t, J=7.2Hz, 3H), 4.57(q, J=7.2Nz, 2H) 4.60(d, J=6.OHz, 2H), 7.00(s, lH), 7.20-7.50(m, lOH), 7.85(d, J=6.6Hz, 2H), 9.01(d, J=6.6Hz, 2H), ~1~532~
.
9.13(t, J=6.OHz, lH) MASS(m/z) : (no M~) , 183, 105 Example 12 A mixture of 2-hydro~y-2,2-diphenyl-N-[(1,2,3,6-tetrahydropyridine-4-yl)methyl]acetamide hydrochloride (0.70 g) and sodium cyanoborohydride (0.18 g) in dry methanol (15 ml) and dry acetone (5 ml) was stirred for 4 days at room temperature, and therl the mixture was evaporated in vacuo. Ethyl acetate and lN sodium hydroxidc solution were added to the residue. The organic layer was separated, washed with brine, dried over magne-sium sulfate, and evaporated in vacuo. The residue was treated with 4N-hydrogenchloride in 1,4-dio~ane, and crystallized to give 2-hydroxy-N-[(1-isopropyl-1,2,3,6-tetrahydropyridine-4-yl)methyl]-2,Z-diphenylacetamide hydrochloride (0.58 g).
mp: 126-127 C (washed with 1,4-dioxane) IR(Nujol) : 3250, 1660, 760, 700cm~' NMR(DMSO-d6, ~) : 1.26(d, J=6.6Hz, 6H), 2.05-2.25(m, lH), 2.30-2.60(m, lH), 2.75-3.10(m, lH), 3.25-3.50(m, 2H), 3.58(br s, 2H), 3.73(d, J=6.OHz, 2H), 5.42(s, lH), 6.83(br s, lH), 7.15-7.60(m, lOH), 8.36(t, J=6.OHz,lH)
mp: 126-127 C (washed with 1,4-dioxane) IR(Nujol) : 3250, 1660, 760, 700cm~' NMR(DMSO-d6, ~) : 1.26(d, J=6.6Hz, 6H), 2.05-2.25(m, lH), 2.30-2.60(m, lH), 2.75-3.10(m, lH), 3.25-3.50(m, 2H), 3.58(br s, 2H), 3.73(d, J=6.OHz, 2H), 5.42(s, lH), 6.83(br s, lH), 7.15-7.60(m, lOH), 8.36(t, J=6.OHz,lH)
10.30(br s, lH) Elemental analysis: C23H2~N202 HCl l/2H20 Calculated value: C 67.39, H 7.38, N 6.83, Cl 8.65 21~320 Actual value: C 67.40, H 7.84, N 6.58, Cl 8.35 E~ample 13 --N-(1-ethylpiperidine-4-yl)-2-hydroxy-2,2-diphenylaceta-m.ltle ful~aratc was obtalncd by rcacting N-(pipcridille-4-yl)-2-11y-dro~y-2,2-diphenylacetamide as a raw material, in a similar manner to that of Example 12.
mp: 197-199 ~ (recrystallization from isopropyl alcohol) IR(Nujol) : 3420, 2350, 1670, 750, 700, 670cm~' NMR(DMSO-d6, ~) : 1.05(t, J=7.2Hz, 3H), 1.45-1.65(m, 4H), 2.15-2.40(m, 2H), 2.54(q, J=7.2Hz, 2H), Z.85-3.05(m, 2H), 3.55-3.75(m, lH), 6.50(s, lH), 7.20-7.40(m, llH), 7.96(d, J=8.OHz, lH) Elemental analysis: C2,Hz6N20 1/2C~H~04 1/2}{zO
Calculated value: C 68.13, H 7.21, N 6.91 Actual value: C 67.97. H 7.41, N 6.67 Example 14 N-(1-isopropylpiperidine-4-yl)-2,2-diphenylacetamide rumarate was obta~ned by reacting N-(piperidine-4-yl)-2,2-diphe-nyl-acetamide hydrochloride as a raw material, in a similar manner to that of E~ample 12.
mp: 175-177 ~ (washed with acetone) IR(Nujol) : 3200, 2650, 2500, 1660, 790, 770, 740, 700cm~' NMR(DMSO-d6. ~) : 1.13(d, J=6.6Hz. 6H), 1.45-1.75(m, 2H), ~ 21~5320 1.75-2.00(m, 2H), 2.65-2.90(m. 2H), 3.00-3.25(m, 3H), 3.65-3.90(m, lH), 4.93(s, lH), 6.54(s, 3H), 7.10-7.35(m, lOH), 8.43(d, J=7.3Hz, lH) MASS(m/z) : 336(M+), 321, 167 Elemental analysis: C22H2~N20-3/2(CqH~0~) Calculated value: C 65.87, H 6.71, N 5.49 Actual value: C 65.60, H 6.84, N 5.57 E~ample 15 N~ ethylpiperidine-4-yl)-2,2-diphenylacetamide fumarate was obtained by reacting N-(piperidine-4-yl)-2,2-diphenylaceta-mide hydrochloride as a raw material, in a similar manner to that o Examle 12.
mp: 179-181 ~ (washed with acetone) IR(Nujol) : 3250, 1690, 1760, 790, 760, 740cm~' NMR(DMS0-d6, ~) : 1 05(t, J=7.2Hz, 3H), 1.30-1.60(m, 2H), 1.70-1.85(m, 2H), 2.25-2.40(m, 2H), 2.55(q, J=7.2Hz, 2H), 2.90-3.10(m, 2H), 3.40-3.55(m, lH), 4.91(s, lH), 6.55(s, 2H), 7.20-7.30(m, lOH), 8.34(d, J=7.4Hz, lH) MASS(m/z) : 322(M+), 307, 167, 111 Elemental analysis: C2,H26N20 C~H~0~ 1/2HzO
Calculated value: C 67.10, H 6.98, N 6.26 Actual value: C 66.78, H 6.97, N 6.05 215~32~
, ,.
Examplc 16 A mi~ture of benzylic acid (2.21 g) and 1,1'-carbonyl-diimidazole (1.73 g) in dry dichloromethane (45 ml) was stirred ror 2.5 hours at room temperature. Then 4-aminomethyl-1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridine (2.25 g) in dry dichlo-romethane (20 ml) was added dropwise over 20 minutes. The mi~ture was stirred for 45 minutes at room temperature and evaporated.
Ethyl acetate and lN sodium hydro~ide were added to the residue.
The organic layer was separated, washed twice with water, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel with a mi~ture of dichlo-romethane and methanol (10:1) as an eluent to give N-[[1-(4-metho~ybenzyl)-1,2,3,6-tetrahydropyridine-4-yl]methyl]-2,2-diphenyl-2-hydro~yacetamide (3.47 g) as a pale yellow oil.
IR(CHCl~) : 3370, 1660, 1610, 750, 730, 700cm~' NMR(CDCl~, ~) : 2.02(br s, 2H), 2.52(t, J=5.8Hz, 2H), 2.91(br s, 21{), 3.50(s, 2H), 3.80(s, 3H), 4.10(br s, lH), 4.14(s, 2H), 5.39(br s, lH), 6.39(br s, lH), 6.85(d, J=12.7Hz, 2H), 7.20-7.50(m, 12H) MASS(m/z) : 442(M+), 202, 121 E~ample 17 N-[(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)methyl]-2,2-diphenyl-2-hydro~yacetamide o~alate was obtained by reacting benzylic acid and 1-methyl-4-aminomethYl-1,2,3,6-tetrahydropyri-21~2~
dine as raw materials, in a similar manner to that of E~ample 16.
mp: 185-190 ~
IR(Nujol) : 1650, 1600, 770, 750, 730, 700cm~' NMR(DMSO~da, ~) : 2.09(br s, 2}1), 2.50(s, 3}1), 2.81(t, J=5.9Hz, 21{), 3.19(br s, 2H), 3.68(d, J=6.OHz, 2H), 4.98(br, 2H), 5.37(s, lH), 7.20-7.45(m, llH), 8.26(t, J=6.OHz, lH) MASS(m/z) : 336(M+), 215, 183, 109 E~ample 18 2-Hydro~y-2,2-diphenyl-N-l(1-propyl-1,2,3,6-tetrahydrop-yridine-4-yl)methyl]acetamide hydrochloride was obtained by reacting benzylic acid and 1-propyl-4-aminomethyl-1,2,3,6-tet-rahydropyridine as raw materials, in a similar manner to that of Example 16.
mp: 96-98 ~ (recrystallization from a mixture of ethyl acetate-methanol-diisoPropyl ether) IR(Nujol) : 3250, 1660, 770, 740, 700cm~' NMR(DMSO-d6, ~) : 0.89(t, J=7.3Hz, 3H), 1.60-1.80(m, 2H), 2.00-2.55(m, 2H), 2.90-4.20(m, 8H), 5.89(br s, lH), 6.82(s, lH), 7.20-7.45(m, lOH), 8.37(t, J=6.lHz, lH), 10.50(br s, lH) MASS(m/z) : 364(M~), 335, 183, 137 Elemental analysis: C28H28N202 HCl Calculated value: C 66.80, H 7.41, N 6.77, Cl 8.57 21~2~
.
Actual value: C 66.77, H 7.76, N 6.44, Cl 8.57 I~ample l9 - ~~
N-[(l-benzyl-1,2,3,6-tetrahYdropyridine-4-yl)methyl]-2-hydroxy-2,2,-diphenylacetamide hydrochloride was obtained by reacting benzylic acid and l-benzyl-4-aminomethyl-l,2,3,6-tet-rahydropyridine as raw materials, in a similar manner to that of Example 16.
mp:139-141 C (recrystallization from a mixture of methanol-ethyl acetate-diisopropyl ether) IR(Nujol) :3450, 3200, 2570, 1660, 750, 710, 680cm~' NMR(DMSO-d6,~) :2.00-2.50(m, 2H), 2.70-3.50(m, 2H), 3.50(br s, 2H), 3.72(d, J=6.OHz, 2H), 4.30(s, 2H), 5.38(s, lH), 6.81(s, lH), 7.25-7.63(m, 15H), 8.36(t, J=6.OHz, lH), 10.92(br s, lH) Elemental analysis: C27Hz8N202 HCl Calculated value: (as 0.8 H20 ) C 69.98, ~ 6.66, N 6.05, Cl 7.65 Actual value: C 69.94, H 6.67, N 5.94, C1 7.63 E~ample 20 N-[(1-ethyl-l,2,3,6,-tetrahydropyridine-3-yl)methyl]-2,2-diphenyl-2-hydro~yacetamide l/2 ~umarate was obtained by reacting benzylic acid and l-ethyl-3-aminomethYl-l,2,3,6-tetrahydropyri-dine as raw materials, in a similar manner to that of Example 16.
mp:185-186 ~ (recrystallization from isopropyl alcohol) 2~5~3~a .
IR(Nujol) : 3400, 2750-2600, 1675, 1590cm~' NMR(DMSO-d6, ~) : 1.02(3H, t, J=7Hz, CH~), 2.09(2H, m, =CHCHzCHz), 2.45-2.65(4H, m, NCHz x 2), 2.92(2H, s, =CCHzN), 3.68(2H, m, CONCHz), 5.52(1H, br s, =CH), 6.51(2H, s, fumaric acid=CH), 7.25-7.4(10H, m, aromatic H), 8.21(lH, br s, CONH) MASS(m/z) : 350(M~), 183, 124(base), 105 Elemental analysis: C2 zH26N202 1/2C~H~O~
Calculated value: C 70.57, H 6.91, N 6.86 Actual value: C 70.36, H 7.11, N 6.72 Example 21 To a mi~ture of 4,4'-difluorobenzophenone (2.0 g) and zinc iodide (0.1 g) in dry dichloromethane (15 ml) was added trimethylsilyl cyanide (1.35 ml) at room temperature. The result-ing mi~ture was stirred for 40 hours at the same temperature, and then the solvent was evaporated in vacuo. Concentrated hydro-chloric acid (30 ml) was added to the residue and the mi~ture was stirred at 90C for 14 hours. The mi~ture was partitioned between ethylacetate and water. The organic layer was separated and evaporated in vacuo. The residue was partitioned between diiso-propylether and lN aqueous sodium hydro~ide. The organic layer was washed with lN aqueous sodium hydro~ide three times. The combined aqueous layers were acidified with concentrated hydrochloric acld and extracted with ethyl acetate twice.
215532~
The combined organic layers were washed with ~ater and brine, dried over magnesium sulfate and evaporated in vacuo to give crude 4,4'-dirluorobenzilic acid (0.80 g). To a solution of this crude 4,4'-difluorobenzilic acid (0.80 g) and N,N'-carbonyl-diimidazole (0.60 g) in dry dichloromethane was added dropwise a solution of 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine (0.60 g) in dichloromethane at room temperature.
The resulting mi~ture was stirred at room temperature, cvaporated in vacuo. The residue was partitioned between ethylac-etate and lN aqueous sodium hydro~ide. The combined organic layers were washed with water and brine, dried over magnesium sulrate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel and then on alumina and treated with 4N hydrogenchloride in ethylacetate to give 2,2-bis(4-~luorophenyl)-2-hydro~y-N-[(1-ethyl-1,2,3,6-tetrahydropyri-dine-4-yl)methyl]acetamide hydrochloride.
mp: 155-157 ~ (washed with diisopropyl ether) IR(Nujol) : 3350, 3270, 2500, 1660, 1600, 820, 770cm~' NMR(DMS0-d~, ~) : 1.24(t, J=7.2Hz, 3H), 2.00-2.45(m, 2H), 2.85-3.80(m, 6H), 3.09(quartet, J=7.2Hz, 2H), 5.39(s, lH), 6.96(s, lH), 7.10-7.20(m, 4H), 7.35-7.45(m, 4H), 8.46(br s, lH), 10.21(br s, lH) MASS(m/z) : 386(M~), 371, 219, 123, 110 Elemental analysis: C2 zH2~NzOzF2 HCl 1/3HzO
Calculated value: C 61.61, H 6.03, N 6.53, Cl 8.27 Actual value: C 61.69, H 6.09, N 6.54, Cl 8.27 2~ ~32~
.
I~'xample 22 A solution of 3-amino-1-azabicyclo[2,2,2]octane in ben-%ene (12 ml) was added dropwise to a stirred solution of 2-chloro-2,2-diphenylacetyl-chloride (6.30 g) in benzene (17 ml)-n-he~ane (11 ml) at room temperature. The resulting mixture was stirred for 3 hours and 30 minutes at room tempera-ture and partitioned between toluene and water. The organic layer was e~tracted twice with lN hydrochloric acid and the aqueous layers were combined, washed with diethyl ether, stirred at 70c for 1 hour, cooled with ice water, basified with 5 % sodium hydroxide aqueous solution, and e~tracted twice with ethyl ace-tate. The ethyl acetate layers were combined, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was washed with diisopropyl ether to afford a colorless powder (2.90 g), which was converted to the hydrochloride in a usual manner. The hydrochloride was recrystallized from ethanol to afford N-(1-azabicyclo[2,2,2,]octan-3-yl)-2,2-diphenyl-2-hydro~-yacetamide hydrochloride as a colorless powder.
mp:261-265 ~ (dec.) IR(Nujol) :3300, 2800-2300, 1660cm~' Il NMR(DMSO-d6,~) :1.6-2.1(5H, m, ~ H ), 3.05-3.6(6H, m, N(CH2)~), 4.15(lH, m, CONHCE), 6.87(1H, S, OH), 7.25-7.45(10H, m, aromatic H), 2I ~532~
.
8.59(1H, d, J=7Hz, CONH), 10.36(1H, br s, HCl) MASS(m/z) :336(M+), 183(base), 105 Elemental analysis: C2,Hz4N20z HCl Calculated value: C 67.64, H 6.76, N 7.51 Actual value: C 67.67, H 7.10, N 7.31 Example 23 N~ etho~yearbonylpiperidine-4-yl)-2-hydroxy-2~2-diphe-nyl acetamide was obtained by reaeting 4-amino-l-etho~yearbonyl-piperidine and benzylic acid as raw materials, in a similar manner to that of Example 16.
mp:128-131 ~ (washed with n-hexane) IR(Nujol) :3300, 1650, 1620, 760, 740, 720cm~' NMR(CDC1~,~) :1.00-1.41(m, 2H), 1.23(t, J=7.lHz, 3H), 1.70-2.00(m, 2H), 2.75-3.00(m, 2H), 3.90-4.20(m, 3H), 4.08(q, J=7.lHz, 2H), 6.67(d, J=8.OHz, lH), 6.93(s, lH), 7.20-7.50(m, lOH) MASS(m/z) :382(M~), 370, 216, 183 Example 24 - ~
2,2-Diphenyl.2-hydroxy-N-[2-(l-methylpiperidine-4-yl)-ethyl]acetamide fumarate was obtained by reacting 4-(2-aminoeth-yl)-l-methylpiperidine and benzylic aeid as raw materials, in a similar manner to that of E~ample 16. The residue was chromato-graphed over siliea gel using ehloroform - methanol as an eluent to afrord white powder.
~l~S320 .
mp: 151-152 ~
IR(Nujol) : 3360, 3250, 3200, 2740-2100, 1700, 1670cm~' NMR(DMSO-d6, ~) : 1.15-1.45(5H, m, CH and CHz x 2), 1.7(2H, m, CH2), 2.35(2H, m, CH2), 2.45(3H, s, CH9), 3.0-3.2(4H, m, CH2x 2), 6.50(2H, s, HC=CH), 7.2-7.4(llH, m, aromatic H and OH), 8.15(1H, t, J=6Hz, NH) MASS(m/z) : 352(M~), 337, 183(base) Elemental analysis: C22H2#N20z C~H40~
Calculated value: C 66.65, H 6.88, N 5.98 Actual value: C 67.02, H 7.05, N 5.94 Example 25 N-[(1-ethylpiperidine-3-yl)methyl]-2,2-diphenyl-2-hydroxyacetamide hydrochloride as a colorless crystallization was obtained by reacting 3-aminomcthyl-1-ethylpiperidine and benzylic acid as raw materials, in a similar manner to that of E~ample 16.
free base:
IR(Nujol) : 3310, 2800-2300, 1660cm~' NMR(CDC13, ~) : 0.95(1H, m, piperidine H), 1.00(3H, t, J=7Hz, CH9), 1.5-1.95(6H, m, piperidine H) 2.30(2H, quartet, J=7Hz, NCHzCH3), 2.7(2H, m, piperidine H), 3.1-3.35(2H, m, CONCH2), 4.15(1H, br, OH), 6.86(1H, br t, NH), 7.25-7.53(1OH, m, aromatic H) 21~32~
MASS(m/z) : 352(M+), 337, 183, 105(base) hydrochloride:
mp: 181-182 ~ (recrystallization from isopropyl alcohol) IR(Nujol) : 3360, 3220, 2660, 2570, 1655cm~' NMR(DMSO-d6, ~) : 1.05(lH, m, piperidine H), 1.16(3H, t, J=7Hz, CH3), 1.75(3H, m, piperidine H), 2.1(lH, m, piperidine H), 2.45(1H, m, piperidine H), 2.7(lH, m, piperidine H), 2.95-3.35(6H, m, NCH2CH3, piperidine H, and CONCH2), 6.79(lH, s, OH), 7.2-7.45(lOH, m, aromatic H), 8.40(1H, t, J=6Hz, NH), 10.2(1H, br, HCl) MASS(m/z) : 352(MI), 337, 183, 105(base) ~lemental analysis: C22H2~N202 HCl Calculated value: C 67.94, H 7.52, N 7.20 Actual value: C 67.76, H 7.68, N 7.15 Example 26 ..
2-llydroxy-N-[2-(1-methylpyrolidine-2-yl)ethyl]-2,2-diphenylacetamide hydrochloride was obtained by reacting 2-(2-aminoethyl)-1-methylpyrrolidine and benzylic acid as raw materi-als, in a similar manner to that o~ Examplc 16 mp: 155-157 ~ (recrystallization from a mixture of ethanol and ethyl acetate) IR(Nujol) : 3400, 3180, 2620, 1660, 770cm~' 21~32~
.
NMR(DMS0-d~ 1.40-1.95(m, 4H), 1.95-2.25(m, 2H), 2.64(s, 3H), 2.75-3.10(m, 2H), 3.10-3.25(m, 2H), 3.35-3.55(m, lH), 6.76(s, lH), 7.20-7.50(m, lOH), 8.38(br s, lH), 10.36(br s, lH) MASS(m/z) : 338(MI), 323, 183, 155, 84 Elemental analysis: C2,H30NzOz HCl Calculated value: C 67.28, H 7.26, N 7.47, Cl 9.46 Actual value: C 67.29, H 7.53, N 7.46, Cl 9.44 Example Z7 N-(1-etho~ycarbonylpiperidine-4-yl)-2,2-diphenylacetamide was obtained by reacting 4-amino-1-etho~ycarbonylpiperidine and benzylic acid as raw materials, in a similar manner to that of Example 16.
mp: 163-165 C (washed with n-hexane) IR(Nujol) : 3300, 1650, 770, 750, 730, 700cm~' NMR(CDcl~, ~) : 1.10-1.35(m, 5H), 1.80-2.00(m, 2H), 2.80-2.95(m, 2H), 3.90-4.15(m, 5H), 4.90(s, lH), 5.52(d, J=7.5Hz, lH), 7.20-7.40(m, lOH) MASS(m/z) : 366(M~), 199 Example 28 N-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)methyl]-3,3-di.phenylpropionamide oxalate was obtained by reacting 4-amino-mcthyl-1-ethyl-1,2,3,6-tetrahydropyridine and diphenylpropion acid as raw materials, in a similar manner to that of E~ample 16.
3 2 ~
p: 133-134 C (recrystallization from a mixture of isopropyl alcohol and diisopropyl ether) IR(Nujol) : 3330, 2600, 1720, 1640, 1600, 750, 710cm~' NMR(DMS0-d~, ~) : 1.18(t, J=7.2Hz, 3H), 1.95(br s, 2H), 2.89(d, J=8.2Hz, 2H), 3.01(q, J=7.2Hz, 2H), 2.95-3.10(m, 2H), 3.39(br s, 2H), 3.54(br s, 2H), 4.47(t, J=8.2Hz, lH), 4.88(s, lH), 7.10-7.30(m, lOH), 8.13(br s, lH) MASS(m/z) : 348(M+), 333, 167, lZ3 Elemental analysis: C2~H2~N20~C2H20~
Calculated value: C 68.47, H 6.90, N 6.39 Actual value: C 68.46, H 6.97, N 6.31 ~xample 29 =- -N-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)methyl~-3,3-diphenyl acrylamide oxalate was obtained by reacting 4-aminometh-yl-1-ethyl-1,2,3,6-tetrahydropyridine and 3,3-diphenylpropene acid as raw materials, in a similar to that of E~ample 16.
mp: 163-164 ~ (recrystallization from a mixture of isopropyl alcohol, ethyl acetate and methanol) IR(Nujol) : 3330, 2720, 1720, 1640, 770, 700cm~' NMR(DMS0-d6, ~) : 1.20(t, J=7.3Hz, 3H), 2.11(br s, 2H~, 3.08(q, J=7.3Hz, 2H), 3.00-3.20(m, 2H), 3.51(br s, 2H) 3.55-3.70(m, 2H), 4.40(br s, 2H), 5.22(s, lH), 6.50(s, lH), 7.10-7.40(m, lOH), 8.15-8.20(m, lH) 2155~2~
MASS(m/z) : 346(M+), 207, 123 Elemental analysis: C2aH26N20-C2H204 Calculated value: C 68.79 , H 6.47, N 6.42 Actual value: C 69.21 , H 6.53, N 6.40 l~xample 30 N-[(l-ethyl-1,2,3,6-te~rahydropyridine-4-yl)methyl]-10,11-dihydro-5-hydroxy-5H-dibenzo[a,d]cycloheptene-5-carbo~amide hydrochloride was obtained by reacting 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine and 5-hydro~y-511-10,11-dihydrobenzo[a,d,]cycloheptene-5-carboxylic acid as raw materi-als, in a similar manner to that of Example 16.
free base: colorless crystals IR(Nujol) : 3460, 3390, Z740, 1640cm~l NMR(DMSO-d6, ~) : 0.98(3H, t, J=7Hz, CH3), 1.86(2H, br s, CH2CHzN), 2.25-2.45(4H, m, CH2CH2NCH2CIls)~
2.75-2.9(4H, m, =CHCH2N and cycloheptene CH2), 3.3-3.45(2H, m, cycloheptene CH2), 3.54(2H, d, J=6Hz, CONCH2), 5.29(lH, s, =CH), 6.81(lH, s, OH), 7.05-7.25(6H, m, aromatic H), 7.46(1H, t, J=6Hz, NH), 7.75-7.85(2H, m, aromatic H) MASS(m/z) :.376(M~), 209, 123(base), 1 io hydrochloride: colorless crystals mp: 158-159.5 ~ (ethyl acetate crystals) _ 3 2 ~
IR(Nujol) : 3420, 3330, 2730-2000, 1655cm~' NMR(DMSO-d6, ~ ) : 1. 23(3H, t, J=7Hz, CH~), 1.95-2. 45(2H, m, CH2CH2N), 2.75-3. 15(5H, m, NCH2CH3, cycloheptene CH2, and pyridine H), 3. 3-3. 45 (4H, m, pyridine Hx 2 and cycloheptene CH2), 3. 35-3. 65(3H, m, CONCH2 and pyridine Hx 2), 5. 30(lH, br s, =CH), 6.89(lH, s, OH), 7. 05-7. 25(6H, m, aromatic H), 7. 75-7. 85(3H, m, NH and aromatic Hx 2), 10. 5(lH, br, HCl) MASS(m/z) : 376(M+), 209 (base), 123, 110 Elemental analysis: C2~H29N202C1-3/2H20 Calculated value: C 65. 52, H 7. 27, N 6. 37, Cl 8. 06 Actual value: C 65. 68, H 7.27, N 6. 38, Cl 8. 06 E~ample 31 A solution of 2,2-diphenyl propionic acid (0.70 g) i.n thionyl chloride (2.3 ml) was refluxed for 2 hours and evapo-rated in vacuo. Toluene (10 ml) was added to the residue and evaporated in vacuo. To a solution of the residue in dry dichlo-romethane (10 ml) was added drop~ise a mixture of 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine (0.43 g) and triethylamine (1.5 ml) in dry dichloromehthane (10 ml) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. Dichloromethane and water were added to the 21s~32a .
reaction mixture, and then the organic layer was separated, washed successively with water three times. lN aqueous sodium hydroxide solution, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chloma-tography on silica gcl with a mixture of dichloromethane and methanol (20:1) as an eluent, treated with 4N hydrogen chloride ln ethyl acetate, recrystallized from isopropyl alcohol and isopropyl ether to give N-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)m~hyl]-2,2-diphenyl propionamide hydrochloride.
mp: 93-94 C
IR(Nujol) : 3450, 3350, 2670, 2600, 1630, 760, 740cm~' NMR(DMS0-~6, ~) : 1.24(t,J=7.2Hz, 3H), 1.89(s, 3H), 2.0~-3.70(m, 8H), 3.06(q, J=7.2Hz, 2H), 5.31(br s, lH) 7.10-7.40(m, lOH), 7.64(br s, lH), 10.08(br s, lH) Elemental analysis: C2~H2~N20 HCl Calculated value: C 68.56, H 7.75, N 6.95, Cl 8.80 Actual value: C 68.82, H 7.95, N 6.89, Cl 8.95 E~ample 32 N-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)methyl~-2,2,-dipl~cnyl acetamidc hydrochloride was obtained by reacting 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine and 2,2-diphenyl acetyl chloride as raw materials, in a similar manner to that of Example 31.
mp: 205-207 ~ (recrystallization from a mixture of ethanol and diisopropyl ether) 215~32~
.
IR(Nujol) : 3270, 3070, 2670, 2550, 2470, 1640, 750, 700cm~' NMR(DMS0-dG, ~) : 1.23(t, J=7.2Hz, 3H), 2.00-2.40(m, 2H), 2.80-3.00(m, 4H), 3.04(q, J=7.2Hz, 2H), 3.60-3.80(m, 2H), 5.06(s, lH), 5.39(s, lH), 7.10-7.35(m, lOH), 8.67(t, J=5.7Hz, lH), 10.43(br s, 111) MASS(m/z) : 334(MI), 167, 123 Elemental analysis: C22H26N20 HCl Calculated value: C 71.24, H 7.34, N 7.55, Cl 9.56 Actual value: C 71.30, H 7.62, N 7.52, Cl 9.73 Example 33 A mi~ture of 2-chloro-2,2-diphenyl acetyl chloride (0.80 g) and 4-diethylaminomethylpiperidine (0.51 g) were stirred for a while at room temperature and diluted with methylene chlo-ridc (10 ml). The resulting mixture was stirred for 1 hour at the same temperature, and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with sodium hydroxide aqueous solution and water, dried over magnesium sulfate, and ~vaporated in vacuo. The residue was dissolved in dio~ane (7.4 ml) and lN hydrochloric acid (3.7 ml). The solution was fitirred at 90C for 1 hour and 30 minutes, evaporated in vacuo, and e~tracted with ethyl acetate. The e~tract was washed with sodium hydro~ide aqueous solution and water, dried over magnesium sulfate, evaporated in vacuo, and chromatographed over silica gel 21~532~
u~ing chlorororm an~ methanol as an eluent to arford 1-(2,2-(liphenyl-2-hydro~yacetyl)-4-diethylaminomethylpiperidine (0.33 g) as an oil, which was con~erted to the hydrochloride (0.20 g) in a usual manner.
free base:
NMR(CDC13, ~) : 0.93(6H, t, J=7Hz, CH~x 2), 0,95-1.95(5H, m, piperidine CH2CHCH2), 2.06(2H, d, J=6.5Hz, CHCH2N), 2.43(4H, quartet, J=7Hz, N(CH2CH3)z), 2.68(2H, m, CONCH x 2), 3.59(lH, m, CONCH), 4.74(lH, m, CONCH), 6.22(lH, s, OH), 7.4(10H, m, aromatic H) MASS(m/z) : 380(M~), 183, 86(base) hydrochloride:
mp: 175-176 C (recrYstallization from isopropyl alcohol) IR(Nujol) : 3400, 3160, 2760-2300, 1610cm~' NMR(DMSO-d6, ~) : 0.7(1H, m, piperidine CH), 1.05(1H, m, piperidine CH), 1.18(6H, t, J=7Hz, CH~x 2) 1.45(1H, m, piperidine CH), 1.9(2H, m, piperidine CH), 2.65(2H, m, CONCH x 2), 2.8(2H, m, CHCH2N), 3.05(4H, m, N(CH2CH3)2), 4.15(1H, m, CONCH), 4.4(lH, m, CONCH), 6.92(lH, s, OH), 7.3(lOH, m, aromatic H), 9.9(lH, br, HCl) MASS(m/z) : 380(M~), 183, 86(base) 21~32~
Elemental analysis: C2~ 2N202 HCl l/2H20 Calculated value: C 67.67, H 8.04, N 6.58, Cl 8.32 Actual value: C 67.62, H 8.08, N 6.51, Cl 8.32 ~ample 34 A solution of 4-bromo-2,2-diphenylbutanoic acid and thionyl chloride (1.37 g) in dry chloroform (20 ml) was refluxed for 4 hours and evaporated in vacuo to afford the corresponding acid chloride.
To a mixture of 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydro-pyridine (0.73 g) and triethylamine (2.6 ml) in di-chloromethane (15 ml) was added the obtained crude acid chloride in dichloromethane (15 ml) at room temperature and the resulting mixture was stirred overnight. The solvent was evaporated in vacuo, and ethyl acetate and lN aqueous sodium hydro~ide were added to the residue. The organic layer was separated, washed with water (three times) and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chlomatography on silica gel with a mi~ture Or dichloromethane and methanol (15:1) as an eluent, further on alumina with a mi~ture of n-he~ane and ethylacetate (20:1) as an eluent. The obtained free base was treated with fumaric acid (229 mg) in a usual manner to give 1-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)methyl]-3,3-diphenyl-2-pyrrolidinone fumarate (0.54 g).
2153 ~2 ~
.
mp: 90C ~ (resolution) (washed with n-hexane) IR(Nujol) : 2500, 1680, 800, 770, 750, 700cm~' NMR(DMSOd6, ~) : l.ll(t, J=7.2Hz, 3H), 2.17(br s, 2H), 2.73(q, J=7.2Hz, 2H), 2.80-2.90(m, 4H), 3.24(br s, 2H) 3.86(s, 2H), 4.11(t, J=6.4Hz, 2H), 5.53(s, lH), 6.52(s, 2H), 7.10-7.40(m, lOH) MASS(m/z) : 360(Ml), 238, 165, 123
mp: 197-199 ~ (recrystallization from isopropyl alcohol) IR(Nujol) : 3420, 2350, 1670, 750, 700, 670cm~' NMR(DMSO-d6, ~) : 1.05(t, J=7.2Hz, 3H), 1.45-1.65(m, 4H), 2.15-2.40(m, 2H), 2.54(q, J=7.2Hz, 2H), Z.85-3.05(m, 2H), 3.55-3.75(m, lH), 6.50(s, lH), 7.20-7.40(m, llH), 7.96(d, J=8.OHz, lH) Elemental analysis: C2,Hz6N20 1/2C~H~04 1/2}{zO
Calculated value: C 68.13, H 7.21, N 6.91 Actual value: C 67.97. H 7.41, N 6.67 Example 14 N-(1-isopropylpiperidine-4-yl)-2,2-diphenylacetamide rumarate was obta~ned by reacting N-(piperidine-4-yl)-2,2-diphe-nyl-acetamide hydrochloride as a raw material, in a similar manner to that of E~ample 12.
mp: 175-177 ~ (washed with acetone) IR(Nujol) : 3200, 2650, 2500, 1660, 790, 770, 740, 700cm~' NMR(DMSO-d6. ~) : 1.13(d, J=6.6Hz. 6H), 1.45-1.75(m, 2H), ~ 21~5320 1.75-2.00(m, 2H), 2.65-2.90(m. 2H), 3.00-3.25(m, 3H), 3.65-3.90(m, lH), 4.93(s, lH), 6.54(s, 3H), 7.10-7.35(m, lOH), 8.43(d, J=7.3Hz, lH) MASS(m/z) : 336(M+), 321, 167 Elemental analysis: C22H2~N20-3/2(CqH~0~) Calculated value: C 65.87, H 6.71, N 5.49 Actual value: C 65.60, H 6.84, N 5.57 E~ample 15 N~ ethylpiperidine-4-yl)-2,2-diphenylacetamide fumarate was obtained by reacting N-(piperidine-4-yl)-2,2-diphenylaceta-mide hydrochloride as a raw material, in a similar manner to that o Examle 12.
mp: 179-181 ~ (washed with acetone) IR(Nujol) : 3250, 1690, 1760, 790, 760, 740cm~' NMR(DMS0-d6, ~) : 1 05(t, J=7.2Hz, 3H), 1.30-1.60(m, 2H), 1.70-1.85(m, 2H), 2.25-2.40(m, 2H), 2.55(q, J=7.2Hz, 2H), 2.90-3.10(m, 2H), 3.40-3.55(m, lH), 4.91(s, lH), 6.55(s, 2H), 7.20-7.30(m, lOH), 8.34(d, J=7.4Hz, lH) MASS(m/z) : 322(M+), 307, 167, 111 Elemental analysis: C2,H26N20 C~H~0~ 1/2HzO
Calculated value: C 67.10, H 6.98, N 6.26 Actual value: C 66.78, H 6.97, N 6.05 215~32~
, ,.
Examplc 16 A mi~ture of benzylic acid (2.21 g) and 1,1'-carbonyl-diimidazole (1.73 g) in dry dichloromethane (45 ml) was stirred ror 2.5 hours at room temperature. Then 4-aminomethyl-1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridine (2.25 g) in dry dichlo-romethane (20 ml) was added dropwise over 20 minutes. The mi~ture was stirred for 45 minutes at room temperature and evaporated.
Ethyl acetate and lN sodium hydro~ide were added to the residue.
The organic layer was separated, washed twice with water, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel with a mi~ture of dichlo-romethane and methanol (10:1) as an eluent to give N-[[1-(4-metho~ybenzyl)-1,2,3,6-tetrahydropyridine-4-yl]methyl]-2,2-diphenyl-2-hydro~yacetamide (3.47 g) as a pale yellow oil.
IR(CHCl~) : 3370, 1660, 1610, 750, 730, 700cm~' NMR(CDCl~, ~) : 2.02(br s, 2H), 2.52(t, J=5.8Hz, 2H), 2.91(br s, 21{), 3.50(s, 2H), 3.80(s, 3H), 4.10(br s, lH), 4.14(s, 2H), 5.39(br s, lH), 6.39(br s, lH), 6.85(d, J=12.7Hz, 2H), 7.20-7.50(m, 12H) MASS(m/z) : 442(M+), 202, 121 E~ample 17 N-[(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)methyl]-2,2-diphenyl-2-hydro~yacetamide o~alate was obtained by reacting benzylic acid and 1-methyl-4-aminomethYl-1,2,3,6-tetrahydropyri-21~2~
dine as raw materials, in a similar manner to that of E~ample 16.
mp: 185-190 ~
IR(Nujol) : 1650, 1600, 770, 750, 730, 700cm~' NMR(DMSO~da, ~) : 2.09(br s, 2}1), 2.50(s, 3}1), 2.81(t, J=5.9Hz, 21{), 3.19(br s, 2H), 3.68(d, J=6.OHz, 2H), 4.98(br, 2H), 5.37(s, lH), 7.20-7.45(m, llH), 8.26(t, J=6.OHz, lH) MASS(m/z) : 336(M+), 215, 183, 109 E~ample 18 2-Hydro~y-2,2-diphenyl-N-l(1-propyl-1,2,3,6-tetrahydrop-yridine-4-yl)methyl]acetamide hydrochloride was obtained by reacting benzylic acid and 1-propyl-4-aminomethyl-1,2,3,6-tet-rahydropyridine as raw materials, in a similar manner to that of Example 16.
mp: 96-98 ~ (recrystallization from a mixture of ethyl acetate-methanol-diisoPropyl ether) IR(Nujol) : 3250, 1660, 770, 740, 700cm~' NMR(DMSO-d6, ~) : 0.89(t, J=7.3Hz, 3H), 1.60-1.80(m, 2H), 2.00-2.55(m, 2H), 2.90-4.20(m, 8H), 5.89(br s, lH), 6.82(s, lH), 7.20-7.45(m, lOH), 8.37(t, J=6.lHz, lH), 10.50(br s, lH) MASS(m/z) : 364(M~), 335, 183, 137 Elemental analysis: C28H28N202 HCl Calculated value: C 66.80, H 7.41, N 6.77, Cl 8.57 21~2~
.
Actual value: C 66.77, H 7.76, N 6.44, Cl 8.57 I~ample l9 - ~~
N-[(l-benzyl-1,2,3,6-tetrahYdropyridine-4-yl)methyl]-2-hydroxy-2,2,-diphenylacetamide hydrochloride was obtained by reacting benzylic acid and l-benzyl-4-aminomethyl-l,2,3,6-tet-rahydropyridine as raw materials, in a similar manner to that of Example 16.
mp:139-141 C (recrystallization from a mixture of methanol-ethyl acetate-diisopropyl ether) IR(Nujol) :3450, 3200, 2570, 1660, 750, 710, 680cm~' NMR(DMSO-d6,~) :2.00-2.50(m, 2H), 2.70-3.50(m, 2H), 3.50(br s, 2H), 3.72(d, J=6.OHz, 2H), 4.30(s, 2H), 5.38(s, lH), 6.81(s, lH), 7.25-7.63(m, 15H), 8.36(t, J=6.OHz, lH), 10.92(br s, lH) Elemental analysis: C27Hz8N202 HCl Calculated value: (as 0.8 H20 ) C 69.98, ~ 6.66, N 6.05, Cl 7.65 Actual value: C 69.94, H 6.67, N 5.94, C1 7.63 E~ample 20 N-[(1-ethyl-l,2,3,6,-tetrahydropyridine-3-yl)methyl]-2,2-diphenyl-2-hydro~yacetamide l/2 ~umarate was obtained by reacting benzylic acid and l-ethyl-3-aminomethYl-l,2,3,6-tetrahydropyri-dine as raw materials, in a similar manner to that of Example 16.
mp:185-186 ~ (recrystallization from isopropyl alcohol) 2~5~3~a .
IR(Nujol) : 3400, 2750-2600, 1675, 1590cm~' NMR(DMSO-d6, ~) : 1.02(3H, t, J=7Hz, CH~), 2.09(2H, m, =CHCHzCHz), 2.45-2.65(4H, m, NCHz x 2), 2.92(2H, s, =CCHzN), 3.68(2H, m, CONCHz), 5.52(1H, br s, =CH), 6.51(2H, s, fumaric acid=CH), 7.25-7.4(10H, m, aromatic H), 8.21(lH, br s, CONH) MASS(m/z) : 350(M~), 183, 124(base), 105 Elemental analysis: C2 zH26N202 1/2C~H~O~
Calculated value: C 70.57, H 6.91, N 6.86 Actual value: C 70.36, H 7.11, N 6.72 Example 21 To a mi~ture of 4,4'-difluorobenzophenone (2.0 g) and zinc iodide (0.1 g) in dry dichloromethane (15 ml) was added trimethylsilyl cyanide (1.35 ml) at room temperature. The result-ing mi~ture was stirred for 40 hours at the same temperature, and then the solvent was evaporated in vacuo. Concentrated hydro-chloric acid (30 ml) was added to the residue and the mi~ture was stirred at 90C for 14 hours. The mi~ture was partitioned between ethylacetate and water. The organic layer was separated and evaporated in vacuo. The residue was partitioned between diiso-propylether and lN aqueous sodium hydro~ide. The organic layer was washed with lN aqueous sodium hydro~ide three times. The combined aqueous layers were acidified with concentrated hydrochloric acld and extracted with ethyl acetate twice.
215532~
The combined organic layers were washed with ~ater and brine, dried over magnesium sulfate and evaporated in vacuo to give crude 4,4'-dirluorobenzilic acid (0.80 g). To a solution of this crude 4,4'-difluorobenzilic acid (0.80 g) and N,N'-carbonyl-diimidazole (0.60 g) in dry dichloromethane was added dropwise a solution of 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine (0.60 g) in dichloromethane at room temperature.
The resulting mi~ture was stirred at room temperature, cvaporated in vacuo. The residue was partitioned between ethylac-etate and lN aqueous sodium hydro~ide. The combined organic layers were washed with water and brine, dried over magnesium sulrate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel and then on alumina and treated with 4N hydrogenchloride in ethylacetate to give 2,2-bis(4-~luorophenyl)-2-hydro~y-N-[(1-ethyl-1,2,3,6-tetrahydropyri-dine-4-yl)methyl]acetamide hydrochloride.
mp: 155-157 ~ (washed with diisopropyl ether) IR(Nujol) : 3350, 3270, 2500, 1660, 1600, 820, 770cm~' NMR(DMS0-d~, ~) : 1.24(t, J=7.2Hz, 3H), 2.00-2.45(m, 2H), 2.85-3.80(m, 6H), 3.09(quartet, J=7.2Hz, 2H), 5.39(s, lH), 6.96(s, lH), 7.10-7.20(m, 4H), 7.35-7.45(m, 4H), 8.46(br s, lH), 10.21(br s, lH) MASS(m/z) : 386(M~), 371, 219, 123, 110 Elemental analysis: C2 zH2~NzOzF2 HCl 1/3HzO
Calculated value: C 61.61, H 6.03, N 6.53, Cl 8.27 Actual value: C 61.69, H 6.09, N 6.54, Cl 8.27 2~ ~32~
.
I~'xample 22 A solution of 3-amino-1-azabicyclo[2,2,2]octane in ben-%ene (12 ml) was added dropwise to a stirred solution of 2-chloro-2,2-diphenylacetyl-chloride (6.30 g) in benzene (17 ml)-n-he~ane (11 ml) at room temperature. The resulting mixture was stirred for 3 hours and 30 minutes at room tempera-ture and partitioned between toluene and water. The organic layer was e~tracted twice with lN hydrochloric acid and the aqueous layers were combined, washed with diethyl ether, stirred at 70c for 1 hour, cooled with ice water, basified with 5 % sodium hydroxide aqueous solution, and e~tracted twice with ethyl ace-tate. The ethyl acetate layers were combined, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was washed with diisopropyl ether to afford a colorless powder (2.90 g), which was converted to the hydrochloride in a usual manner. The hydrochloride was recrystallized from ethanol to afford N-(1-azabicyclo[2,2,2,]octan-3-yl)-2,2-diphenyl-2-hydro~-yacetamide hydrochloride as a colorless powder.
mp:261-265 ~ (dec.) IR(Nujol) :3300, 2800-2300, 1660cm~' Il NMR(DMSO-d6,~) :1.6-2.1(5H, m, ~ H ), 3.05-3.6(6H, m, N(CH2)~), 4.15(lH, m, CONHCE), 6.87(1H, S, OH), 7.25-7.45(10H, m, aromatic H), 2I ~532~
.
8.59(1H, d, J=7Hz, CONH), 10.36(1H, br s, HCl) MASS(m/z) :336(M+), 183(base), 105 Elemental analysis: C2,Hz4N20z HCl Calculated value: C 67.64, H 6.76, N 7.51 Actual value: C 67.67, H 7.10, N 7.31 Example 23 N~ etho~yearbonylpiperidine-4-yl)-2-hydroxy-2~2-diphe-nyl acetamide was obtained by reaeting 4-amino-l-etho~yearbonyl-piperidine and benzylic acid as raw materials, in a similar manner to that of Example 16.
mp:128-131 ~ (washed with n-hexane) IR(Nujol) :3300, 1650, 1620, 760, 740, 720cm~' NMR(CDC1~,~) :1.00-1.41(m, 2H), 1.23(t, J=7.lHz, 3H), 1.70-2.00(m, 2H), 2.75-3.00(m, 2H), 3.90-4.20(m, 3H), 4.08(q, J=7.lHz, 2H), 6.67(d, J=8.OHz, lH), 6.93(s, lH), 7.20-7.50(m, lOH) MASS(m/z) :382(M~), 370, 216, 183 Example 24 - ~
2,2-Diphenyl.2-hydroxy-N-[2-(l-methylpiperidine-4-yl)-ethyl]acetamide fumarate was obtained by reacting 4-(2-aminoeth-yl)-l-methylpiperidine and benzylic aeid as raw materials, in a similar manner to that of E~ample 16. The residue was chromato-graphed over siliea gel using ehloroform - methanol as an eluent to afrord white powder.
~l~S320 .
mp: 151-152 ~
IR(Nujol) : 3360, 3250, 3200, 2740-2100, 1700, 1670cm~' NMR(DMSO-d6, ~) : 1.15-1.45(5H, m, CH and CHz x 2), 1.7(2H, m, CH2), 2.35(2H, m, CH2), 2.45(3H, s, CH9), 3.0-3.2(4H, m, CH2x 2), 6.50(2H, s, HC=CH), 7.2-7.4(llH, m, aromatic H and OH), 8.15(1H, t, J=6Hz, NH) MASS(m/z) : 352(M~), 337, 183(base) Elemental analysis: C22H2#N20z C~H40~
Calculated value: C 66.65, H 6.88, N 5.98 Actual value: C 67.02, H 7.05, N 5.94 Example 25 N-[(1-ethylpiperidine-3-yl)methyl]-2,2-diphenyl-2-hydroxyacetamide hydrochloride as a colorless crystallization was obtained by reacting 3-aminomcthyl-1-ethylpiperidine and benzylic acid as raw materials, in a similar manner to that of E~ample 16.
free base:
IR(Nujol) : 3310, 2800-2300, 1660cm~' NMR(CDC13, ~) : 0.95(1H, m, piperidine H), 1.00(3H, t, J=7Hz, CH9), 1.5-1.95(6H, m, piperidine H) 2.30(2H, quartet, J=7Hz, NCHzCH3), 2.7(2H, m, piperidine H), 3.1-3.35(2H, m, CONCH2), 4.15(1H, br, OH), 6.86(1H, br t, NH), 7.25-7.53(1OH, m, aromatic H) 21~32~
MASS(m/z) : 352(M+), 337, 183, 105(base) hydrochloride:
mp: 181-182 ~ (recrystallization from isopropyl alcohol) IR(Nujol) : 3360, 3220, 2660, 2570, 1655cm~' NMR(DMSO-d6, ~) : 1.05(lH, m, piperidine H), 1.16(3H, t, J=7Hz, CH3), 1.75(3H, m, piperidine H), 2.1(lH, m, piperidine H), 2.45(1H, m, piperidine H), 2.7(lH, m, piperidine H), 2.95-3.35(6H, m, NCH2CH3, piperidine H, and CONCH2), 6.79(lH, s, OH), 7.2-7.45(lOH, m, aromatic H), 8.40(1H, t, J=6Hz, NH), 10.2(1H, br, HCl) MASS(m/z) : 352(MI), 337, 183, 105(base) ~lemental analysis: C22H2~N202 HCl Calculated value: C 67.94, H 7.52, N 7.20 Actual value: C 67.76, H 7.68, N 7.15 Example 26 ..
2-llydroxy-N-[2-(1-methylpyrolidine-2-yl)ethyl]-2,2-diphenylacetamide hydrochloride was obtained by reacting 2-(2-aminoethyl)-1-methylpyrrolidine and benzylic acid as raw materi-als, in a similar manner to that o~ Examplc 16 mp: 155-157 ~ (recrystallization from a mixture of ethanol and ethyl acetate) IR(Nujol) : 3400, 3180, 2620, 1660, 770cm~' 21~32~
.
NMR(DMS0-d~ 1.40-1.95(m, 4H), 1.95-2.25(m, 2H), 2.64(s, 3H), 2.75-3.10(m, 2H), 3.10-3.25(m, 2H), 3.35-3.55(m, lH), 6.76(s, lH), 7.20-7.50(m, lOH), 8.38(br s, lH), 10.36(br s, lH) MASS(m/z) : 338(MI), 323, 183, 155, 84 Elemental analysis: C2,H30NzOz HCl Calculated value: C 67.28, H 7.26, N 7.47, Cl 9.46 Actual value: C 67.29, H 7.53, N 7.46, Cl 9.44 Example Z7 N-(1-etho~ycarbonylpiperidine-4-yl)-2,2-diphenylacetamide was obtained by reacting 4-amino-1-etho~ycarbonylpiperidine and benzylic acid as raw materials, in a similar manner to that of Example 16.
mp: 163-165 C (washed with n-hexane) IR(Nujol) : 3300, 1650, 770, 750, 730, 700cm~' NMR(CDcl~, ~) : 1.10-1.35(m, 5H), 1.80-2.00(m, 2H), 2.80-2.95(m, 2H), 3.90-4.15(m, 5H), 4.90(s, lH), 5.52(d, J=7.5Hz, lH), 7.20-7.40(m, lOH) MASS(m/z) : 366(M~), 199 Example 28 N-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)methyl]-3,3-di.phenylpropionamide oxalate was obtained by reacting 4-amino-mcthyl-1-ethyl-1,2,3,6-tetrahydropyridine and diphenylpropion acid as raw materials, in a similar manner to that of E~ample 16.
3 2 ~
p: 133-134 C (recrystallization from a mixture of isopropyl alcohol and diisopropyl ether) IR(Nujol) : 3330, 2600, 1720, 1640, 1600, 750, 710cm~' NMR(DMS0-d~, ~) : 1.18(t, J=7.2Hz, 3H), 1.95(br s, 2H), 2.89(d, J=8.2Hz, 2H), 3.01(q, J=7.2Hz, 2H), 2.95-3.10(m, 2H), 3.39(br s, 2H), 3.54(br s, 2H), 4.47(t, J=8.2Hz, lH), 4.88(s, lH), 7.10-7.30(m, lOH), 8.13(br s, lH) MASS(m/z) : 348(M+), 333, 167, lZ3 Elemental analysis: C2~H2~N20~C2H20~
Calculated value: C 68.47, H 6.90, N 6.39 Actual value: C 68.46, H 6.97, N 6.31 ~xample 29 =- -N-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)methyl~-3,3-diphenyl acrylamide oxalate was obtained by reacting 4-aminometh-yl-1-ethyl-1,2,3,6-tetrahydropyridine and 3,3-diphenylpropene acid as raw materials, in a similar to that of E~ample 16.
mp: 163-164 ~ (recrystallization from a mixture of isopropyl alcohol, ethyl acetate and methanol) IR(Nujol) : 3330, 2720, 1720, 1640, 770, 700cm~' NMR(DMS0-d6, ~) : 1.20(t, J=7.3Hz, 3H), 2.11(br s, 2H~, 3.08(q, J=7.3Hz, 2H), 3.00-3.20(m, 2H), 3.51(br s, 2H) 3.55-3.70(m, 2H), 4.40(br s, 2H), 5.22(s, lH), 6.50(s, lH), 7.10-7.40(m, lOH), 8.15-8.20(m, lH) 2155~2~
MASS(m/z) : 346(M+), 207, 123 Elemental analysis: C2aH26N20-C2H204 Calculated value: C 68.79 , H 6.47, N 6.42 Actual value: C 69.21 , H 6.53, N 6.40 l~xample 30 N-[(l-ethyl-1,2,3,6-te~rahydropyridine-4-yl)methyl]-10,11-dihydro-5-hydroxy-5H-dibenzo[a,d]cycloheptene-5-carbo~amide hydrochloride was obtained by reacting 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine and 5-hydro~y-511-10,11-dihydrobenzo[a,d,]cycloheptene-5-carboxylic acid as raw materi-als, in a similar manner to that of Example 16.
free base: colorless crystals IR(Nujol) : 3460, 3390, Z740, 1640cm~l NMR(DMSO-d6, ~) : 0.98(3H, t, J=7Hz, CH3), 1.86(2H, br s, CH2CHzN), 2.25-2.45(4H, m, CH2CH2NCH2CIls)~
2.75-2.9(4H, m, =CHCH2N and cycloheptene CH2), 3.3-3.45(2H, m, cycloheptene CH2), 3.54(2H, d, J=6Hz, CONCH2), 5.29(lH, s, =CH), 6.81(lH, s, OH), 7.05-7.25(6H, m, aromatic H), 7.46(1H, t, J=6Hz, NH), 7.75-7.85(2H, m, aromatic H) MASS(m/z) :.376(M~), 209, 123(base), 1 io hydrochloride: colorless crystals mp: 158-159.5 ~ (ethyl acetate crystals) _ 3 2 ~
IR(Nujol) : 3420, 3330, 2730-2000, 1655cm~' NMR(DMSO-d6, ~ ) : 1. 23(3H, t, J=7Hz, CH~), 1.95-2. 45(2H, m, CH2CH2N), 2.75-3. 15(5H, m, NCH2CH3, cycloheptene CH2, and pyridine H), 3. 3-3. 45 (4H, m, pyridine Hx 2 and cycloheptene CH2), 3. 35-3. 65(3H, m, CONCH2 and pyridine Hx 2), 5. 30(lH, br s, =CH), 6.89(lH, s, OH), 7. 05-7. 25(6H, m, aromatic H), 7. 75-7. 85(3H, m, NH and aromatic Hx 2), 10. 5(lH, br, HCl) MASS(m/z) : 376(M+), 209 (base), 123, 110 Elemental analysis: C2~H29N202C1-3/2H20 Calculated value: C 65. 52, H 7. 27, N 6. 37, Cl 8. 06 Actual value: C 65. 68, H 7.27, N 6. 38, Cl 8. 06 E~ample 31 A solution of 2,2-diphenyl propionic acid (0.70 g) i.n thionyl chloride (2.3 ml) was refluxed for 2 hours and evapo-rated in vacuo. Toluene (10 ml) was added to the residue and evaporated in vacuo. To a solution of the residue in dry dichlo-romethane (10 ml) was added drop~ise a mixture of 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine (0.43 g) and triethylamine (1.5 ml) in dry dichloromehthane (10 ml) at room temperature. The resulting mixture was stirred for 3 hours at room temperature. Dichloromethane and water were added to the 21s~32a .
reaction mixture, and then the organic layer was separated, washed successively with water three times. lN aqueous sodium hydroxide solution, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chloma-tography on silica gcl with a mixture of dichloromethane and methanol (20:1) as an eluent, treated with 4N hydrogen chloride ln ethyl acetate, recrystallized from isopropyl alcohol and isopropyl ether to give N-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)m~hyl]-2,2-diphenyl propionamide hydrochloride.
mp: 93-94 C
IR(Nujol) : 3450, 3350, 2670, 2600, 1630, 760, 740cm~' NMR(DMS0-~6, ~) : 1.24(t,J=7.2Hz, 3H), 1.89(s, 3H), 2.0~-3.70(m, 8H), 3.06(q, J=7.2Hz, 2H), 5.31(br s, lH) 7.10-7.40(m, lOH), 7.64(br s, lH), 10.08(br s, lH) Elemental analysis: C2~H2~N20 HCl Calculated value: C 68.56, H 7.75, N 6.95, Cl 8.80 Actual value: C 68.82, H 7.95, N 6.89, Cl 8.95 E~ample 32 N-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)methyl~-2,2,-dipl~cnyl acetamidc hydrochloride was obtained by reacting 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine and 2,2-diphenyl acetyl chloride as raw materials, in a similar manner to that of Example 31.
mp: 205-207 ~ (recrystallization from a mixture of ethanol and diisopropyl ether) 215~32~
.
IR(Nujol) : 3270, 3070, 2670, 2550, 2470, 1640, 750, 700cm~' NMR(DMS0-dG, ~) : 1.23(t, J=7.2Hz, 3H), 2.00-2.40(m, 2H), 2.80-3.00(m, 4H), 3.04(q, J=7.2Hz, 2H), 3.60-3.80(m, 2H), 5.06(s, lH), 5.39(s, lH), 7.10-7.35(m, lOH), 8.67(t, J=5.7Hz, lH), 10.43(br s, 111) MASS(m/z) : 334(MI), 167, 123 Elemental analysis: C22H26N20 HCl Calculated value: C 71.24, H 7.34, N 7.55, Cl 9.56 Actual value: C 71.30, H 7.62, N 7.52, Cl 9.73 Example 33 A mi~ture of 2-chloro-2,2-diphenyl acetyl chloride (0.80 g) and 4-diethylaminomethylpiperidine (0.51 g) were stirred for a while at room temperature and diluted with methylene chlo-ridc (10 ml). The resulting mixture was stirred for 1 hour at the same temperature, and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with sodium hydroxide aqueous solution and water, dried over magnesium sulfate, and ~vaporated in vacuo. The residue was dissolved in dio~ane (7.4 ml) and lN hydrochloric acid (3.7 ml). The solution was fitirred at 90C for 1 hour and 30 minutes, evaporated in vacuo, and e~tracted with ethyl acetate. The e~tract was washed with sodium hydro~ide aqueous solution and water, dried over magnesium sulfate, evaporated in vacuo, and chromatographed over silica gel 21~532~
u~ing chlorororm an~ methanol as an eluent to arford 1-(2,2-(liphenyl-2-hydro~yacetyl)-4-diethylaminomethylpiperidine (0.33 g) as an oil, which was con~erted to the hydrochloride (0.20 g) in a usual manner.
free base:
NMR(CDC13, ~) : 0.93(6H, t, J=7Hz, CH~x 2), 0,95-1.95(5H, m, piperidine CH2CHCH2), 2.06(2H, d, J=6.5Hz, CHCH2N), 2.43(4H, quartet, J=7Hz, N(CH2CH3)z), 2.68(2H, m, CONCH x 2), 3.59(lH, m, CONCH), 4.74(lH, m, CONCH), 6.22(lH, s, OH), 7.4(10H, m, aromatic H) MASS(m/z) : 380(M~), 183, 86(base) hydrochloride:
mp: 175-176 C (recrYstallization from isopropyl alcohol) IR(Nujol) : 3400, 3160, 2760-2300, 1610cm~' NMR(DMSO-d6, ~) : 0.7(1H, m, piperidine CH), 1.05(1H, m, piperidine CH), 1.18(6H, t, J=7Hz, CH~x 2) 1.45(1H, m, piperidine CH), 1.9(2H, m, piperidine CH), 2.65(2H, m, CONCH x 2), 2.8(2H, m, CHCH2N), 3.05(4H, m, N(CH2CH3)2), 4.15(1H, m, CONCH), 4.4(lH, m, CONCH), 6.92(lH, s, OH), 7.3(lOH, m, aromatic H), 9.9(lH, br, HCl) MASS(m/z) : 380(M~), 183, 86(base) 21~32~
Elemental analysis: C2~ 2N202 HCl l/2H20 Calculated value: C 67.67, H 8.04, N 6.58, Cl 8.32 Actual value: C 67.62, H 8.08, N 6.51, Cl 8.32 ~ample 34 A solution of 4-bromo-2,2-diphenylbutanoic acid and thionyl chloride (1.37 g) in dry chloroform (20 ml) was refluxed for 4 hours and evaporated in vacuo to afford the corresponding acid chloride.
To a mixture of 4-aminomethyl-1-ethyl-1,2,3,6-tetrahydro-pyridine (0.73 g) and triethylamine (2.6 ml) in di-chloromethane (15 ml) was added the obtained crude acid chloride in dichloromethane (15 ml) at room temperature and the resulting mixture was stirred overnight. The solvent was evaporated in vacuo, and ethyl acetate and lN aqueous sodium hydro~ide were added to the residue. The organic layer was separated, washed with water (three times) and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chlomatography on silica gel with a mi~ture Or dichloromethane and methanol (15:1) as an eluent, further on alumina with a mi~ture of n-he~ane and ethylacetate (20:1) as an eluent. The obtained free base was treated with fumaric acid (229 mg) in a usual manner to give 1-[(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)methyl]-3,3-diphenyl-2-pyrrolidinone fumarate (0.54 g).
2153 ~2 ~
.
mp: 90C ~ (resolution) (washed with n-hexane) IR(Nujol) : 2500, 1680, 800, 770, 750, 700cm~' NMR(DMSOd6, ~) : l.ll(t, J=7.2Hz, 3H), 2.17(br s, 2H), 2.73(q, J=7.2Hz, 2H), 2.80-2.90(m, 4H), 3.24(br s, 2H) 3.86(s, 2H), 4.11(t, J=6.4Hz, 2H), 5.53(s, lH), 6.52(s, 2H), 7.10-7.40(m, lOH) MASS(m/z) : 360(Ml), 238, 165, 123
Claims (2)
1. Substituted acetamide compound and a pharmaceutically acceptable salt thereof wherein the general formula is represent-ed by the following formula (I):
(I) wherein R1 and R2 are each aryl which may have suitable sub-stituent, R3 is hydrogen, hydroxy or lower alkyl, R4 is a group represented by the following formula (i), (ii), (iii) and (iv):
(i) wherein R5 is hydrogen, methyl, ethyl, propyl, isopropyl or imino protective group, (ii) wherein R6 is lower alkyl, (iii) (iv) wherein R7 is hydrogen, lower alkyl or imino protective group, A1 and A2 are each lower alkylene, and m and n are each 0 or 1, provided that (a) R5 is not ethyl when R1 and R2 are both phenyl, R3 is hydroxy, A2 is methylene, m is 0 and n is 1, (b) R7 is not methyl when R1 and R2 are both phenyl, and m and n are both 0.
(I) wherein R1 and R2 are each aryl which may have suitable sub-stituent, R3 is hydrogen, hydroxy or lower alkyl, R4 is a group represented by the following formula (i), (ii), (iii) and (iv):
(i) wherein R5 is hydrogen, methyl, ethyl, propyl, isopropyl or imino protective group, (ii) wherein R6 is lower alkyl, (iii) (iv) wherein R7 is hydrogen, lower alkyl or imino protective group, A1 and A2 are each lower alkylene, and m and n are each 0 or 1, provided that (a) R5 is not ethyl when R1 and R2 are both phenyl, R3 is hydroxy, A2 is methylene, m is 0 and n is 1, (b) R7 is not methyl when R1 and R2 are both phenyl, and m and n are both 0.
2. Pharmaceutical preparation for prevention and/or treat-ment of dysuria comprising, as an active ingredient, substituted acetamide compound as defined in claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929202443A GB9202443D0 (en) | 1992-02-05 | 1992-02-05 | A novel substituted-acetamide compound and a process for the preparation thereof |
| GB9202443.9 | 1992-02-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2155320A1 true CA2155320A1 (en) | 1993-08-19 |
Family
ID=10709880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2155320 Abandoned CA2155320A1 (en) | 1992-02-05 | 1993-02-04 | Substituted acetamide compound |
Country Status (3)
| Country | Link |
|---|---|
| CA (1) | CA2155320A1 (en) |
| GB (1) | GB9202443D0 (en) |
| WO (1) | WO1993016048A1 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6140333A (en) * | 1998-02-04 | 2000-10-31 | Banyu Pharmaceutical Co Ltd | N-acyl cyclic amine derivatives |
| EP1302458A1 (en) * | 2000-07-11 | 2003-04-16 | Banyu Pharmaceutical Co., Ltd. | Ester derivatives |
| WO2004005285A1 (en) * | 2002-07-02 | 2004-01-15 | Almirall Prodesfarma Ag | New quinuclidine amide derivatives |
| WO2004089364A1 (en) * | 2003-04-11 | 2004-10-21 | Ranbaxy Laboratories Limited | Azabicyclo derivatives as muscarinic receptor antagonists |
| US7208501B2 (en) | 2000-12-22 | 2007-04-24 | Almirall Prodesfarma Ag | Quinuclidine carbamate derivatives and their use as M3 antagonists |
| EA009942B1 (en) * | 2002-07-08 | 2008-04-28 | Рэнбакси Лабораториз Лтд. | Azabicyclo derivatives as muscarinic receptor antagonists |
| US7435742B2 (en) | 2002-06-21 | 2008-10-14 | Laboratorios Almirall S.A. | Quinuclidine derivatives and pharmaceutical compositions containing the same |
| US7517905B2 (en) | 2003-04-09 | 2009-04-14 | Ranbaxy Laboratories Limited | Substituted azabicyclo hexane derivatives as muscarinic receptor antagonists |
| WO2015181837A3 (en) * | 2014-05-30 | 2016-02-18 | Sphaera Pharma Pvt. Ltd. | Novel compounds as anti-tubercular agents |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9122988D0 (en) * | 1991-10-30 | 1991-12-18 | Ici Plc | Heterocyclic compounds |
| JPH06508377A (en) * | 1992-04-10 | 1994-09-22 | ゼネカ リミテッド | heterocyclic compound |
| GB9211796D0 (en) * | 1992-06-04 | 1992-07-15 | Ici Plc | Heterocyclic derivatives |
| GB9216721D0 (en) * | 1992-08-06 | 1992-09-23 | Ici Plc | Therapeutic heterocyclic derivatives |
| GB9218334D0 (en) * | 1992-08-28 | 1992-10-14 | Ici Plc | Heterocyclic compounds |
| GB9226573D0 (en) * | 1992-12-21 | 1993-02-17 | Ici Plc | Heterocyclic compounds |
| AU7545894A (en) * | 1993-09-02 | 1995-03-22 | Yamanouchi Pharmaceutical Co., Ltd. | Carbamate derivative and medicine containing the same |
| NO2005012I1 (en) * | 1994-12-28 | 2005-06-06 | Debio Rech Pharma Sa | Triptorelin and pharmaceutically acceptable salts thereof |
| WO1996033973A1 (en) * | 1995-04-28 | 1996-10-31 | Banyu Pharmaceutical Co., Ltd. | 1,4-disubstituted piperidine derivatives |
| CA2179574A1 (en) * | 1995-06-26 | 1996-12-27 | Tomomi Okada | Substituted piperidine derivative and medicine comprising the same |
| KR19990037220A (en) * | 1997-10-31 | 1999-05-25 | 타이도 나오카타 | Arylacetic acid amide derivatives or salts thereof and pharmaceuticals containing the same |
| WO2000031078A1 (en) * | 1998-11-20 | 2000-06-02 | Banyu Pharmaceutical Co., Ltd. | 1-acylazetidine derivatives |
| DE60226906D1 (en) | 2002-07-31 | 2008-07-10 | Ranbaxy Lab Ltd | 3,6-DISUBSTITUTED AZABICYCLO Ä3.1.0ÜHEXANDERIVATES SUITED AS MUSCARIN RECEPTOR ANTAGONISTS |
| AU2002321711A1 (en) | 2002-08-09 | 2004-02-25 | Ranbaxy Laboratories Limited | 3,6-disubstituted azabicyclo (3.1.0) hexane derivatives useful as muscarinic receptor antagonist |
| EP1534675B1 (en) | 2002-08-23 | 2009-02-25 | Ranbaxy Laboratories, Ltd. | Fluoro and sulphonylamino containing 3,6-disubstituted azabicyclo¬3.1.0 hexane derivatives as muscarinic receptor antagonists |
| JP2006518707A (en) | 2002-12-10 | 2006-08-17 | ランバクシー ラボラトリーズ リミテッド | 3,6-Disubstituted azabicyclo [3.1.0] hexane derivatives as muscarinic receptor antagonists |
| EP1581522B1 (en) | 2002-12-23 | 2008-02-20 | Ranbaxy Laboratories Limited | Flavaxate derivatives as muscarinic receptor antagonists |
| AU2002347552A1 (en) | 2002-12-23 | 2004-07-14 | Ranbaxy Laboratories Limited | 1-substituted-3-pyrrolidine derivatives as muscarinic receptor antagonists |
| US7488748B2 (en) | 2003-01-28 | 2009-02-10 | Ranbaxy Laboratories Limited | 3,6-Disubstituted azabicyclo hexane derivatives as muscarinic receptor antagonists |
| US7560479B2 (en) | 2003-04-10 | 2009-07-14 | Ranbaxy Laboratories Limited | 3,6-Disubstituted azabicyclo hexane derivatives as muscarinic receptor antagonists |
| US7592359B2 (en) | 2003-04-10 | 2009-09-22 | Ranbaxy Laboratories Limited | Substituted azabicyclo hexane derivatives as muscarinic receptor antagonists |
| AU2006305619A1 (en) | 2005-10-19 | 2007-04-26 | Ranbaxy Laboratories Limited | Pharmaceutical compositions of muscarinic receptor antagonists |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1220937B (en) * | 1979-05-30 | 1990-06-21 | Italiana Schoum Spa | SPASMOLITHIC COMPOUNDS SIMILAR TO PHENPYRAMIN |
| US5066680A (en) * | 1989-02-14 | 1991-11-19 | Fujisawa Pharmaceutical Co., Ltd. | Novel substituted-acetamide compound and a process for the preparation thereof |
-
1992
- 1992-02-05 GB GB929202443A patent/GB9202443D0/en active Pending
-
1993
- 1993-02-04 CA CA 2155320 patent/CA2155320A1/en not_active Abandoned
- 1993-02-04 WO PCT/JP1993/000142 patent/WO1993016048A1/en active Application Filing
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6140333A (en) * | 1998-02-04 | 2000-10-31 | Banyu Pharmaceutical Co Ltd | N-acyl cyclic amine derivatives |
| EP1302458A1 (en) * | 2000-07-11 | 2003-04-16 | Banyu Pharmaceutical Co., Ltd. | Ester derivatives |
| EP1302458A4 (en) * | 2000-07-11 | 2005-10-19 | Banyu Pharma Co Ltd | Ester derivatives |
| US7208501B2 (en) | 2000-12-22 | 2007-04-24 | Almirall Prodesfarma Ag | Quinuclidine carbamate derivatives and their use as M3 antagonists |
| US7776879B2 (en) | 2000-12-22 | 2010-08-17 | Almirall, S.A. | Quinuclidine carbamate derivatives and their use as M3 antagonists |
| US7312231B2 (en) | 2000-12-22 | 2007-12-25 | Almirall Prodesfarma Ag | Quinuclidine carbamate derivatives and their use as M3 antagonists |
| US7435742B2 (en) | 2002-06-21 | 2008-10-14 | Laboratorios Almirall S.A. | Quinuclidine derivatives and pharmaceutical compositions containing the same |
| ES2204295A1 (en) * | 2002-07-02 | 2004-04-16 | Almirall Prodesfarma, S.A. | Quinuclidine amide derivatives |
| ES2204295B1 (en) * | 2002-07-02 | 2005-08-01 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF QUINUCLIDINE-AMIDE. |
| US7718670B2 (en) | 2002-07-02 | 2010-05-18 | Laboratorios Almirall S.A | Quinuclidine amide derivatives |
| AU2003242757B2 (en) * | 2002-07-02 | 2009-01-08 | Laboratorios Almirall, S.A. | New quinuclidine amide derivatives |
| WO2004005285A1 (en) * | 2002-07-02 | 2004-01-15 | Almirall Prodesfarma Ag | New quinuclidine amide derivatives |
| US7488735B2 (en) | 2002-07-02 | 2009-02-10 | Laboratorios Almirall S.A. | Quinuclidine amide derivatives |
| US7399779B2 (en) | 2002-07-08 | 2008-07-15 | Ranbaxy Laboratories Limited | 3,6-disubstituted azabicyclo [3.1.0] hexane derivatives useful as muscarinic receptor antagonists |
| US7544708B2 (en) | 2002-07-08 | 2009-06-09 | Ranbaxy Laboratories Limited | Azabicyclo derivatives as muscarinic receptor antagonists |
| EA009942B1 (en) * | 2002-07-08 | 2008-04-28 | Рэнбакси Лабораториз Лтд. | Azabicyclo derivatives as muscarinic receptor antagonists |
| US7517905B2 (en) | 2003-04-09 | 2009-04-14 | Ranbaxy Laboratories Limited | Substituted azabicyclo hexane derivatives as muscarinic receptor antagonists |
| US7446123B2 (en) | 2003-04-11 | 2008-11-04 | Ranbaxy Laboratories Limited | Azabicyclo derivatives as muscarinic receptor antagonists |
| WO2004089364A1 (en) * | 2003-04-11 | 2004-10-21 | Ranbaxy Laboratories Limited | Azabicyclo derivatives as muscarinic receptor antagonists |
| WO2015181837A3 (en) * | 2014-05-30 | 2016-02-18 | Sphaera Pharma Pvt. Ltd. | Novel compounds as anti-tubercular agents |
| US10100012B2 (en) | 2014-05-30 | 2018-10-16 | Sphaera Pharma Pvt. Ltd. | Compounds as anti-tubercular agents |
| US10207993B2 (en) | 2014-05-30 | 2019-02-19 | Sphaera Pharma Pvt. Ltd. | Compounds as anti-tubercular agents |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993016048A1 (en) | 1993-08-19 |
| GB9202443D0 (en) | 1992-03-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2155320A1 (en) | Substituted acetamide compound | |
| AU678023B2 (en) | Substituted pyrrolidin-3-yl-alkyl-piperidines useful as tachykinin antagonists | |
| US5340822A (en) | Polycyclic amine compounds and their enantiomers, their method of preparation and pharmaceutical compositions in which they are present | |
| US6037352A (en) | Muscarinic antagonists | |
| FI114470B (en) | New substituted piperidines useful in the treatment of allergic diseases | |
| US5270328A (en) | Peripherally selective piperidine opioid antagonists | |
| RU2089547C1 (en) | N-alkylenepiperidine derivatives, method of their synthesis, pharmaceutical composition based on thereof, optically pure derivatives of n-alkylenepiperidine | |
| DE60123420T2 (en) | Cyclohexyl derivatives and their use as therapeutic agents | |
| DE68920482T2 (en) | 1-indolylalkyl-4- (substituted pyridinyl) piperazines. | |
| AU675786B2 (en) | Azacyclic compounds | |
| EP0506468B1 (en) | N-substituted 4-phenyl-piperidine opioid-antagonists | |
| AU2005202257B2 (en) | Azacyclic compounds for use in the treatment of serotonin related diseases | |
| DE69400824T2 (en) | INDOL DERIVATIVES AS 5-HT1-LIKE ANTAGONISTS FOR TREATING MIGRAINE | |
| US7601868B2 (en) | Amine derivative | |
| TW531537B (en) | 1-(1,2-disubstituted piperidinyl)-4-substituted piperidine derivatives | |
| KR100904829B1 (en) | 4-aminopiperidine derivatives | |
| US8293770B2 (en) | Pyrrolidine derivatives as NK-3 receptor antagonists | |
| HRP970426A2 (en) | Fluorine containing 1,4-disubstituted piperidine derivatives | |
| KR20060094079A (en) | Derivatives of n-phenyl(piperidine-2-yl)methyl benzamide, preparation method thereof and applications of same in therapeutics | |
| CZ293134B6 (en) | Substituted heterocyclic compounds, preparation method and intermediates therefor and pharmaceutical composition containing such compounds | |
| AU2001256509A1 (en) | Cyclohexane derivatives and their use as therapeutic agents | |
| SI9300513A (en) | Basic quaternary amids, procedure for their preparation and pharmaceutical compositions comprising them | |
| NO303448B1 (en) | 1-acylpiperidine compounds, their use in the manufacture of pharmaceuticals and drugs containing them | |
| US5556860A (en) | Quinazolinone derivatives possessing calcium uptake inhibiting activity | |
| CA2009897A1 (en) | Substituted-acetamide compound and a process for the preparation thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |