CA2107665A1 - 1,3,4-trisubstituted piperidine derivatives, the preparation and use thereof - Google Patents
1,3,4-trisubstituted piperidine derivatives, the preparation and use thereofInfo
- Publication number
- CA2107665A1 CA2107665A1 CA002107665A CA2107665A CA2107665A1 CA 2107665 A1 CA2107665 A1 CA 2107665A1 CA 002107665 A CA002107665 A CA 002107665A CA 2107665 A CA2107665 A CA 2107665A CA 2107665 A1 CA2107665 A1 CA 2107665A1
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- hydroxy
- fluorophenyl
- piperidinyl
- methyl
- 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
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Classifications
-
- 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
- C07D211/20—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 singly bound oxygen or sulphur atoms
- C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
-
- 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The description relates to compounds of formula (I) in which A-B-D, R1, R2, R3 and n have the meanings given in the specification, and their production. The compounds are suitable for the treatment of diseases.
Description
~ 21~ U~
O.Z. 0050/42360 1,3.4-Trisubstituted Pi~eridine derivatives, the , . .
~ preparation and use thereof .: .
.~ The present invention relates to 1,3,4-tri~ubstituted piperidine derivatives, to a process for their preparation and to their use as drugs.
It is known that butyrophenone derivatives with ~- basic substituents have neuroleptic and cerebroprotective : effects (US 4,605,655, EP 410 114). It appears in this ,~ connection that the observed affinities for a receptors . 10 are particularly important.
We have now found that 1,3,4-trisubstituted . piperidine derivatives of the formula I
A-B~
(CH~
.~ R~ .
'~ where R1 is hydrogen, fluorine, chlorine or bromine, R2 is hydroxyl, or phenyl which is unsubstituted or sub~tituted by fluorine, chlorine or bromine, ~: R3 is hydrogen, or R2 and R3 together are oxygen, and A-B-D is ~i --CH2--CIy~ - q~ , ~ R5 or i R7 R '~ R ~
. i --CH 2~ R 6 .i~ R 7 ~j .
where "
.` :
., -- .:
~, , :: .
-~ . 2 ~
.. . .
: - 2 - O.Z. 0050/42360 .; ., .- . .
;` R~ is C~3-alkyl or is phenyl or thienyl which can be sub~tituted.by fluorine or chlorine, - Rs is hydrogen or hydroxyl, . Rc is hydrogen, - 5 R' is hydroxyl, or .. R6 and R7 together are oxygen, and their ~alts with physiologically tolerated acids have .~ valuable pharmacological propertie~.
.- Rl to R' and n in the formula I preferably have .: 10 the following meanings:
R1: hydrogen, fluorine, chlorine .~ R~: hydroxyl, p-fluorophenyl -~.q R3: hydrogen or together with R2 oxygen i R': methyl, ethyl, phenyl, p-fluorophenyl, 2-thienyl ;~. 15 R5: hydrogen, hydroxyl . R6: hydrogen l............... R7: hydroxyl or with R6 oxygen.
The following compounds are particularly.
:. preferred:
.. 20 1-(4-Fluorophenyl)-4-[4-hydroxy-tran~-3-phenyl-. (hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanone, 1-(4-' fluorophenyl)-4-[trans-(3-phenyl-hydroxymethyl-4-phenyl)-4-hydroxy-piperidin-1-yl]-butan-1-ol, 1-(4-fluorophenyl)-4-(3-benzoyl-4-phenyl-~-dehydro-piperidin-1-yl)-butan-1-~` 25 one,1-(4-fluorophenyl)-4-(3-benzoyl-4-phenyl-~3-dehydro-.: piperidin-l-yl)-butan-1-one, 1-(bis-4-fluorophenyl)-4-.
~. ttran~-(3-phenyl-hydroxymethyl-4-phenyl)-4-hydroxy-.~ piperidin-1-yl]-butane, 1-(4-fluorophenyl)-4-[trans-(3-p-` fluorophenyl-hydroxymethyl-4-p-fluorophenyl-4-hydroxy-piperidin-l-yl]-butan-1-one, 1-~4-fluorophenyl)-4-[tran~-~: (3-p-fluorophenyl-hydroxymethyl-4-p-fluorophenyl-4-iy hydroxypiperidin-l-yl]-butan-l-ol~ 1-(4-fluorophenyl)-4-[trans-(3-acetyl-4-methyl)-4-hydroxy-piperidin-1-yl]-^~ butan-1-one, 1-(4-fluorophenyl)-4-[tran~-(3-acetyl-4-methyl)-4-hydroxy-piperidin-1-yl]-butan-1-ol, 1-(4-.. ~. fluorophenyl)-4-(3-acetyl-4-methyl-~3-dehydropiperidin-1-.yl)-butan-l-one~ 4-fluorophenyl)-4-(3-acetyl-4-methyl- ..
~3 ., .
~., -. .: : .
...
- ~, 21Gr~
~ 3 - O.z. 0050/42360 . . .
~3-dehydropiperidin-l-yl)-butan-l-ol, 1-(bis-4-fluoro-phenyl)-4-(3-acetyl-4-methyl-~3-dehydro-piperidin-l-yl)-- butane.
The compounds of the formula I according to the 5 invention can be prepared by reacting a compound of the formula II
,:. ,;,., ;, R 2 " ~U--(CH2)3~< Il, ;: .............................. R 3 R 1 ..-" where Rl, R2, R3 and n have the stated meanings, and Nu is a nucleofugic leaving group, with a 3,4-disubstituted piperidine derivative of the formula III
:~".
B`II
~'.' ~ ~Ir, - H
; 10 where A, B and D have the meanings stated for formula I, - and converting the resulting compound where appropriate Y,~ into the addition salt with a physiologically tolerated '~ acid.
.- A suitable and preferred nucleofugic leaving group for Nu is halogen, especially bromine or chlorine.
~- The reaction is expediently carried out in the presence of an inert base such as triethylamine or pota~3ium carbonate to trap acid in an inert solvent such a~ a cyclic saturated ether, especially tetrahydrofuran or dioxane, or an alkylbenzene such a~ toluene or xylene.
~ The reaction is usually carried out at from 80 to A~'.. i 150C and is generally complete within from 1 to 10 hours.
The products of the formula I can be converted by ~ubsequent reaction~ as indicated in the examples.
These reaction~ comprise oxidations of the 3-hydroxymethylpiperidine structure (R~ = OH in formula I) ~ to the corresponding carbonyl derivative3 with Jones ^~ reagent (chromium(VI) oxide in 25 % strength sulfuric .
. .
" , . ' ', ' ~":
':
O.Z. 0050/42360 1,3.4-Trisubstituted Pi~eridine derivatives, the , . .
~ preparation and use thereof .: .
.~ The present invention relates to 1,3,4-tri~ubstituted piperidine derivatives, to a process for their preparation and to their use as drugs.
It is known that butyrophenone derivatives with ~- basic substituents have neuroleptic and cerebroprotective : effects (US 4,605,655, EP 410 114). It appears in this ,~ connection that the observed affinities for a receptors . 10 are particularly important.
We have now found that 1,3,4-trisubstituted . piperidine derivatives of the formula I
A-B~
(CH~
.~ R~ .
'~ where R1 is hydrogen, fluorine, chlorine or bromine, R2 is hydroxyl, or phenyl which is unsubstituted or sub~tituted by fluorine, chlorine or bromine, ~: R3 is hydrogen, or R2 and R3 together are oxygen, and A-B-D is ~i --CH2--CIy~ - q~ , ~ R5 or i R7 R '~ R ~
. i --CH 2~ R 6 .i~ R 7 ~j .
where "
.` :
., -- .:
~, , :: .
-~ . 2 ~
.. . .
: - 2 - O.Z. 0050/42360 .; ., .- . .
;` R~ is C~3-alkyl or is phenyl or thienyl which can be sub~tituted.by fluorine or chlorine, - Rs is hydrogen or hydroxyl, . Rc is hydrogen, - 5 R' is hydroxyl, or .. R6 and R7 together are oxygen, and their ~alts with physiologically tolerated acids have .~ valuable pharmacological propertie~.
.- Rl to R' and n in the formula I preferably have .: 10 the following meanings:
R1: hydrogen, fluorine, chlorine .~ R~: hydroxyl, p-fluorophenyl -~.q R3: hydrogen or together with R2 oxygen i R': methyl, ethyl, phenyl, p-fluorophenyl, 2-thienyl ;~. 15 R5: hydrogen, hydroxyl . R6: hydrogen l............... R7: hydroxyl or with R6 oxygen.
The following compounds are particularly.
:. preferred:
.. 20 1-(4-Fluorophenyl)-4-[4-hydroxy-tran~-3-phenyl-. (hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanone, 1-(4-' fluorophenyl)-4-[trans-(3-phenyl-hydroxymethyl-4-phenyl)-4-hydroxy-piperidin-1-yl]-butan-1-ol, 1-(4-fluorophenyl)-4-(3-benzoyl-4-phenyl-~-dehydro-piperidin-1-yl)-butan-1-~` 25 one,1-(4-fluorophenyl)-4-(3-benzoyl-4-phenyl-~3-dehydro-.: piperidin-l-yl)-butan-1-one, 1-(bis-4-fluorophenyl)-4-.
~. ttran~-(3-phenyl-hydroxymethyl-4-phenyl)-4-hydroxy-.~ piperidin-1-yl]-butane, 1-(4-fluorophenyl)-4-[trans-(3-p-` fluorophenyl-hydroxymethyl-4-p-fluorophenyl-4-hydroxy-piperidin-l-yl]-butan-1-one, 1-~4-fluorophenyl)-4-[tran~-~: (3-p-fluorophenyl-hydroxymethyl-4-p-fluorophenyl-4-iy hydroxypiperidin-l-yl]-butan-l-ol~ 1-(4-fluorophenyl)-4-[trans-(3-acetyl-4-methyl)-4-hydroxy-piperidin-1-yl]-^~ butan-1-one, 1-(4-fluorophenyl)-4-[tran~-(3-acetyl-4-methyl)-4-hydroxy-piperidin-1-yl]-butan-1-ol, 1-(4-.. ~. fluorophenyl)-4-(3-acetyl-4-methyl-~3-dehydropiperidin-1-.yl)-butan-l-one~ 4-fluorophenyl)-4-(3-acetyl-4-methyl- ..
~3 ., .
~., -. .: : .
...
- ~, 21Gr~
~ 3 - O.z. 0050/42360 . . .
~3-dehydropiperidin-l-yl)-butan-l-ol, 1-(bis-4-fluoro-phenyl)-4-(3-acetyl-4-methyl-~3-dehydro-piperidin-l-yl)-- butane.
The compounds of the formula I according to the 5 invention can be prepared by reacting a compound of the formula II
,:. ,;,., ;, R 2 " ~U--(CH2)3~< Il, ;: .............................. R 3 R 1 ..-" where Rl, R2, R3 and n have the stated meanings, and Nu is a nucleofugic leaving group, with a 3,4-disubstituted piperidine derivative of the formula III
:~".
B`II
~'.' ~ ~Ir, - H
; 10 where A, B and D have the meanings stated for formula I, - and converting the resulting compound where appropriate Y,~ into the addition salt with a physiologically tolerated '~ acid.
.- A suitable and preferred nucleofugic leaving group for Nu is halogen, especially bromine or chlorine.
~- The reaction is expediently carried out in the presence of an inert base such as triethylamine or pota~3ium carbonate to trap acid in an inert solvent such a~ a cyclic saturated ether, especially tetrahydrofuran or dioxane, or an alkylbenzene such a~ toluene or xylene.
~ The reaction is usually carried out at from 80 to A~'.. i 150C and is generally complete within from 1 to 10 hours.
The products of the formula I can be converted by ~ubsequent reaction~ as indicated in the examples.
These reaction~ comprise oxidations of the 3-hydroxymethylpiperidine structure (R~ = OH in formula I) ~ to the corresponding carbonyl derivative3 with Jones ^~ reagent (chromium(VI) oxide in 25 % strength sulfuric .
. .
" , . ' ', ' ~":
':
2 1 ~
- 4 - o.Z. 0050/42360 ~` acid), reduction of the 2-butanone moiety (R2 + R3 =
oxygen) to the corresponding 2-butanol derivative with sodium boranate, elimination of H2O from the 4-hydroxy-piperidine moiety (Rs = OH) to give ~4-dehydropiperidine derivative with concentrated sulfuric acid, and the base-catalyzed double-bond shift to give the ~3-dehydro-~ i piperidine compound.
; The compounds of the formula I according to the invention are usually obtained in the form of yellowish or yellow crystals and can be purified byrecrystallization from the conventional organic ~olvents, preferably from a lower alcohol, such as ethanol, or by column chromatography.
The free 1,3,4-trisubstituted piperidine deriva-tive~ of the formula I can be converted in a conventionalway into the addition ~alt~ with a phy~iologically tolerated acid, preferably by adding one equivalent of the appropriate acid to a solution. Examples of pharma-ceutically tolerated acids are hydrochloric acid, phos-phoric acid, eulfuric acid, methanesulfonic acid, ` ~ulfamic acid, maleic acid, fumaric acid, oxalic acid, ~ tartaric acid and citric acid.
J` -' ' ~he compounds according to the invention have -~ valuable pharmacological properties. They can be used as - 25 neuroleptics, antidepressants, sedatives, hypnotics or i~j cerebroprotectivec. It is possible for a plurality of the said propertie~ to be combined in one compound according ~1 to the invention.
They are therefore suitable for the treatment of p~ychoses, preferably ~chizophrenia, and anxiety states, for the treatment and prevention of strokes or distur-bances of cerebral function with an organic cause, and for the treatment of sleep disturbance~.
The present invention accordingly also relates to a therapeutic composition which contains a compound of the formula I or its physiologically tolerated acid ;i addition salt a~ active substance in addition to ~;
:~.
~ - :
.,~ . ,. . , - :
;s - 5 - O.z. 0050/42360 ~ conventional carriers and diluents, and to the use of the - novel copounds for controlling diseases.
The compound according to the invention can be 'r. administered in a conventional way orally or parenteral-ly, intravenously or intramuscularly.
The dosage dependR on the age, condition and weight of the patient and on the mode of administration.
As a rule, the daily dose of active ~ubstance i~ about 1-100 mg/kg of body weight on oral administration and 0.1-`;- 10 2 mg/kg of body weight on parenteral administration.
; The novel compounds can be used in conventional solid or liquid pharmaceutical forms, e.g. as uncoated or (film-~coated tablets, capsules, powders, granules, ~ suppositories, solutions, ointments, creams or spray~.
; 15 These are produced in a conventional way. The active sub~tances can for this purpose be processed with conven-tional pharmaceutical aids ~uch as tablet binders, fillerc, preservatives, tablet disintegrant~, flow i' regulators, plasticizers, wetting agents, disper~ants, emulsifiers, solvents, retardants, antioxidants and/or propellant gases tcf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The forms - obtained in this way normally contain the active sub-;~ ~ stance in an amount of from 0.1 to 99 % by weight.
The substances of the formula II which are required a~ starting materials for synthesizing the novel compounds are known.
The substances of the formula III have not previously been described (but see DE 41 12 352). They ';'!' 30 are prepared, for example, by reacting 2 mole equivalents of an a,~-unsaturated ketone of the formula IV
CH2=CH-C0-~4 IV
;!
; or a ~-halo ketone of the formula V
Hal-C~2-CH2-C0-R~ V, where R' ha~ the abovementioned meanings, with an amine ,~ I
, , .~
. Y
... .
- . . , , . : - ~
. -' .~ ' ~' \ ' ' :
~: :
.. . . ~ ~
-` 2~ ~7~5 .~
6 - o.z. 0050/42360 ~- H2N-Ra where R8 is benzyl which is unsubstit-lted or substituted by halogen, methoxy or nitro, or is allyl, in - the presence of 1 mole equivalent of sodium hydroxide solution in methanol at 50C. This reaction iR usually diastereoRelective to give the compound VI with di equatorial trans configuration with respect to R4 . ' ,,~
HO. R4 J v r, ,:
which can be converted by elimination of R~ and, where appropriate, subRequent elimination of water and pos~ible rearrangement and reduction as described above for the ; 10 final products into the compounds of the formula III.
The following examples illustrate the invention: ~
:.
a) Preparation of the starting material 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenylpiperidine 600 g (1.62 mol) of trans-3-benzoyl-4-phenyl-4-hydroxy-l-benzylpiperidine in 1.4 l of ethyl acetate - mixed with 1.4 l of methanol were catalytically hydro-: genated with the addition of 20 g of palladium llO %) on ; carbon at 70C under a hydrogen pre~3ure of 100 bar for 3 20 12 h. The mixture was filtered at 50C to remove cata--~ lyst, evaporated to dryness, taken up in 0.6 l of acetone and stirred while cooling. The precipitated product was ~''1 filtered off with ~uction, the filtrate was concentrated, the re~idue was ~tirred in 300 ml of acetone again while cooling, and a ~econd product fraction was filtered off ~ with ~uction.
i~ Yield: 345 g ~75 %) of the pure diastereomer of the product, melting point 167-169C.
b) Preparation of the final product 1-(4-fluorophenyl)-4-[4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanone 20.0 g (70.7 mmol) of 4-hydroxy-trans-3-phenyl-(hydroxy3methyl-4-phenylpiperidine in 210 ml of xylene , ;
~ .
.... ~ . . . . -. . .
'. ~. . . : ' ~ :
~,~ , - .
I . .. ........ .. . .
2 1 ~
: - 7 - o.z. 0050/42360 were mixed with 26.7 ml (162-mmol) of ~-chloro-4-fluoro-butyrophenone and with 18.8 g (136 mmol) of finely powdered potas~ium carbonate in addition to 1.0 g of potassium iodide and refluxed while stirring vigorously for 16 h. After cooling, 200 ml of toluene were added and the mixture was ~tirred vigorously while the pale solid precipitated. The crude product was filtered off with suction, washed with toluene and dried at 50C under reduced pre3sure. The ~olid was then digested in l 1 of water at 50C and finally the product wa~ filtered off with ~uction (melting point 182-183C), yield: 22.6 g (72 %).
The following can be prepared in a Yimilar way:
- 2. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-phenyl-(hydroxy)methyl-4-phenyl-1-piperidinyl]butane Alkylating reagent: l-(p-fluorophenyl)-4--chlorobutane 3. 1-Phenyl-4-[4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanone, Melting point 173-175C
4. 1-Phenyl-4-[4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl]butane 5. 1-(4-~romophenyl)-4-[4-hydroxy-trans-3-phenyl-(hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanone, - 25 Melting point 186-187C
a) Preparation of the starting material 4-Hydroxy-trans-3-p-fluorophenyl(hydroxy)methyl-4-p-fluorophenylpiperidine 30.0 g ~67.6 mmol) of4-hydroxy-1-benzyl-trans-3-p-fluorobenzoyl-4-p-fluorophenylpiperidine hydrochloride in 1 1 of methanol were catalytically hydrogenated with the addition of 4.0 g of palladium (10 %) on carbon at , 50C for 8 h. After filtration and washing with methanol, the filtrate was evaporated to dryne~s. The residue wa~
taken up in a mixture of 140 ml of methanol and 500 ml of water at 70C, concentrated ammonia was added until the .
: . :
~ ~ , ~ ~:
`~ 2 1 O ~ ~ ~ 5 - 8 - O.Z. 0050/42360 mixture was alkaline, and the precipitated product was filtered off with suction and washed thoroughly with water. Drying at 60C under reduced pressure resulted in 20.2 g (94 %) of product of melting point 215-217C.
b) Preparation of the f inal product 1-(4-Fluorophenyl)-4-[4-hydroxy-tran~-3-p-fluoro-phenyl(hydroxy)methyl-4-p-fluorophenyl-l-` piperidinyl]-1-butanone ; 20.0 g (63.0 mmol) of 4-hydroxy-tran~-3-p-fluoro-phenyl(hydroxy)methyl-4-p-fluorophenylpiperidine in a -~ mixture of 250 ml of toluene and 25 ml of dimethyl-formamide were mixed with 20.6 ml (125 mmol) of ~-chloro-4-fluorobutyrophenone and with finely powdered potas~ium carbonate in addition to 1.0 g of potas~ium iodide and refluxe~ while stirring vigorou~ly for 8 h. After cool-ing, the mixture wa~ evaporated in a rotary evaporator,-the residue was taken up in a little dimethylformamide, and the solution was poured into vigorously stirred ice-water. The precipitated solid was filtered off with - 20 suction, thoroughly washed with water and recrystallized - from ethanol to give 23.5 g (78 %) of product of melting ~- point 175-177C.
'~7 The following can be prepared in a similar way:
;~ 7. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-p-fluoro-'~, 25 phenyl(hydroxy)methyl-4-p-fluorophenyl-1-~'1 piperidinyl]butane, melting point 170-171C.
8. 1-Phenyl-4-[4-hydroxy-trans-3-p-fluorophenyl-'j (hydroxy)methyl-4-p-fluorophenyl-1-piperidinyl]-1-butanone ;~ 30 9. 1-Phenyl-4-[4-hydroxy-trans-3-p-fluorophenyl-(hydroxy)methyl-4-p-fluorophenyl-1-piperidinyl]-~, butane ~ EXAMPLE 10 i; a) Preparation of the starting material 4-hydroxy-cis-3-acetyl-4-methylpiperidine 20.1 g (81.0 mmol) of 4-hydroxy-1-benzyl-ci~-3-acetyl-4-methylpiperidine in 700 ml of methanol were .' .
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- , -~ 21 ~7~5 - . ,.. -_ g - o.z. 0050/42360 catalytically hydrogenated with the addition of 2.5 g of palladium (10 %) on carbon at room temperature for 8 h.
- After filtration and wa~hing with methanol, the filtrate was evaporated to dryne~s. 11.9 g (94 %) of product were isolated, melting point 91-93C. The hydrochloride melts at 118-199C.
.:;,; .
- The tran~ isomer can be prepared in a ~imilar way: decomposition above 133C (hydrochloride).
b) Preparation of the final product ` 10 1-(4-Fluorophenyl)-4-[4-hydroxy-cis-3-acetyl-4-`; methyl-1-piperidinyl)-1-butanone 20.5 g (131 mmol) of 4-hydroxy-ci~-3-acetyl-4-methylpiperidine in a mixture of 250 ml of toluene and 25 ml of dimethylformamide were mixed with 21.4 ml (131 mmol) of ~-chloro-4-~luorobutyrophenone and with 18 g (131 mmol) of finely powdered potassium carbonate in addition to 1.0 g of potassium iodide and refluxed while stirring viyorously for 3 h. After cooling, the mixture ~' was evaporated in a rotary evaporator, and the residue wa~ partitioned between methylene chloride and water. The aqueous pha~e wa~ extracted with methylene chloride, and ; then the organic phase was dried with sodium ~ulfate and ~: evaporated. The crude product was purified by column s~ chromatography (~ilica gel, methylene chloride/methanol 98/~2). 9.5 g (22 %) of product were isolated, de-compo~ition above 90C (tartrate).
The following can be prepared in a ~imilar way:
(4-Fluorophenyl)-4-[4-hydroxy-trans-3-acetyl-4-methyl-1-piperidinyl]-1-butanone, i~ 30 Melting point 174-175C (hydrochloride) 12. 1-~4-Fluorophenyl)-4-[4-hytroxy-cis-3-acetyl-4-methyl)-1-piperidinyl]-1-butanol, Alkylating reagent: l-hydroxy-1-(p-fluorophenyl)-4-` chlorobutane ~' 35 13. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-acetyl-4-methyl-l-piperidinyl]-l-butanol~ melting point 97-99C, Alkylating reagent: 1-hydroxy-1-(p-fluorophenyl)-~ . .
``3 . ~ .
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- 10 - O.z. 0050/42360 4-chlorobutane - 14. 1-(4-Fluorophenyl)-4-[4-hydroxy-ci~-3-acetyl-4-methyl-l-piperidinyl]butane, melting point 85-88c (hydrochloride) .: 5 15. 1-(4-Fluorophenyl)-4-~4-hydroxy-trans-3-acetyl-4-. methyl-1-piperidinyl]butane, melting point 105-107C
; (hydrochloride) - 16. 1-(4-Phenyl)-4-[4-hydroxy-cis-3-acetyl-4-methyl-1-. piperidinyl]-l-butanone 17. 1-(4-Phenyl)-4-[4-hydroxy-trans-3-acetyl-4-methyl-1-piperidinyl]-1-butanone ; 18. 1-(4-Phenyl)-4-[4-hydroxy-cis-3-acetyl-4-methyl-1-piperidinyl]butane 19. 1-(4-Phenyl)-4-[4-hydroxy-tran~-3-acetyl-4-methyl-1-piperidinyl]butane ; 20. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-propionyl-4-. .
ethyl-l-piperidinyl]-l-butanone . EXAMPLE 21 ~ 4-fluorophenyl)-4-[4-hydroxy-trans-3-phenyl-20 (hydroxy)methyl-4-phenyl-1-piperidinyl]butane .^~ 22.8 g t80.6 mmol) of 4-hydroxy-trans-3-phenyl-.~ (hydroxy)methyl-4-phenylpiperidine (Example la) in400 ml .S- of xylene mixed with 40 ml of DMF were mixed with 22.6 g (80.6 mmol) of 1,1-bis(4-fluorophenyl)-4-chlorobutane and 25 with 18.6 g (132 mmol) of finely powdered pota~sium :1 carbonate in addition to 0-3 g of potassium iodide and refluxed while stirring vigorously for 8 h. The mixture -. was ~ooled and then evaporated to dryness. The residue ' was disaolved in DMF, and the solution was poured into `~ 30 2.5 1 of vigorously stirred ice-water. After stirring for . 1 hour, the precipitated solid was filtered off with : suction to give 40.1 g (95 %) of product of melting point ~ 160-162~C.
,1 The following can be prepared in a similar way:
22. 1,1-~is~4-fluorophenyl)-4-[4-hydroxy-trans-3-p-fluonq~Ysyl~ xxy)m~yl~t~~KrqpYIyl-l-l4yr~lyl]b~ne 23. 1,1-~is(4-fluorophenyl)-4-[cis-3-acetyl-4-hydroxy-1-~ .
, ., ~
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..... .
;'`-"' '~- - 11 - O.Z. 0050/42360 ~, .
:.- piperidinyl]butane, melting point 116-ll9~C
(hydrochloride) ~', 24. 1,1-Bist4-fluorophenyl)-4-[tran~-3-acetyl-4-hydroxy-1-piperidinyl]butane, melting point 93-96C
' , 5 (hydrochloride) ~" 1-(4-Fluorophenyl)-4-[4-hydroxy-tran~-3-phenyl(hydroxy)-, methyl 4-phenyl-1-piperidinyl]-1-butanol 5.0 g (11.6 mmol) of 1-t4-fluorophenyl)-4-[4-' , 10 hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-' piperidinyl]-1-butanone (Example lb) were dis~olved in a ',, mixture of 80 ml of methanol and 100 ml of tetra-hydrofuran, and 0.6 g (16 mmol) of sodium boranate was added. The mixture was stirred at room temperature for ' 15 2 h and then concentrated in a rotary evaporator. The ~ residue was partitioned between methylene chloride and, ;',, water at pH 10, and the organic phase waR dried with 'i sodium ~ulfate and evaporated to give 4.6 g (88 %) of, product of melting point 90-92C (decomposition).
.,~ 20 The following can be prepared in a similar way: -26. 1-Phenyl-4-t4-hydroxy-tran~-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanol Melting point: 90-92C
,~ 27. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-p-fluoro-'', 25 phenyl(hydroxy)methyl-4 -p-f luorophenyl-1-', piperidinyl]-1-butanol ;,j 28. 1-~4-Fluorophenyl)-4-[4-hydroxy-tran~-3-p-fluoro-'~, phenyl~hydroxy)methyl-4-p-fluorophenyl-1-,~, piperidinyl]butane ,~' 30 29. 1-Phenyl-4-[4-h'ydroxy-trans-3-p-fluorophenyl-~ (hydroxy)methyl-4-p-fluorophenyl-1-piperidinyl]-``^, 1-butanol '~' 30. 1-(4-Fluorophenyl)-4-[4-hydroxy-cis-3-a-hydroxy-'`~ ethyl-4-methyl-1-piperidinyl]-1-butanol 31. 1-~4-Fluorophenyl)-4-~4-hydroxy-trans-3-a-hydroxy-ethyl-4-methyl-1-piperidinyl]-1-butanol 32. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-a-hydroxy-'; .
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- - 12 - O.Z. 0050/42360 ethyl-4-methyl-1-piperidinyl]butane 33. l-(4-Bromophenyl)-4-[4-hydroxy-tran~-3-phenyl-(hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanol, Melting point 92-93C
- 5 34. 1,1-si~(4-fluorophenyl)-4-[4-hydroxy-ci~-3-a-~, hydroxyethyl-4-methyl-l-piperidinyl]butane 35. 1,1-Bi~(4-fluorophenyl)-4-[4-hydroxy-trans-3--hydroxyethyl-4-methyl-1-piperidinyl]butane 1-(4-Fluorophenyl)-4-[4-hydroxy-tran~-3-benzoyl-4-phenyl-1-piperidinyl]-1-butanone 22.6 g (50.7 mmol~ of 1-t4-fluorophenyl)-4-[4-hydroxy-tran~-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl)-l-butanone (Example lb) were ~uspended in 500 ml of acetone and then, while stirring vigorously, 21 ml (56 mmol) of JoneY reagent were added dropwise. The-temperature rose to 32C during thi~. The mixture was stirred at room temperature for 12 h and then evaporated in a rotary evaporator. The mixture was then poured into ice-water, methylene chloride was added, dilute sodium hydroxide solution was added until alkaline, and the precipitated chromium oxide was filtered off with suction. The aqueous phase was extracted with methylene chloride and then the organic phase was dried with ~odium sulfate and concentrated to give 21.1 g (95 %) of product of melting point 128-130C.
The following can be prepared in a similar way:
37. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-p-fluorobenzoyl-4-p-fluorophenyl-1-piperidinyl]-1-butanone, Melting point 111-113C
38. 1-Phenyl-4-[4-hydroxy-trans-3-p-fluorobenzoyl-4-p-fluorophenyl-1-piperidinyl]-1-butanone 1,1-Bis(4-fluorophenyl)-4-[4-hydroxy-trans-3-benzoyl-4-phenyl-1-piperidinyl]butane 4.0 g (7.6 mmol) of 1,1-bi~(4-fluoroph-nyl)-4-[4-.
13 - O.z. 0050/42360 hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl~
piperidinyl]butane (Example 21) were di~olved in 50 ml of glacial acetic acid and then, while stirring vigorous-ly, 4.3 ml (11.4 mmol) of Jones reagent were added dropwi~e. The mixture was ~tirred at 60C for 12 h and' ; then the ~olution was decanted off the precip'itated chromium salts. The mixture wa~ then poured into ice-water, methylene chloride was added, and sodium hydroxide ~olution was added until alkaline. The aqueous phase was extracted with methylene ~hloride and then the organic ' phase was dried with sodium ~ulfate and concentrated. The ' crude product was purified by column chromatography '~' (silica gel, methylene chloride/methanol 98/2) to give ~ 1.0 g (50 %) of product ~oil).
;~`' 15 'The following can be prepared in a ~imilar way:
40. 1,1-Bis(4-fluorophenyl)-4-t4-hydroxy-trans-3-p-; fluorobenzoyl-4-p-fluorophenyl-1-piperidinyl]butane '' EXAMPLE 41 ~ a) Preparation of the starting material i` 20 1. 4-Hydroxy-trans-3-benzoyl-4-phenylpiperidine '~ 8 ml (21.4 mmol) of Jones reagent were added dropwise to 6.0 g (21.2 mmol) of 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenylpiperidine (Example la) in ~ ' 150 ml of acetone. The temperature rose to 30C during '~ 25 this. The mixture was stirred at room temperature for :j 1 h, and the solution was decanted off the precipitated i~ chromium oxide and evaporated to half the volume in a "~ rotary evaporator. The mixture wa~ then poured into ice-water, dilute sodium hydroxide solution was added until `' 30 alkaline, the mixture was extracted several times with methylene chloride, and the organic phase was dried with odium sulfate and evaporated. 5.2 g (87 %) of product were isolated and, after recrystallization from ethyl acetate, melted at 128-129C.
1 35 2. 3-Benzoyl-4-phenyl-~'-dehydropiperidine 'i 400 ml of methylene chloride and then 112.6 g 3 (304 mmol) of 4-hydroxy-tran~-3-benzoyl-4-phenyl-~, .j . . . .
. ~ , , .
; . , ~'` 2~7~
`~ - 14 - O.Z. 0050/42360 piperidine dissolved in 350 ml c.ff methylene chloride were added dropwise to 186 g (1.9 mol) of concentrated ~ul-furic acid while cooling in ice to 0-5C. The mixture was ~tirred while cooling in ice for 2-3 h and then poured into ice-water, concentrated sodium hydroxide solution waff~ added (to pH 10). The mixture was partitioned between methylene chloride and water, and the organic phase was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (fqilica ~- 10 gel, methylene chloride + 5 ~ methanol) to fgiVe a yield of 61 g (57 ~) of melting point 118-119C.
-- b) Preparation of the final product 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~-dehydro-1-piperidinyl]-1-butanone 15.4 g (59 mmol) of 3-benzoyl-4-phenyl-f~4-dehydropiperidine in 90 ml of xylene were mixed with-~-;; 11.5 ml (70 mmol) of ~ff-chloro-4-fluorobutyrophenone and with 12.1 g ( Iff~-ff8 mmol) of finely powdered potaRqium ,~, carbonate tngether with 0.5 g of potassium iodide and re~luxed while stirring vigorouqly for 15 h. The mixture was concentrated in a rotary evaporator and then the ' ~ residue was partitioned between ice-water and methylene chloride, making alkaline with dilute sodium hydroxide solution. The aqueous phase wa~ extracted with methylene chloride and then the organic phase wa~ dried with sodium sulfate and concentrated. The crude product was purified f by column chromatography (silica gel, methylene chloride/methanol 98/2) to give 5.2 g (21 ~ of product ' of melting point 89-91C (hydrochloride).
The following can be prepared in a similar way:
42. 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-f~'-dehydro-l-piperidinyl]-l-butanol . f~ EXAMPLE 43 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~-dehydro-1-`~ 35 piperidinyl]-l-butanone ;~ 100 ml of methylene chloride and then 10.0 g (22.4 mmol) of 1-(4-fluorophenyl)-4-[4-hydroxy-trans-3-., :
.
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; ~ - 15 - O.Z. 0050/42360 ~enzoyl-4-phenyl-1-piperidinyl]-1-butanone (Example 36) dissolved in 50 ml of methylene chloride were added dropwise to 18.0 ml (336 mmol) of concentrated ~ulfuric acid while cooling in ice to 0-5C. The mixture wa~
~tirred while cooling in ice for 2 h and then poured into ice-water, adjusted to pH 10 with concentrated sodium ,7 hydroxide solution and partitioned between methylene chloride and water, and the organic phase was dried over sodium ~ulfate and concentrated. The crude product was purified by column chromatography (silica gel, methylene chloride 99/1) to give a yield of 4.2 g (44 %) of pale oil. The hydrochloride melts at 89-91C.
- The following can be prepared in a similar way:
44. 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~-dehydro-l-piperidinyl]butane 45. 1-(4-Fluorophenyl)-4-[3-p-fluorobenzoyl-4-fluoro-phenyl- ~4 -dehydro-l-piperidinyl]-l-butanone 46. 1-(4-Fluorophenyl)-4-[3-p-fluorobenzoyl-4-fluoro-phenyl-~-dehydro-1-piperidinyl]butane - 20 47. l-Phenyl-4-[3-benzoyl-4-phenyl-~4-dehydro-1-piperidinyl]-l-butanone 48. 1-Phenyl-4-[3-p-fluorobenzoyl-4-p-fluorophenyl-~'-- dehydro-1-piperidinyl]-1-butanone 49. 1,1-~is(4-fluorophenyl)-4-[3-benzoyl-4-phenyl-~
dehydro-l-piperidinyl]butane, Melting point 85-87C (hydrochloride) ~' 50. 1,1-Bis(4-fluorophenyl)-4-[3-p-fluorobenzoyl-4-p-:~ fluorophenyl-~'-dehydro-l-piperidinyl]butane :3 30 l-(4-Fluorophenyl)-4-[3-acetyl-4-methyl-~3-dehydro-l-piperidinyl]-1-butanone 200 ml of methylene chloride and then 22.0 g 3~ (68.5 mmol)ofl-(4-fluorophenyl)-4-[4-hydroxy-cis,trans-3-acetyl-4-methyl-1-piperidinyl]-1-butanone (Example 10, 11) dissolved in 100 ml of methylene chloride were added dropwi~e to 40 ml (747 mmol) of concentrated sulfuric acid while cooling in ice to 0-5C. The mixture was .
, .3' ' ':
.'.' ' ' ~ ' 2 L~7 ~ ~ 5 16 - o.z. 0050/42360 - stirred while cooling in ice for 2 h and then at 30-35C
~- for l h, and was then poured into ice-water, adjuYted to :. pH 10 with concentrated sodium hydroxide solution and ^i partitioned between methylene chloride and water, and the organic phase wai3 dried with sodium sulfate and con-~; centrated. The crude product wa~ purified ~y column chromatography (silica gel, methylene chloride 99/1) to yield 9.8 g (45 %) of melting point 67-70C (tartrate).
The following can be prepared in a i~imilar way:
: 10 52. 1-(4-Fluorophenyl)-4-[3-acetyl-4-methyl-~3-dehydro-l-piperidinyl]butane 53. 1-Phenyl-4-[3-acetyl-4-methyl-~3-dehydro-1-piperidinyl]-1-butanone 54. 1-Phenyl-4-[3-acetyl-4-methyl-~3-dehydro-1-piperidinyl]butane 1-(4-Fluorophenyl)-4-[3-phenyl(hydroxy)methyl-4-phenyl--dehydro-l-piperidinyl]-1-butanone 4.0 g (9.0 mmol) of 1-(4-fluorophenyl)-4-[3-' 20 benzoyl-4-phenyl-~-dehydro-1-piperidinyl]-1-butanone (Example 41, 43) were suspended in 50 ml of methanol and, at 30C, 0.34 g (9.0 mmol) of sodium boronate wa8 810wly.
added. The mixture was stirred at room temperature for 2 h and then evaporated in a rotary evaporator. The residue was partitioned between methylene chloride and water at pH 10, and the organic phase wa~ dried with sodium sulfate and concentrated to give 3.8 g (95 %) of `~ product of melting point 191-192C (hydrochloride).
i~ 30 a) Preparation of t~e starting material ; 3-3enzoyl-4-phenyl-~'-dehydropiperidine 12.0 g (66 mmol) of 30 % sodium methylate ~olu-tion were added to 4.2 g (16.0 mmol) of 3-benzoyl-4-phenyl-~-dehydropiperidine (Example 41 a) in 60 ml of methanol, and the mixture was refluxed for 8 h and then stirred at room temperature overnight and evaporated to ; dryness in a rotary evaporator. The residue was poured . '. .
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.....
.. ........
: ~ - 17 - o.Z. 0050/42360 into ice-water, the mixture was extracted several times with methylene chloride, and the organic phases were ,~ dried with sodium sulfate and evaporated. The crude product was purified by column chromatography (silica ; 5 gel, methylene chloride + 1 % methanol) to yield 1.9 g (45 %) of melting point 189-192C.
b) Preparation of the final product 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~3-dehydro-1-piperidinyl]-1-butanone 2.8 g (10.6 mmol) of 3-benzoyl-4-phenyl-~3-dehydropiperidine in 50 ml of xylene were mixed with ~`~ 2.6 ml (15.4 mmol) of ~-chloro-4-fluoro~utyrophenone and with 2.2 g (16 mmol) of finely powdered potassium car-~ bonate together with 0.5 g of potassium iodide and ; 15 refluxed while stirring vigorously for 13 h. The mixture was partitioned between methylene chloride and water, and-the organic pha~e was dried with ~odium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, methylene chloride + 5 %
methanol) to yield 1.4 g (31 %) of product with melting point 171-172C.
. ~
The following can be prepared in a similar way:
57. 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~3-dehydro-piperidinyl]-l-butanol .~ 25 EXAMPLE 58 3 l-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~3-dehydro-l-piperidinyl]-1-butanone 5.7 g (32 mmol) of 30 ~ sodium methylate solution were added to 4.5 g (10.5 mmol) of 1-(4-fluorophenyl)-4-t3-benzoyl-4-phenyl-~4-dehydro-l-piperidinyl]-l-butanone (Example 41, 43) in 60 ml of methanol, and the mixture j was refluxed for 1.5 h, then stirred at room temperature overnight and evaporated to dryness in a rotary , evaporator. The re~idue was poured into ice-water, the ; 35 mixture was partitioned between methylene chloride and water, the pH was adjusted to 10, and the organic phase was dried over ~odium sulfate and concentrated. The crude ,, ~
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` - - 18 - O.Z. 0050/42360 product was purified by column chromatography (silica gel, methylene chloride ~ 2.5 % methanol) to yield 2.2 g ~ (48 %) of product whose maleate melt~ at 171 172C.
- The following can be prepared in a ~imilar way:
59. l-(4-Fluorophenyl)-4-~3-benzoyl-4-phenyl-~3-dehydro-~ 1-piperidinyl]butane ; 60. 1-(4-Fluorophenyl)-4-[3-p-fluorobenzoyl-4-p-fluoro-phenyl-~3-dehydro-l-piperidinyl]-1-butanone, Melting point 211-213C (hydrochloride) 61. 1-(4-Fluorophenyl)-4-[3-p-fluorobenzoyl-4-p-fluoro-phenyl-~3-dehydro-l-piperidinyl]butane -~ 62. 1-Phenyl-4-[3-benzoyl-4-phenyl-~3-dehydro-1-piperidinyl]-l-butanone 63. l-Phenyl-4-[3-p-fluorobenzoyl-4-p-fluorophenyl-~3-lS dehydro-1-piperidinyl]-1-butanone 64. l,1-Bi~(4-fluorophenyl)-4-[3-benzoyl-4-phenyl-A3--dçhydro-1-piperidinyl~butane Melting point 85-87C (hydrochloride) - 65. 1,1-Bis(4-fluorophenylJ-4-t3-p-fluorobenzoyl-4-p--- 20 fluorophenyl-~3-dehydro-l-piperidinyl]butane.
-~1 -) a) Preparation of the starting material Ci3- 3-phenyl(hydroxy)methyl-4-phenylpiperidine 7.8 g (22.1 mmol) of 3-benzoyl-4-phenyl-1-benzyl-~-dehydropiperidine (prepared as in Example 41 a) in , 300 ml of ethanol were catalytically hydrogenated with ; the addition of 1.6 g of palladium (10 ~) on carbon at t room temperature under atmospheric pressure for 48 h. The -~ mixture was filtered to remove the catalyst, evaporated to dryne~s, taken up in 40 ml of acetone with heating, r" and cooled while stirring. The precipitated product waq ~l filtered off with suction and washed with acetone. Yield:
,~ , 2.3 g (39 ~); the hydrochloride melt~ at 239-240C.
b) Preparation of the final product 1-(4-Fluorophenyl)-4-tcis-3-phenyl(hydroxyjmethyl-4-I phenyl-l-piperidinyl]-l-butanone ~ 4.0 g (15.0 mmol) ofcis-3-phenyl(hydroxy~methyl-, ..
~, , ~i 23 ~75~5 9 - O ~ Z,~ 0050/42360 - 4-phenylpiperidine in 50 ml of toluene were mixed with - 3.8 ml (23 mmol) of ~-chloro-4-fluorobutyrophenone and with finely powdered potas~ium carbonate in addition to 1.O g of potassium iodide and refluxed while stirring ; 5 vigorou~ly for 25 h. After cooling, the filtrate was concentrated, the reRidue wa~ partitioned at pH 10 between methylene chloride and water, and the organic phase was dried and concentrated. The crude product wa~
purified by column chromatography (~ilioa gel, methylene chloride + 5 % methanol) to i~olate 3.5 g (54 ~) of product of melting point 113-114C.
~; The following can be prepared in a ~imilar way:
67. 1-(4-Fluorophenyl)-4-~ci~-3-phenyl(hydroxy)methyl-4-phenyl-l-piperidinyl]butane - 15 68. 1-(4-Fluorophenyl)-4-[cis-3-p-fluorophenyl(hydroxy)-~ methyl-4-p-fluorophenyl-1-piperidinyl]-1-butanone -;,~,?,, 69. 1-(4-Fluorophenyl)-4-[ci~-3-acetyl-4-methyl-1-.i piperidinyl]-l-butanone 70. 1-(4-Fluorophenyl)-4-tci~-3-acetyl-4-methyl-1-~ 20 piperidinyllbutane .~ :
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- 4 - o.Z. 0050/42360 ~` acid), reduction of the 2-butanone moiety (R2 + R3 =
oxygen) to the corresponding 2-butanol derivative with sodium boranate, elimination of H2O from the 4-hydroxy-piperidine moiety (Rs = OH) to give ~4-dehydropiperidine derivative with concentrated sulfuric acid, and the base-catalyzed double-bond shift to give the ~3-dehydro-~ i piperidine compound.
; The compounds of the formula I according to the invention are usually obtained in the form of yellowish or yellow crystals and can be purified byrecrystallization from the conventional organic ~olvents, preferably from a lower alcohol, such as ethanol, or by column chromatography.
The free 1,3,4-trisubstituted piperidine deriva-tive~ of the formula I can be converted in a conventionalway into the addition ~alt~ with a phy~iologically tolerated acid, preferably by adding one equivalent of the appropriate acid to a solution. Examples of pharma-ceutically tolerated acids are hydrochloric acid, phos-phoric acid, eulfuric acid, methanesulfonic acid, ` ~ulfamic acid, maleic acid, fumaric acid, oxalic acid, ~ tartaric acid and citric acid.
J` -' ' ~he compounds according to the invention have -~ valuable pharmacological properties. They can be used as - 25 neuroleptics, antidepressants, sedatives, hypnotics or i~j cerebroprotectivec. It is possible for a plurality of the said propertie~ to be combined in one compound according ~1 to the invention.
They are therefore suitable for the treatment of p~ychoses, preferably ~chizophrenia, and anxiety states, for the treatment and prevention of strokes or distur-bances of cerebral function with an organic cause, and for the treatment of sleep disturbance~.
The present invention accordingly also relates to a therapeutic composition which contains a compound of the formula I or its physiologically tolerated acid ;i addition salt a~ active substance in addition to ~;
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;s - 5 - O.z. 0050/42360 ~ conventional carriers and diluents, and to the use of the - novel copounds for controlling diseases.
The compound according to the invention can be 'r. administered in a conventional way orally or parenteral-ly, intravenously or intramuscularly.
The dosage dependR on the age, condition and weight of the patient and on the mode of administration.
As a rule, the daily dose of active ~ubstance i~ about 1-100 mg/kg of body weight on oral administration and 0.1-`;- 10 2 mg/kg of body weight on parenteral administration.
; The novel compounds can be used in conventional solid or liquid pharmaceutical forms, e.g. as uncoated or (film-~coated tablets, capsules, powders, granules, ~ suppositories, solutions, ointments, creams or spray~.
; 15 These are produced in a conventional way. The active sub~tances can for this purpose be processed with conven-tional pharmaceutical aids ~uch as tablet binders, fillerc, preservatives, tablet disintegrant~, flow i' regulators, plasticizers, wetting agents, disper~ants, emulsifiers, solvents, retardants, antioxidants and/or propellant gases tcf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The forms - obtained in this way normally contain the active sub-;~ ~ stance in an amount of from 0.1 to 99 % by weight.
The substances of the formula II which are required a~ starting materials for synthesizing the novel compounds are known.
The substances of the formula III have not previously been described (but see DE 41 12 352). They ';'!' 30 are prepared, for example, by reacting 2 mole equivalents of an a,~-unsaturated ketone of the formula IV
CH2=CH-C0-~4 IV
;!
; or a ~-halo ketone of the formula V
Hal-C~2-CH2-C0-R~ V, where R' ha~ the abovementioned meanings, with an amine ,~ I
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6 - o.z. 0050/42360 ~- H2N-Ra where R8 is benzyl which is unsubstit-lted or substituted by halogen, methoxy or nitro, or is allyl, in - the presence of 1 mole equivalent of sodium hydroxide solution in methanol at 50C. This reaction iR usually diastereoRelective to give the compound VI with di equatorial trans configuration with respect to R4 . ' ,,~
HO. R4 J v r, ,:
which can be converted by elimination of R~ and, where appropriate, subRequent elimination of water and pos~ible rearrangement and reduction as described above for the ; 10 final products into the compounds of the formula III.
The following examples illustrate the invention: ~
:.
a) Preparation of the starting material 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenylpiperidine 600 g (1.62 mol) of trans-3-benzoyl-4-phenyl-4-hydroxy-l-benzylpiperidine in 1.4 l of ethyl acetate - mixed with 1.4 l of methanol were catalytically hydro-: genated with the addition of 20 g of palladium llO %) on ; carbon at 70C under a hydrogen pre~3ure of 100 bar for 3 20 12 h. The mixture was filtered at 50C to remove cata--~ lyst, evaporated to dryness, taken up in 0.6 l of acetone and stirred while cooling. The precipitated product was ~''1 filtered off with ~uction, the filtrate was concentrated, the re~idue was ~tirred in 300 ml of acetone again while cooling, and a ~econd product fraction was filtered off ~ with ~uction.
i~ Yield: 345 g ~75 %) of the pure diastereomer of the product, melting point 167-169C.
b) Preparation of the final product 1-(4-fluorophenyl)-4-[4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanone 20.0 g (70.7 mmol) of 4-hydroxy-trans-3-phenyl-(hydroxy3methyl-4-phenylpiperidine in 210 ml of xylene , ;
~ .
.... ~ . . . . -. . .
'. ~. . . : ' ~ :
~,~ , - .
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2 1 ~
: - 7 - o.z. 0050/42360 were mixed with 26.7 ml (162-mmol) of ~-chloro-4-fluoro-butyrophenone and with 18.8 g (136 mmol) of finely powdered potas~ium carbonate in addition to 1.0 g of potassium iodide and refluxed while stirring vigorously for 16 h. After cooling, 200 ml of toluene were added and the mixture was ~tirred vigorously while the pale solid precipitated. The crude product was filtered off with suction, washed with toluene and dried at 50C under reduced pre3sure. The ~olid was then digested in l 1 of water at 50C and finally the product wa~ filtered off with ~uction (melting point 182-183C), yield: 22.6 g (72 %).
The following can be prepared in a Yimilar way:
- 2. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-phenyl-(hydroxy)methyl-4-phenyl-1-piperidinyl]butane Alkylating reagent: l-(p-fluorophenyl)-4--chlorobutane 3. 1-Phenyl-4-[4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanone, Melting point 173-175C
4. 1-Phenyl-4-[4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl]butane 5. 1-(4-~romophenyl)-4-[4-hydroxy-trans-3-phenyl-(hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanone, - 25 Melting point 186-187C
a) Preparation of the starting material 4-Hydroxy-trans-3-p-fluorophenyl(hydroxy)methyl-4-p-fluorophenylpiperidine 30.0 g ~67.6 mmol) of4-hydroxy-1-benzyl-trans-3-p-fluorobenzoyl-4-p-fluorophenylpiperidine hydrochloride in 1 1 of methanol were catalytically hydrogenated with the addition of 4.0 g of palladium (10 %) on carbon at , 50C for 8 h. After filtration and washing with methanol, the filtrate was evaporated to dryne~s. The residue wa~
taken up in a mixture of 140 ml of methanol and 500 ml of water at 70C, concentrated ammonia was added until the .
: . :
~ ~ , ~ ~:
`~ 2 1 O ~ ~ ~ 5 - 8 - O.Z. 0050/42360 mixture was alkaline, and the precipitated product was filtered off with suction and washed thoroughly with water. Drying at 60C under reduced pressure resulted in 20.2 g (94 %) of product of melting point 215-217C.
b) Preparation of the f inal product 1-(4-Fluorophenyl)-4-[4-hydroxy-tran~-3-p-fluoro-phenyl(hydroxy)methyl-4-p-fluorophenyl-l-` piperidinyl]-1-butanone ; 20.0 g (63.0 mmol) of 4-hydroxy-tran~-3-p-fluoro-phenyl(hydroxy)methyl-4-p-fluorophenylpiperidine in a -~ mixture of 250 ml of toluene and 25 ml of dimethyl-formamide were mixed with 20.6 ml (125 mmol) of ~-chloro-4-fluorobutyrophenone and with finely powdered potas~ium carbonate in addition to 1.0 g of potas~ium iodide and refluxe~ while stirring vigorou~ly for 8 h. After cool-ing, the mixture wa~ evaporated in a rotary evaporator,-the residue was taken up in a little dimethylformamide, and the solution was poured into vigorously stirred ice-water. The precipitated solid was filtered off with - 20 suction, thoroughly washed with water and recrystallized - from ethanol to give 23.5 g (78 %) of product of melting ~- point 175-177C.
'~7 The following can be prepared in a similar way:
;~ 7. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-p-fluoro-'~, 25 phenyl(hydroxy)methyl-4-p-fluorophenyl-1-~'1 piperidinyl]butane, melting point 170-171C.
8. 1-Phenyl-4-[4-hydroxy-trans-3-p-fluorophenyl-'j (hydroxy)methyl-4-p-fluorophenyl-1-piperidinyl]-1-butanone ;~ 30 9. 1-Phenyl-4-[4-hydroxy-trans-3-p-fluorophenyl-(hydroxy)methyl-4-p-fluorophenyl-1-piperidinyl]-~, butane ~ EXAMPLE 10 i; a) Preparation of the starting material 4-hydroxy-cis-3-acetyl-4-methylpiperidine 20.1 g (81.0 mmol) of 4-hydroxy-1-benzyl-ci~-3-acetyl-4-methylpiperidine in 700 ml of methanol were .' .
,; .
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- , -~ 21 ~7~5 - . ,.. -_ g - o.z. 0050/42360 catalytically hydrogenated with the addition of 2.5 g of palladium (10 %) on carbon at room temperature for 8 h.
- After filtration and wa~hing with methanol, the filtrate was evaporated to dryne~s. 11.9 g (94 %) of product were isolated, melting point 91-93C. The hydrochloride melts at 118-199C.
.:;,; .
- The tran~ isomer can be prepared in a ~imilar way: decomposition above 133C (hydrochloride).
b) Preparation of the final product ` 10 1-(4-Fluorophenyl)-4-[4-hydroxy-cis-3-acetyl-4-`; methyl-1-piperidinyl)-1-butanone 20.5 g (131 mmol) of 4-hydroxy-ci~-3-acetyl-4-methylpiperidine in a mixture of 250 ml of toluene and 25 ml of dimethylformamide were mixed with 21.4 ml (131 mmol) of ~-chloro-4-~luorobutyrophenone and with 18 g (131 mmol) of finely powdered potassium carbonate in addition to 1.0 g of potassium iodide and refluxed while stirring viyorously for 3 h. After cooling, the mixture ~' was evaporated in a rotary evaporator, and the residue wa~ partitioned between methylene chloride and water. The aqueous pha~e wa~ extracted with methylene chloride, and ; then the organic phase was dried with sodium ~ulfate and ~: evaporated. The crude product was purified by column s~ chromatography (~ilica gel, methylene chloride/methanol 98/~2). 9.5 g (22 %) of product were isolated, de-compo~ition above 90C (tartrate).
The following can be prepared in a ~imilar way:
(4-Fluorophenyl)-4-[4-hydroxy-trans-3-acetyl-4-methyl-1-piperidinyl]-1-butanone, i~ 30 Melting point 174-175C (hydrochloride) 12. 1-~4-Fluorophenyl)-4-[4-hytroxy-cis-3-acetyl-4-methyl)-1-piperidinyl]-1-butanol, Alkylating reagent: l-hydroxy-1-(p-fluorophenyl)-4-` chlorobutane ~' 35 13. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-acetyl-4-methyl-l-piperidinyl]-l-butanol~ melting point 97-99C, Alkylating reagent: 1-hydroxy-1-(p-fluorophenyl)-~ . .
``3 . ~ .
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~ 2~7~5 .
- 10 - O.z. 0050/42360 4-chlorobutane - 14. 1-(4-Fluorophenyl)-4-[4-hydroxy-ci~-3-acetyl-4-methyl-l-piperidinyl]butane, melting point 85-88c (hydrochloride) .: 5 15. 1-(4-Fluorophenyl)-4-~4-hydroxy-trans-3-acetyl-4-. methyl-1-piperidinyl]butane, melting point 105-107C
; (hydrochloride) - 16. 1-(4-Phenyl)-4-[4-hydroxy-cis-3-acetyl-4-methyl-1-. piperidinyl]-l-butanone 17. 1-(4-Phenyl)-4-[4-hydroxy-trans-3-acetyl-4-methyl-1-piperidinyl]-1-butanone ; 18. 1-(4-Phenyl)-4-[4-hydroxy-cis-3-acetyl-4-methyl-1-piperidinyl]butane 19. 1-(4-Phenyl)-4-[4-hydroxy-tran~-3-acetyl-4-methyl-1-piperidinyl]butane ; 20. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-propionyl-4-. .
ethyl-l-piperidinyl]-l-butanone . EXAMPLE 21 ~ 4-fluorophenyl)-4-[4-hydroxy-trans-3-phenyl-20 (hydroxy)methyl-4-phenyl-1-piperidinyl]butane .^~ 22.8 g t80.6 mmol) of 4-hydroxy-trans-3-phenyl-.~ (hydroxy)methyl-4-phenylpiperidine (Example la) in400 ml .S- of xylene mixed with 40 ml of DMF were mixed with 22.6 g (80.6 mmol) of 1,1-bis(4-fluorophenyl)-4-chlorobutane and 25 with 18.6 g (132 mmol) of finely powdered pota~sium :1 carbonate in addition to 0-3 g of potassium iodide and refluxed while stirring vigorously for 8 h. The mixture -. was ~ooled and then evaporated to dryness. The residue ' was disaolved in DMF, and the solution was poured into `~ 30 2.5 1 of vigorously stirred ice-water. After stirring for . 1 hour, the precipitated solid was filtered off with : suction to give 40.1 g (95 %) of product of melting point ~ 160-162~C.
,1 The following can be prepared in a similar way:
22. 1,1-~is~4-fluorophenyl)-4-[4-hydroxy-trans-3-p-fluonq~Ysyl~ xxy)m~yl~t~~KrqpYIyl-l-l4yr~lyl]b~ne 23. 1,1-~is(4-fluorophenyl)-4-[cis-3-acetyl-4-hydroxy-1-~ .
, ., ~
- . .
~ 2~ L~ 7~
..... .
;'`-"' '~- - 11 - O.Z. 0050/42360 ~, .
:.- piperidinyl]butane, melting point 116-ll9~C
(hydrochloride) ~', 24. 1,1-Bist4-fluorophenyl)-4-[tran~-3-acetyl-4-hydroxy-1-piperidinyl]butane, melting point 93-96C
' , 5 (hydrochloride) ~" 1-(4-Fluorophenyl)-4-[4-hydroxy-tran~-3-phenyl(hydroxy)-, methyl 4-phenyl-1-piperidinyl]-1-butanol 5.0 g (11.6 mmol) of 1-t4-fluorophenyl)-4-[4-' , 10 hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl-1-' piperidinyl]-1-butanone (Example lb) were dis~olved in a ',, mixture of 80 ml of methanol and 100 ml of tetra-hydrofuran, and 0.6 g (16 mmol) of sodium boranate was added. The mixture was stirred at room temperature for ' 15 2 h and then concentrated in a rotary evaporator. The ~ residue was partitioned between methylene chloride and, ;',, water at pH 10, and the organic phase waR dried with 'i sodium ~ulfate and evaporated to give 4.6 g (88 %) of, product of melting point 90-92C (decomposition).
.,~ 20 The following can be prepared in a similar way: -26. 1-Phenyl-4-t4-hydroxy-tran~-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanol Melting point: 90-92C
,~ 27. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-p-fluoro-'', 25 phenyl(hydroxy)methyl-4 -p-f luorophenyl-1-', piperidinyl]-1-butanol ;,j 28. 1-~4-Fluorophenyl)-4-[4-hydroxy-tran~-3-p-fluoro-'~, phenyl~hydroxy)methyl-4-p-fluorophenyl-1-,~, piperidinyl]butane ,~' 30 29. 1-Phenyl-4-[4-h'ydroxy-trans-3-p-fluorophenyl-~ (hydroxy)methyl-4-p-fluorophenyl-1-piperidinyl]-``^, 1-butanol '~' 30. 1-(4-Fluorophenyl)-4-[4-hydroxy-cis-3-a-hydroxy-'`~ ethyl-4-methyl-1-piperidinyl]-1-butanol 31. 1-~4-Fluorophenyl)-4-~4-hydroxy-trans-3-a-hydroxy-ethyl-4-methyl-1-piperidinyl]-1-butanol 32. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-a-hydroxy-'; .
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.
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- - 12 - O.Z. 0050/42360 ethyl-4-methyl-1-piperidinyl]butane 33. l-(4-Bromophenyl)-4-[4-hydroxy-tran~-3-phenyl-(hydroxy)methyl-4-phenyl-1-piperidinyl]-1-butanol, Melting point 92-93C
- 5 34. 1,1-si~(4-fluorophenyl)-4-[4-hydroxy-ci~-3-a-~, hydroxyethyl-4-methyl-l-piperidinyl]butane 35. 1,1-Bi~(4-fluorophenyl)-4-[4-hydroxy-trans-3--hydroxyethyl-4-methyl-1-piperidinyl]butane 1-(4-Fluorophenyl)-4-[4-hydroxy-tran~-3-benzoyl-4-phenyl-1-piperidinyl]-1-butanone 22.6 g (50.7 mmol~ of 1-t4-fluorophenyl)-4-[4-hydroxy-tran~-3-phenyl(hydroxy)methyl-4-phenyl-1-piperidinyl)-l-butanone (Example lb) were ~uspended in 500 ml of acetone and then, while stirring vigorously, 21 ml (56 mmol) of JoneY reagent were added dropwise. The-temperature rose to 32C during thi~. The mixture was stirred at room temperature for 12 h and then evaporated in a rotary evaporator. The mixture was then poured into ice-water, methylene chloride was added, dilute sodium hydroxide solution was added until alkaline, and the precipitated chromium oxide was filtered off with suction. The aqueous phase was extracted with methylene chloride and then the organic phase was dried with ~odium sulfate and concentrated to give 21.1 g (95 %) of product of melting point 128-130C.
The following can be prepared in a similar way:
37. 1-(4-Fluorophenyl)-4-[4-hydroxy-trans-3-p-fluorobenzoyl-4-p-fluorophenyl-1-piperidinyl]-1-butanone, Melting point 111-113C
38. 1-Phenyl-4-[4-hydroxy-trans-3-p-fluorobenzoyl-4-p-fluorophenyl-1-piperidinyl]-1-butanone 1,1-Bis(4-fluorophenyl)-4-[4-hydroxy-trans-3-benzoyl-4-phenyl-1-piperidinyl]butane 4.0 g (7.6 mmol) of 1,1-bi~(4-fluoroph-nyl)-4-[4-.
13 - O.z. 0050/42360 hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenyl~
piperidinyl]butane (Example 21) were di~olved in 50 ml of glacial acetic acid and then, while stirring vigorous-ly, 4.3 ml (11.4 mmol) of Jones reagent were added dropwi~e. The mixture was ~tirred at 60C for 12 h and' ; then the ~olution was decanted off the precip'itated chromium salts. The mixture wa~ then poured into ice-water, methylene chloride was added, and sodium hydroxide ~olution was added until alkaline. The aqueous phase was extracted with methylene ~hloride and then the organic ' phase was dried with sodium ~ulfate and concentrated. The ' crude product was purified by column chromatography '~' (silica gel, methylene chloride/methanol 98/2) to give ~ 1.0 g (50 %) of product ~oil).
;~`' 15 'The following can be prepared in a ~imilar way:
40. 1,1-Bis(4-fluorophenyl)-4-t4-hydroxy-trans-3-p-; fluorobenzoyl-4-p-fluorophenyl-1-piperidinyl]butane '' EXAMPLE 41 ~ a) Preparation of the starting material i` 20 1. 4-Hydroxy-trans-3-benzoyl-4-phenylpiperidine '~ 8 ml (21.4 mmol) of Jones reagent were added dropwise to 6.0 g (21.2 mmol) of 4-hydroxy-trans-3-phenyl(hydroxy)methyl-4-phenylpiperidine (Example la) in ~ ' 150 ml of acetone. The temperature rose to 30C during '~ 25 this. The mixture was stirred at room temperature for :j 1 h, and the solution was decanted off the precipitated i~ chromium oxide and evaporated to half the volume in a "~ rotary evaporator. The mixture wa~ then poured into ice-water, dilute sodium hydroxide solution was added until `' 30 alkaline, the mixture was extracted several times with methylene chloride, and the organic phase was dried with odium sulfate and evaporated. 5.2 g (87 %) of product were isolated and, after recrystallization from ethyl acetate, melted at 128-129C.
1 35 2. 3-Benzoyl-4-phenyl-~'-dehydropiperidine 'i 400 ml of methylene chloride and then 112.6 g 3 (304 mmol) of 4-hydroxy-tran~-3-benzoyl-4-phenyl-~, .j . . . .
. ~ , , .
; . , ~'` 2~7~
`~ - 14 - O.Z. 0050/42360 piperidine dissolved in 350 ml c.ff methylene chloride were added dropwise to 186 g (1.9 mol) of concentrated ~ul-furic acid while cooling in ice to 0-5C. The mixture was ~tirred while cooling in ice for 2-3 h and then poured into ice-water, concentrated sodium hydroxide solution waff~ added (to pH 10). The mixture was partitioned between methylene chloride and water, and the organic phase was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (fqilica ~- 10 gel, methylene chloride + 5 ~ methanol) to fgiVe a yield of 61 g (57 ~) of melting point 118-119C.
-- b) Preparation of the final product 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~-dehydro-1-piperidinyl]-1-butanone 15.4 g (59 mmol) of 3-benzoyl-4-phenyl-f~4-dehydropiperidine in 90 ml of xylene were mixed with-~-;; 11.5 ml (70 mmol) of ~ff-chloro-4-fluorobutyrophenone and with 12.1 g ( Iff~-ff8 mmol) of finely powdered potaRqium ,~, carbonate tngether with 0.5 g of potassium iodide and re~luxed while stirring vigorouqly for 15 h. The mixture was concentrated in a rotary evaporator and then the ' ~ residue was partitioned between ice-water and methylene chloride, making alkaline with dilute sodium hydroxide solution. The aqueous phase wa~ extracted with methylene chloride and then the organic phase wa~ dried with sodium sulfate and concentrated. The crude product was purified f by column chromatography (silica gel, methylene chloride/methanol 98/2) to give 5.2 g (21 ~ of product ' of melting point 89-91C (hydrochloride).
The following can be prepared in a similar way:
42. 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-f~'-dehydro-l-piperidinyl]-l-butanol . f~ EXAMPLE 43 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~-dehydro-1-`~ 35 piperidinyl]-l-butanone ;~ 100 ml of methylene chloride and then 10.0 g (22.4 mmol) of 1-(4-fluorophenyl)-4-[4-hydroxy-trans-3-., :
.
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; ~ - 15 - O.Z. 0050/42360 ~enzoyl-4-phenyl-1-piperidinyl]-1-butanone (Example 36) dissolved in 50 ml of methylene chloride were added dropwise to 18.0 ml (336 mmol) of concentrated ~ulfuric acid while cooling in ice to 0-5C. The mixture wa~
~tirred while cooling in ice for 2 h and then poured into ice-water, adjusted to pH 10 with concentrated sodium ,7 hydroxide solution and partitioned between methylene chloride and water, and the organic phase was dried over sodium ~ulfate and concentrated. The crude product was purified by column chromatography (silica gel, methylene chloride 99/1) to give a yield of 4.2 g (44 %) of pale oil. The hydrochloride melts at 89-91C.
- The following can be prepared in a similar way:
44. 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~-dehydro-l-piperidinyl]butane 45. 1-(4-Fluorophenyl)-4-[3-p-fluorobenzoyl-4-fluoro-phenyl- ~4 -dehydro-l-piperidinyl]-l-butanone 46. 1-(4-Fluorophenyl)-4-[3-p-fluorobenzoyl-4-fluoro-phenyl-~-dehydro-1-piperidinyl]butane - 20 47. l-Phenyl-4-[3-benzoyl-4-phenyl-~4-dehydro-1-piperidinyl]-l-butanone 48. 1-Phenyl-4-[3-p-fluorobenzoyl-4-p-fluorophenyl-~'-- dehydro-1-piperidinyl]-1-butanone 49. 1,1-~is(4-fluorophenyl)-4-[3-benzoyl-4-phenyl-~
dehydro-l-piperidinyl]butane, Melting point 85-87C (hydrochloride) ~' 50. 1,1-Bis(4-fluorophenyl)-4-[3-p-fluorobenzoyl-4-p-:~ fluorophenyl-~'-dehydro-l-piperidinyl]butane :3 30 l-(4-Fluorophenyl)-4-[3-acetyl-4-methyl-~3-dehydro-l-piperidinyl]-1-butanone 200 ml of methylene chloride and then 22.0 g 3~ (68.5 mmol)ofl-(4-fluorophenyl)-4-[4-hydroxy-cis,trans-3-acetyl-4-methyl-1-piperidinyl]-1-butanone (Example 10, 11) dissolved in 100 ml of methylene chloride were added dropwi~e to 40 ml (747 mmol) of concentrated sulfuric acid while cooling in ice to 0-5C. The mixture was .
, .3' ' ':
.'.' ' ' ~ ' 2 L~7 ~ ~ 5 16 - o.z. 0050/42360 - stirred while cooling in ice for 2 h and then at 30-35C
~- for l h, and was then poured into ice-water, adjuYted to :. pH 10 with concentrated sodium hydroxide solution and ^i partitioned between methylene chloride and water, and the organic phase wai3 dried with sodium sulfate and con-~; centrated. The crude product wa~ purified ~y column chromatography (silica gel, methylene chloride 99/1) to yield 9.8 g (45 %) of melting point 67-70C (tartrate).
The following can be prepared in a i~imilar way:
: 10 52. 1-(4-Fluorophenyl)-4-[3-acetyl-4-methyl-~3-dehydro-l-piperidinyl]butane 53. 1-Phenyl-4-[3-acetyl-4-methyl-~3-dehydro-1-piperidinyl]-1-butanone 54. 1-Phenyl-4-[3-acetyl-4-methyl-~3-dehydro-1-piperidinyl]butane 1-(4-Fluorophenyl)-4-[3-phenyl(hydroxy)methyl-4-phenyl--dehydro-l-piperidinyl]-1-butanone 4.0 g (9.0 mmol) of 1-(4-fluorophenyl)-4-[3-' 20 benzoyl-4-phenyl-~-dehydro-1-piperidinyl]-1-butanone (Example 41, 43) were suspended in 50 ml of methanol and, at 30C, 0.34 g (9.0 mmol) of sodium boronate wa8 810wly.
added. The mixture was stirred at room temperature for 2 h and then evaporated in a rotary evaporator. The residue was partitioned between methylene chloride and water at pH 10, and the organic phase wa~ dried with sodium sulfate and concentrated to give 3.8 g (95 %) of `~ product of melting point 191-192C (hydrochloride).
i~ 30 a) Preparation of t~e starting material ; 3-3enzoyl-4-phenyl-~'-dehydropiperidine 12.0 g (66 mmol) of 30 % sodium methylate ~olu-tion were added to 4.2 g (16.0 mmol) of 3-benzoyl-4-phenyl-~-dehydropiperidine (Example 41 a) in 60 ml of methanol, and the mixture was refluxed for 8 h and then stirred at room temperature overnight and evaporated to ; dryness in a rotary evaporator. The residue was poured . '. .
~ ~ .
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.....
.. ........
: ~ - 17 - o.Z. 0050/42360 into ice-water, the mixture was extracted several times with methylene chloride, and the organic phases were ,~ dried with sodium sulfate and evaporated. The crude product was purified by column chromatography (silica ; 5 gel, methylene chloride + 1 % methanol) to yield 1.9 g (45 %) of melting point 189-192C.
b) Preparation of the final product 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~3-dehydro-1-piperidinyl]-1-butanone 2.8 g (10.6 mmol) of 3-benzoyl-4-phenyl-~3-dehydropiperidine in 50 ml of xylene were mixed with ~`~ 2.6 ml (15.4 mmol) of ~-chloro-4-fluoro~utyrophenone and with 2.2 g (16 mmol) of finely powdered potassium car-~ bonate together with 0.5 g of potassium iodide and ; 15 refluxed while stirring vigorously for 13 h. The mixture was partitioned between methylene chloride and water, and-the organic pha~e was dried with ~odium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, methylene chloride + 5 %
methanol) to yield 1.4 g (31 %) of product with melting point 171-172C.
. ~
The following can be prepared in a similar way:
57. 1-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~3-dehydro-piperidinyl]-l-butanol .~ 25 EXAMPLE 58 3 l-(4-Fluorophenyl)-4-[3-benzoyl-4-phenyl-~3-dehydro-l-piperidinyl]-1-butanone 5.7 g (32 mmol) of 30 ~ sodium methylate solution were added to 4.5 g (10.5 mmol) of 1-(4-fluorophenyl)-4-t3-benzoyl-4-phenyl-~4-dehydro-l-piperidinyl]-l-butanone (Example 41, 43) in 60 ml of methanol, and the mixture j was refluxed for 1.5 h, then stirred at room temperature overnight and evaporated to dryness in a rotary , evaporator. The re~idue was poured into ice-water, the ; 35 mixture was partitioned between methylene chloride and water, the pH was adjusted to 10, and the organic phase was dried over ~odium sulfate and concentrated. The crude ,, ~
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` - - 18 - O.Z. 0050/42360 product was purified by column chromatography (silica gel, methylene chloride ~ 2.5 % methanol) to yield 2.2 g ~ (48 %) of product whose maleate melt~ at 171 172C.
- The following can be prepared in a ~imilar way:
59. l-(4-Fluorophenyl)-4-~3-benzoyl-4-phenyl-~3-dehydro-~ 1-piperidinyl]butane ; 60. 1-(4-Fluorophenyl)-4-[3-p-fluorobenzoyl-4-p-fluoro-phenyl-~3-dehydro-l-piperidinyl]-1-butanone, Melting point 211-213C (hydrochloride) 61. 1-(4-Fluorophenyl)-4-[3-p-fluorobenzoyl-4-p-fluoro-phenyl-~3-dehydro-l-piperidinyl]butane -~ 62. 1-Phenyl-4-[3-benzoyl-4-phenyl-~3-dehydro-1-piperidinyl]-l-butanone 63. l-Phenyl-4-[3-p-fluorobenzoyl-4-p-fluorophenyl-~3-lS dehydro-1-piperidinyl]-1-butanone 64. l,1-Bi~(4-fluorophenyl)-4-[3-benzoyl-4-phenyl-A3--dçhydro-1-piperidinyl~butane Melting point 85-87C (hydrochloride) - 65. 1,1-Bis(4-fluorophenylJ-4-t3-p-fluorobenzoyl-4-p--- 20 fluorophenyl-~3-dehydro-l-piperidinyl]butane.
-~1 -) a) Preparation of the starting material Ci3- 3-phenyl(hydroxy)methyl-4-phenylpiperidine 7.8 g (22.1 mmol) of 3-benzoyl-4-phenyl-1-benzyl-~-dehydropiperidine (prepared as in Example 41 a) in , 300 ml of ethanol were catalytically hydrogenated with ; the addition of 1.6 g of palladium (10 ~) on carbon at t room temperature under atmospheric pressure for 48 h. The -~ mixture was filtered to remove the catalyst, evaporated to dryne~s, taken up in 40 ml of acetone with heating, r" and cooled while stirring. The precipitated product waq ~l filtered off with suction and washed with acetone. Yield:
,~ , 2.3 g (39 ~); the hydrochloride melt~ at 239-240C.
b) Preparation of the final product 1-(4-Fluorophenyl)-4-tcis-3-phenyl(hydroxyjmethyl-4-I phenyl-l-piperidinyl]-l-butanone ~ 4.0 g (15.0 mmol) ofcis-3-phenyl(hydroxy~methyl-, ..
~, , ~i 23 ~75~5 9 - O ~ Z,~ 0050/42360 - 4-phenylpiperidine in 50 ml of toluene were mixed with - 3.8 ml (23 mmol) of ~-chloro-4-fluorobutyrophenone and with finely powdered potas~ium carbonate in addition to 1.O g of potassium iodide and refluxed while stirring ; 5 vigorou~ly for 25 h. After cooling, the filtrate was concentrated, the reRidue wa~ partitioned at pH 10 between methylene chloride and water, and the organic phase was dried and concentrated. The crude product wa~
purified by column chromatography (~ilioa gel, methylene chloride + 5 % methanol) to i~olate 3.5 g (54 ~) of product of melting point 113-114C.
~; The following can be prepared in a ~imilar way:
67. 1-(4-Fluorophenyl)-4-~ci~-3-phenyl(hydroxy)methyl-4-phenyl-l-piperidinyl]butane - 15 68. 1-(4-Fluorophenyl)-4-[cis-3-p-fluorophenyl(hydroxy)-~ methyl-4-p-fluorophenyl-1-piperidinyl]-1-butanone -;,~,?,, 69. 1-(4-Fluorophenyl)-4-[ci~-3-acetyl-4-methyl-1-.i piperidinyl]-l-butanone 70. 1-(4-Fluorophenyl)-4-tci~-3-acetyl-4-methyl-1-~ 20 piperidinyllbutane .~ :
"-'i~
. `~ .
~,js ~ ' .
....
~;,1, ~
.,;;
' .
. ~ , :i: , .
:. .
Claims (3)
1. A 1,3,4-trisubstituted piperidine derivative of the formula I
I, where R1 is hydrogen, fluorine, chlorine or bromine, R2 is hydroxyl, or phenyl which is unsubstituted or substituted by fluorine, chlorine or bromine, R3 is hydrogen, or R2 and R3 together are oxygen, and A-B-D is , or .
where R4 is C1-3-alkyl or is phenyl or thienyl which can be substituted by fluorine or chlorine, R5 is hydrogen or hydroxyl, R6 is hydrogen, R7 is hydroxyl, or R6 and R7 together are oxygen, and its salts with physiologically tolerated acids.
I, where R1 is hydrogen, fluorine, chlorine or bromine, R2 is hydroxyl, or phenyl which is unsubstituted or substituted by fluorine, chlorine or bromine, R3 is hydrogen, or R2 and R3 together are oxygen, and A-B-D is , or .
where R4 is C1-3-alkyl or is phenyl or thienyl which can be substituted by fluorine or chlorine, R5 is hydrogen or hydroxyl, R6 is hydrogen, R7 is hydroxyl, or R6 and R7 together are oxygen, and its salts with physiologically tolerated acids.
2. A process for preparing a compound of the for-mula I as claimed in claim 1, which comprises reacting a compound of the formula II
II, where R1, R2, R3 and n have the stated meanings, and Nu is a nucleofugic leaving group, with a 3,4-disubstituted piperidine derivative of the formula III
III, where A, B and D have the meanings stated for formula I, and converting the resulting compound where appropriate into the addition salt with a physiologically tolerated acid.
II, where R1, R2, R3 and n have the stated meanings, and Nu is a nucleofugic leaving group, with a 3,4-disubstituted piperidine derivative of the formula III
III, where A, B and D have the meanings stated for formula I, and converting the resulting compound where appropriate into the addition salt with a physiologically tolerated acid.
3. A compound of the formula I as claimed in claim 1 for use for controlling diseases.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4112353.0 | 1991-04-16 | ||
| DE4112353A DE4112353A1 (en) | 1991-04-16 | 1991-04-16 | 1,3,4-TRISUBSTITUTED PIPERIDINE DERIVATIVES, THEIR PRODUCTION AND USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2107665A1 true CA2107665A1 (en) | 1992-10-17 |
Family
ID=6429675
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002107665A Abandoned CA2107665A1 (en) | 1991-04-16 | 1992-04-04 | 1,3,4-trisubstituted piperidine derivatives, the preparation and use thereof |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0580644B1 (en) |
| JP (1) | JPH06506920A (en) |
| AT (1) | ATE124398T1 (en) |
| CA (1) | CA2107665A1 (en) |
| DE (2) | DE4112353A1 (en) |
| DK (1) | DK0580644T3 (en) |
| ES (1) | ES2073919T3 (en) |
| WO (1) | WO1992018480A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4219973A1 (en) * | 1992-06-19 | 1993-12-23 | Basf Ag | N-substituted azabicycloheptane derivatives, their preparation and use |
| DE4341402A1 (en) * | 1993-12-04 | 1995-06-08 | Basf Ag | N-substituted azabicycloheptane derivatives, their preparation and use |
| DE4341403A1 (en) * | 1993-12-04 | 1995-06-08 | Basf Ag | N-substituted 3-azabicycloalkane derivatives, their preparation and use |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3655533A (en) * | 1970-11-12 | 1972-04-11 | Allied Chem | Zinc electroplating process and acidic zinc fluoborate electrolyte therefor |
| GB1422263A (en) * | 1973-01-30 | 1976-01-21 | Ferrosan As | 4-phenyl-piperidine compounds |
| CA1337418C (en) * | 1988-03-28 | 1995-10-24 | Engelbert Ciganek | 4-aryl-4-piperiding (or pyrrolidine or hexahydroazepine) carbinols and heterocyclic analogs thereof |
-
1991
- 1991-04-16 DE DE4112353A patent/DE4112353A1/en not_active Withdrawn
-
1992
- 1992-04-04 CA CA002107665A patent/CA2107665A1/en not_active Abandoned
- 1992-04-04 AT AT92907778T patent/ATE124398T1/en active
- 1992-04-04 JP JP4507140A patent/JPH06506920A/en active Pending
- 1992-04-04 DK DK92907778.2T patent/DK0580644T3/en active
- 1992-04-04 ES ES92907778T patent/ES2073919T3/en not_active Expired - Lifetime
- 1992-04-04 WO PCT/EP1992/000765 patent/WO1992018480A1/en active IP Right Grant
- 1992-04-04 EP EP92907778A patent/EP0580644B1/en not_active Expired - Lifetime
- 1992-04-04 DE DE59202744T patent/DE59202744D1/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| DE4112353A1 (en) | 1992-10-22 |
| JPH06506920A (en) | 1994-08-04 |
| ES2073919T3 (en) | 1995-08-16 |
| EP0580644A1 (en) | 1994-02-02 |
| WO1992018480A1 (en) | 1992-10-29 |
| DK0580644T3 (en) | 1995-08-28 |
| ATE124398T1 (en) | 1995-07-15 |
| EP0580644B1 (en) | 1995-06-28 |
| DE59202744D1 (en) | 1995-08-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |