CA2186010A1 - New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptor - Google Patents
New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptorInfo
- Publication number
- CA2186010A1 CA2186010A1 CA002186010A CA2186010A CA2186010A1 CA 2186010 A1 CA2186010 A1 CA 2186010A1 CA 002186010 A CA002186010 A CA 002186010A CA 2186010 A CA2186010 A CA 2186010A CA 2186010 A1 CA2186010 A1 CA 2186010A1
- Authority
- CA
- Canada
- Prior art keywords
- piperidyl
- ketone
- naphthyloxy
- fluorophenyl
- propyl
- 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
-
- 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
- C07D211/30—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Toxicology (AREA)
- Nutrition Science (AREA)
- Obesity (AREA)
- Anesthesiology (AREA)
- Otolaryngology (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Compounds of formula I <IMG> (I), (I), as well as their production and use in pharmaceutical agents are described.
Description
.
21 86a~&
New Piperidine Derivatives The invention relates to new piperidine derivatives, process for their production and pharmaceutical agents that contain these compounds .
It i8 known of piperidine derivatives that they have rh~rr~^ological actions and are suitable, for example, for treating psychotropic and cerebraL vascular disorders. It has now been found, surprisingly enough, that the piperidine derivatives according to the invention functionally influence the glutamate receptor or the glutamate receptor~ r-on~ nt ionic rh;lnn~l ~ .
The object of the invention are the c, _ 'c of formula I
R~N~_~B ( I ), in which R1 means substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstitute~
naphthalene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted indole, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzofuran, substituted or unsubstituted tetrahydroquinoline, substituted or unsubstituted tetrahydroisoquinoline, substituted or unsubstituted tetralin, substituted or unsubstituted dihydronaphthalene, substituted or unsubstituted indan, substituted or unsubstituted indanone, subs~ituted or ~ 2 2~ ~60 1 0 unsubstituted tetralone, substituted or unsu~stituted chromen-2-one, substituted or unsubstituted naphthoquinone, Z means oxygen, sulfur, So or SO2, X means (CH2) m--CR2R3--(CH2) p or --( CH2 ) m--CHR2--( CH2 ) ~--CHR3--( CH2 ) p--, B means ~ CH--R4, and m, p, g each mean 0, 1, 2 or 3, R2 and R3 are the 6ame or different and mean ~IydLoy~ll~
hydroxy, C1,4 alkyl, C14 alkoxy or C1 6 alkanoyloxy, R4 means straight-chain or branched, C1 6 alkyl, ~Y: or a phenyl, benzyl, benzoyl, o:-hydroxy-benzyl, pyridinyl or naphthoyl radical optionally sub6tituted with C1 4 alkyl, C14 alkoxy, halogen, hydroxy, --CF3 or --O--CF3 ~ whereby the substituent can be the same or different in one to three places, and Y means oxygen, sulfur or --NH--, as well as their physiologically compatible salts and isomers.
Substituent R1 can be substituted the same or different in one to three places with C14 alkyl, C14 alkoxy, halogen, NO2, CF
--OCF3~ hydroxy, carboxyl, C14 alkoxycarbonyl, formyl, C1 4 alkylcarbonyl, phenyl, phenoxy, benzyl, R5 / Rs --N ~ or ~o~N ~ whereby \ R6 , \ R6 Rs and R6 are the same or different and mean hydrogen, C14 alkyl, phenyl, C1 6 alkanoyl or together with the nitrogen atom a 2~860io 5- or 6-membered saturated or unsaturated heterocycle, which can be substituted in one or more places with C~ 4 alkyl or phenyl an~
can contain another 0, N or S atom. For example, there can be mentioned piperidine, pyrrolidine, morpholine, thi~ oline, piperazine, N-methylpiperazine, 2, 6-dimethylmorpholine, phenylpiperazine as saturated heterocyclepe and imidazole, pyrazole, pyrrole or triazole as unsaturated heterocyclene.
Halogen is defined as fluorine, chiorine, bromine or iodine.
Alkyl means respectively a straight-chain or branched alky radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl.
The C1 6 alkanoyl radical is derived in each case from straight-chain or branched aliphatic carboxylic acids, sueh as, for example, formic aeid, aeetic acid, propionic aeid, butyric acid, trimethylacetic acid or caproic acid.
If R1 is substituted, the substituent can be in any position. As radical R1, there can be mentioned by way of example: pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, l-naphthyl, ~-naphthyl, isoquinolin-5-yl, isoquinolyl-4-yl, isoquinolin-6-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, 1,2,3,4-tetrahydro-5-naphthyl, 1,2,3,4-tetrallydL~ G naphthyl, 7,8-dihydro-2-naphthyl, 7, 8-dihydro-1-naphthyl, chromen-2-on-7-yl, chromen-2-on-4-yl, 1-oxo-1, 2, 3, 4-tetrahydro-5-naphthyl, 1-oxo-1, 2, 3, 4-tetrahydro-6-naphthyl, 2-oxo-1, 2, 3, 4-tetrahydro-5-naphthyl, 2-oxo-1, 2, 3, 4-tetrahydro-6-naphthyl, indan-4-yl, indan-5-yl, indan-1-on-4-yl, naphthoquinone.
2186~10 Oxygen can be viewed as a preferred meaning o~ Z, and Cl 4 alkylene, which can be straight-chain or branched and can be substituted at any position, can be cited as a preferred meaning of X. Especially preferred are combinations with hydrogenated or nonhydrogenated naphthyl derivatives.
The physiologically compatible salts are derived from inorganic and organic acids. Inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or organic acids, such as, for example, aliphatic or aromatic mono- or dicarboxylic acids, such as formic acid, acetic acid; maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for example C1 4 AlkAn~culfonic acids, such as methAn~c~ll fonic acid or benzenesulfonic acids, such as p-tolll~n~clll fonic acid, optionally substituted by halogen or Cl 4 alkyl, are suitable.
If an acid function is contained, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali and il 1 kA l; ne-earth salts, as well as N-methylglucamine, dimethylglucamine, ethylglll- AminP, lysine, 1,6-h~YA~l;Am;na, ethanolamine, glll~a~Am;no~ sarcosine, serinol, tris(~lydLuxy -thyl)Am;n~ l_hane, aminopropanediol, Sovak base, l-amino-2, 3, 4-butanetriol .
The compounds of formula I comprise all possible optical isomers and their mixtures.
I
21~601~
The production of the compounds of formula I and their physiologically compatible salts takes place in a way known in the art, by a) a compound of formula II
R1_Z--E~ (II), in which R1 and Z have the above meaning, being reacted with a compound of formula III
A--X--N B (III), in which X and B have the above meaning and A represents a leaving group, or b) a ~ ulld of formula IV
A--X--Z--R1 ( IV), in which X, Z and R1 have the above meaning and A represents a leaving group, being reacted with an amine of formula V
H--N\ B (V), in which B has the above meaning, or c) an epoxide of formula VI
R~Z (CH2)m~--CH2 (VI) ~
in which R1, z and m have the above meaning, being reacted with an amine of formula V
~I--N\ B (V~, 2 ~ 86{~
or d) a compound of formula VII
H~X--N\ B (VII) in which X and B have the above meaning, being reacted with a ~ uul-d of formula R1-OH according to Mitsunobu and then optionally a carbonyl group being reduced or a hydroxy group being esterified or etherified or the physiologically compatible salts being formed or the isomers being separated.
The nucleophilic substitution of leaving group A according, to process variants a) and b) i6 performed under basic conditions according to the usual methods in an organic solvent that is inert under the reaction conditions.
As leaving groups A, for example, halogens such as chlorine, bromine or iodine or organic sulfonic acid radicals such as the radical of an llk~nlo~ulfonic acid, for example, mesylate, triflate or the radical of an aromatic sulfonic acid, for examplle toluenesulfonic acid or bromobenzenesulfonic acid, are suitable.
As inert organic solvents, polar solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide or alcohols such as ethanol, methanol or cyclic ethers such as dioxane ~ tetrallydLu r UL an, halogenated hydrocarbons, aromatic hydrocarbons or mixtures of the mentioned solvents are suitable.
As bases, inorganic and organic bases are suitable.
Examples of organic bases are alkali hydroxide or Alk~l in~-earth hydroxide, ;~lk~l ino-earth carbonates, ;llk~l in~--earth hydrogen 218601~
carbonates or alkaline-earth alcoholates. Examples of organic j bases are tertiary organic amines, such as tripropylamine, triethylamine, N-alkylmorpholine, N-alkylpiperidine, Hunig base, 1,4-diazabicyclo(2,2,2)octane, 1,5-diazabicyclo(5,4,0)undec-5-ene.
The reaction temperature can be between room temperature and boiling temperature of the solvent.
The reaction according to process c) takes place, i.a., in protic solvents, such as alcohols at elevated temperature up to boiling temperature.
The reaction according to Mitsunobi (process d) is carried out in the presence of triphenylphosphine and azodicarboxylic acid ethyl ester in an inert solvent at elevated temperature or else in the presence of an organic acid at room temperature (Synthesis, 1981, 1).
The reduction of the carbonyl group can be performed with reducing agents that are commonly used, such as, for example, with sodium borohydride, to the corresponding hydroxy ' or with triethylsilane and trifluoroacetic acid at room temperature to a methylene compound. I
If esteri~ication is desired, this is carried out in a way;
known in the art by reaction with an activated acid derivative, such as, for example, acid anhydride, acid halide or acid imidazol ide .
The optional etherification of the hydroxy group is carried out according to the usual methods in the presence of bases, for 2~86~10 example by reaction with methyl iodide in ethylene glycol dimethyl ether in the presence of sodium hydride. I
The compounds of formula I can be isolated from the reaction mixture and purif ied in a way known in the art. Acid addition salts can be converted in the usual way to free bases and the latter optionally in a known way to physiologically compatible acid addition salts, for example by the solution being mixed with a concentrated solution of the desired acid.
If the compounds of formula I have one or more chiral atoms the optically active ~ c can be obtained starting from optically active starting __ ~c or in a way known in the art from the racemates. The enantiomer separation can take place, I
for example, by chromatography on optically active vehicles, by reaction with optically active acids and then fractionated crystallization .
The compounds of formula I as well as their physiologically compatible salts can be used as pharmaceutical agents based on their functional effect on the glutamate receptor or the glutamate receptor-dependent ionic rh;~nn~l s, The pharmacological effectiveness of the ~ c of formula I was determined by the tests described below:
Male NMRI mice weighing 18-22 g were kept under controlled conditions (0600-1800 hours of light/dark cycle, with free access to food and water) and their assignment to groups was randomized.
The groups consisted of 5-16 animals. The observation of the animals was performed between 0800 and 1300 hours.
AMPA was sprayed into the left ventricle of freely movable mice. The applicator consisted of a cannula with a device made of StAinlPf:~ steel, which limits the depth of injection to 3.2 mm. The applicator was connected to an injection pump. The hypodermic needle was inserted perpendicular to the surface of the skull according to the coordinates of Montemurro and Dukelow.
The animals were observed until the occurrence of clonic or tonic seizures up to 180 seconds. The clonic movements, which last longer than 5 seconds, were counted as seizures. The beginning of the clonic seizures was used as an end point for the determination of the seizure threshold. The dose that was nP-!PSsAry to increase or decrease the seizure threshold by 50%
tTHRDSo) was detPrm;nPd in 4-5 experiments. The THRDso limit and the confidence limit were ~1ptprm;npd in a regression analysis.
The results of these tests show that the, ' of formu a I and its acid addition salts influence functional disturbances of the AMPA receptor. They are suitable, therefore, in the production of pharmaceutical agents for symptomatic and preventive treatment of diseases, which are triggered by a change of the function of the AMPA receptor complex.
The treatment with the compounds according to the invention prevents or delays the cell damages and functional disorders that occur because of disease and reduce the symptoms that are thus produced .
The diseases which can be triggered by the dysfunction of excitatory amino acids or changed glutamatergic neurotrAn~m; ~ i on are part of, for example, neurodegenerative disturbances such as 2~86ol~
Parkinson's disease, Huntington's disease, Al~hl~ir-r's disease, senile dementia, multiinfarct dementia, AIDS dementia, AIDS
encephalopathy, amyotrophic lateral sclerosis, olivopontocerebellar degeneration, epilepsy; cell damages by hypoglycemia, hypoxia, ischemia and disturbances of the energy metabolism; neuronal damages, which are triggered by damage of the brain, such as stroke, brain trauma and asphyxia, as well as psychoses, schizophrenia, anxiety conditions, attacks of pain, migraines and vomiting. Also, functional disorders such as impaired memory (amnesia), disturbances of the learning process , vigilance symptoms and deprivation symptoms after chronic intak~
of diagnostic agents such as sedative ph~rr~ tical agents, hallucinogens, alcohol, cocaine and opiates based on the dysfunction of glutamatergic neurotransmission.
The indications can be shown by pharmacological tests that are commonly used.
The invention also comprises pharmaceutical agents, which contain the mentioned compounds, their production as well as th~
use of the _ _ullds according to the invention for the production of pharmaceutical agents, which are used for the treatment and prophylaxis of the above-mentioned diseases. The pharmaceutical agents are produced according to processes known in the art, by the active ingredient being brought with suitable vehicles, adjuvants and/or additives into the form of a pharmaceutical preparation, which is suitable for enteral or parenteral administration. The administration can be carried o7t orally or sublingually as solid in the form of capsules or ll 2~86010 tablet6 or as liquid in the ~orm of 601utions, 6u6pen6ions, elixirs or emul6ion6 or rectally in the form of 6uppo6itorie6 or in the form of optionally also subcutaneously usable injection solutions. A6 adjuvants for the desired pharmaceutical agent formulation, the inert organic and inorganic vehicles that are known to one 6killed in the art are suitable, such as, for example, water, gelatin, gum arabic, lactose, 6tarch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.
Moreover, preservative6, stabilizers, wetting agents, emulsifiers or salts optionally can be contained for changing the osmotic pres6ure or buffer.
The pharmaceutical preparation6 can be present in solid form, for example a6 tablets, coated tablets, suppositories, capsules or in liquid form, for example as solutions, suspension6 or emul6ions.
As vehicle sy6tem6, near-interface adjuvants, such as salts of bile acids or animal or plant phospholipids, but also their mixtures as well as liposomes or their components, can also be u6ed.
For oral u6e, P~ciAlly tablets, coated tablets or capsule6 with talc and/or hydrocarbon vehicles or binders, such as, for example, lacto6e, corn or potato 6tarch, are 6uitable. The u6e 1 can al60 be carried out in liquid form, 6uch as, for example, a6 juice, to which optionally a 6weetener i6 added.
For parenteral use, especially injection solutions or su6pen6ion6, e6pecially aqueou6 601utions of active compounds in polyllydL~,~Ly~thoxylated ca6tor oil, are 6uitable.
~ 12 21860~0 The dosage o~ the active ingredients can vary depending on the type of use, age and weight o~ the patient, type and severity of the disease to be treated and similar factors. The daily dose can be given as a single dose to be administered once or dividec into 2 or more daily doses. The compounds are introduced in a dosage unit of o. 05 to 100 mg of active substance into a physiologically compatible vehicle. In general, a dose of 0.1 tlo 500 ~g/day, preferably 0.1 to 50 mg/day, is used.
If the production of the starting compounds is not described, the latter are known or can be produced analogously to known compounds or processes described here.
The following examples are to explain the production of the compounds Oe eom~
, ~ 13 21860tO
Examp l e ~l-r3-(3-Dimethylaminol~henoxy)-proPYl1-4-t~ eridYl~-(4 f luorol~henyl ) -ketone 265 mg of 3-dimethylaminophenyl is introduced in 20 ml of acetone, mixed with 265 mg of potassium carbonate and 824 mg of (4-fluorophenyl)-[1-(3-methylsulfonyl~xy~lu~yl)-4-piperidyl]-ketone and ref luxed for 3 hours under argon. After the organic phase is concentrated by evaporation, it is chromatou,- a~hed on silica gel with methylene chloride and acetone = 1 + 1. 375 mg of {1-[3-(dimethylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 48-50C, is obtained.
The (4-fluorophenyl)-1-[1-(3-methylsulfonyloxy-propyl)-4-piperidyl]-ketone is obtained according to methods known in the literature by alkylation of 4-(4-fluorobenzoyl)-piperidine with 3-~ pru,uanol-l and potassium carbonate in dimethylf-rr-m;r~e and subsequent reaction with m h~n~ulfonic acid and triethylamine in methylene chloride.
Analogously, there are produced:
{1-[3-(2-Dimethylaminophenoxy) -propyl]-4-piperidyl}-(4-f luorophenyl ) -ketone {1-[3-(4-dimethylaminophenoxy) -propyl]-4-piperidyl}-(4-f luorophenyl ) -ketone {1-[3-(3-morpholinophenoxy)-propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 110-111C
{1-[3-(1-naphthyloxy) -propyl] -4-piperidyl}-(4-fluorophenyli -ketone, melting point 61-64C
* 14 2t86~tO
{1-[3-(2-naphthyloxy)-propyl]-4-piperidyl}-(4-Lluorophenyl) -ketone, melting point 114-115C
{1-[3-(3-dibutylaminophenoxy) -propyl] -4-piperidyl}-(4-f luorophenyl ~ -ketone {1-[3-t2-nitro-1-naphthyloxy) -propyl]-4-piperidyl}-(4-f luorophenyl ) -ketone {1-[3-(1-nitro-2-naphthyloxy) -propyl]-4-piperidyl}-(4-f luorophenyl ) -ketone, me lt ing po int 13 7 -13 8 C
{1-[3- (2, 4-dinitro-1-naphthyloxy) -propyl] -4-piperidyl}- (4-f luorophenyl) -ketone {1-[3-(3-anilinophenoxy) -propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 75-78C
{1-[3-(1-bromo-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 97-100C
{1-[3-(4-chloro-1-naphthyloxy)-propyl]-4-piperidyl}-(4-f luorophenyl ) -ketone {1-[3-(3-acetylaminophenoxy) -propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 108-111C
( 4 - f luoropheny 1 ) - { 1- [ 3 - ( 5 - i s oqu ino ly loxy ) -propy 1 ] -4 -piperidyl}-ketone, melting point 31-33C .
(4-f luorophenyl) -{1- [3- (3-pyridyloxy) -propyl] -4-piperidyl}-ketone, melting point 52-55C
(4-fluorophenyl)-{1-[3-(3-(N-methyl~ni~;n~)-phenoxy)-propyl]-4-piperidyl}-ketone, melting point 75-77C
21 86a~&
New Piperidine Derivatives The invention relates to new piperidine derivatives, process for their production and pharmaceutical agents that contain these compounds .
It i8 known of piperidine derivatives that they have rh~rr~^ological actions and are suitable, for example, for treating psychotropic and cerebraL vascular disorders. It has now been found, surprisingly enough, that the piperidine derivatives according to the invention functionally influence the glutamate receptor or the glutamate receptor~ r-on~ nt ionic rh;lnn~l ~ .
The object of the invention are the c, _ 'c of formula I
R~N~_~B ( I ), in which R1 means substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstitute~
naphthalene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted indole, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzofuran, substituted or unsubstituted tetrahydroquinoline, substituted or unsubstituted tetrahydroisoquinoline, substituted or unsubstituted tetralin, substituted or unsubstituted dihydronaphthalene, substituted or unsubstituted indan, substituted or unsubstituted indanone, subs~ituted or ~ 2 2~ ~60 1 0 unsubstituted tetralone, substituted or unsu~stituted chromen-2-one, substituted or unsubstituted naphthoquinone, Z means oxygen, sulfur, So or SO2, X means (CH2) m--CR2R3--(CH2) p or --( CH2 ) m--CHR2--( CH2 ) ~--CHR3--( CH2 ) p--, B means ~ CH--R4, and m, p, g each mean 0, 1, 2 or 3, R2 and R3 are the 6ame or different and mean ~IydLoy~ll~
hydroxy, C1,4 alkyl, C14 alkoxy or C1 6 alkanoyloxy, R4 means straight-chain or branched, C1 6 alkyl, ~Y: or a phenyl, benzyl, benzoyl, o:-hydroxy-benzyl, pyridinyl or naphthoyl radical optionally sub6tituted with C1 4 alkyl, C14 alkoxy, halogen, hydroxy, --CF3 or --O--CF3 ~ whereby the substituent can be the same or different in one to three places, and Y means oxygen, sulfur or --NH--, as well as their physiologically compatible salts and isomers.
Substituent R1 can be substituted the same or different in one to three places with C14 alkyl, C14 alkoxy, halogen, NO2, CF
--OCF3~ hydroxy, carboxyl, C14 alkoxycarbonyl, formyl, C1 4 alkylcarbonyl, phenyl, phenoxy, benzyl, R5 / Rs --N ~ or ~o~N ~ whereby \ R6 , \ R6 Rs and R6 are the same or different and mean hydrogen, C14 alkyl, phenyl, C1 6 alkanoyl or together with the nitrogen atom a 2~860io 5- or 6-membered saturated or unsaturated heterocycle, which can be substituted in one or more places with C~ 4 alkyl or phenyl an~
can contain another 0, N or S atom. For example, there can be mentioned piperidine, pyrrolidine, morpholine, thi~ oline, piperazine, N-methylpiperazine, 2, 6-dimethylmorpholine, phenylpiperazine as saturated heterocyclepe and imidazole, pyrazole, pyrrole or triazole as unsaturated heterocyclene.
Halogen is defined as fluorine, chiorine, bromine or iodine.
Alkyl means respectively a straight-chain or branched alky radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl.
The C1 6 alkanoyl radical is derived in each case from straight-chain or branched aliphatic carboxylic acids, sueh as, for example, formic aeid, aeetic acid, propionic aeid, butyric acid, trimethylacetic acid or caproic acid.
If R1 is substituted, the substituent can be in any position. As radical R1, there can be mentioned by way of example: pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, l-naphthyl, ~-naphthyl, isoquinolin-5-yl, isoquinolyl-4-yl, isoquinolin-6-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, 1,2,3,4-tetrahydro-5-naphthyl, 1,2,3,4-tetrallydL~ G naphthyl, 7,8-dihydro-2-naphthyl, 7, 8-dihydro-1-naphthyl, chromen-2-on-7-yl, chromen-2-on-4-yl, 1-oxo-1, 2, 3, 4-tetrahydro-5-naphthyl, 1-oxo-1, 2, 3, 4-tetrahydro-6-naphthyl, 2-oxo-1, 2, 3, 4-tetrahydro-5-naphthyl, 2-oxo-1, 2, 3, 4-tetrahydro-6-naphthyl, indan-4-yl, indan-5-yl, indan-1-on-4-yl, naphthoquinone.
2186~10 Oxygen can be viewed as a preferred meaning o~ Z, and Cl 4 alkylene, which can be straight-chain or branched and can be substituted at any position, can be cited as a preferred meaning of X. Especially preferred are combinations with hydrogenated or nonhydrogenated naphthyl derivatives.
The physiologically compatible salts are derived from inorganic and organic acids. Inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or organic acids, such as, for example, aliphatic or aromatic mono- or dicarboxylic acids, such as formic acid, acetic acid; maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for example C1 4 AlkAn~culfonic acids, such as methAn~c~ll fonic acid or benzenesulfonic acids, such as p-tolll~n~clll fonic acid, optionally substituted by halogen or Cl 4 alkyl, are suitable.
If an acid function is contained, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali and il 1 kA l; ne-earth salts, as well as N-methylglucamine, dimethylglucamine, ethylglll- AminP, lysine, 1,6-h~YA~l;Am;na, ethanolamine, glll~a~Am;no~ sarcosine, serinol, tris(~lydLuxy -thyl)Am;n~ l_hane, aminopropanediol, Sovak base, l-amino-2, 3, 4-butanetriol .
The compounds of formula I comprise all possible optical isomers and their mixtures.
I
21~601~
The production of the compounds of formula I and their physiologically compatible salts takes place in a way known in the art, by a) a compound of formula II
R1_Z--E~ (II), in which R1 and Z have the above meaning, being reacted with a compound of formula III
A--X--N B (III), in which X and B have the above meaning and A represents a leaving group, or b) a ~ ulld of formula IV
A--X--Z--R1 ( IV), in which X, Z and R1 have the above meaning and A represents a leaving group, being reacted with an amine of formula V
H--N\ B (V), in which B has the above meaning, or c) an epoxide of formula VI
R~Z (CH2)m~--CH2 (VI) ~
in which R1, z and m have the above meaning, being reacted with an amine of formula V
~I--N\ B (V~, 2 ~ 86{~
or d) a compound of formula VII
H~X--N\ B (VII) in which X and B have the above meaning, being reacted with a ~ uul-d of formula R1-OH according to Mitsunobu and then optionally a carbonyl group being reduced or a hydroxy group being esterified or etherified or the physiologically compatible salts being formed or the isomers being separated.
The nucleophilic substitution of leaving group A according, to process variants a) and b) i6 performed under basic conditions according to the usual methods in an organic solvent that is inert under the reaction conditions.
As leaving groups A, for example, halogens such as chlorine, bromine or iodine or organic sulfonic acid radicals such as the radical of an llk~nlo~ulfonic acid, for example, mesylate, triflate or the radical of an aromatic sulfonic acid, for examplle toluenesulfonic acid or bromobenzenesulfonic acid, are suitable.
As inert organic solvents, polar solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide or alcohols such as ethanol, methanol or cyclic ethers such as dioxane ~ tetrallydLu r UL an, halogenated hydrocarbons, aromatic hydrocarbons or mixtures of the mentioned solvents are suitable.
As bases, inorganic and organic bases are suitable.
Examples of organic bases are alkali hydroxide or Alk~l in~-earth hydroxide, ;~lk~l ino-earth carbonates, ;llk~l in~--earth hydrogen 218601~
carbonates or alkaline-earth alcoholates. Examples of organic j bases are tertiary organic amines, such as tripropylamine, triethylamine, N-alkylmorpholine, N-alkylpiperidine, Hunig base, 1,4-diazabicyclo(2,2,2)octane, 1,5-diazabicyclo(5,4,0)undec-5-ene.
The reaction temperature can be between room temperature and boiling temperature of the solvent.
The reaction according to process c) takes place, i.a., in protic solvents, such as alcohols at elevated temperature up to boiling temperature.
The reaction according to Mitsunobi (process d) is carried out in the presence of triphenylphosphine and azodicarboxylic acid ethyl ester in an inert solvent at elevated temperature or else in the presence of an organic acid at room temperature (Synthesis, 1981, 1).
The reduction of the carbonyl group can be performed with reducing agents that are commonly used, such as, for example, with sodium borohydride, to the corresponding hydroxy ' or with triethylsilane and trifluoroacetic acid at room temperature to a methylene compound. I
If esteri~ication is desired, this is carried out in a way;
known in the art by reaction with an activated acid derivative, such as, for example, acid anhydride, acid halide or acid imidazol ide .
The optional etherification of the hydroxy group is carried out according to the usual methods in the presence of bases, for 2~86~10 example by reaction with methyl iodide in ethylene glycol dimethyl ether in the presence of sodium hydride. I
The compounds of formula I can be isolated from the reaction mixture and purif ied in a way known in the art. Acid addition salts can be converted in the usual way to free bases and the latter optionally in a known way to physiologically compatible acid addition salts, for example by the solution being mixed with a concentrated solution of the desired acid.
If the compounds of formula I have one or more chiral atoms the optically active ~ c can be obtained starting from optically active starting __ ~c or in a way known in the art from the racemates. The enantiomer separation can take place, I
for example, by chromatography on optically active vehicles, by reaction with optically active acids and then fractionated crystallization .
The compounds of formula I as well as their physiologically compatible salts can be used as pharmaceutical agents based on their functional effect on the glutamate receptor or the glutamate receptor-dependent ionic rh;~nn~l s, The pharmacological effectiveness of the ~ c of formula I was determined by the tests described below:
Male NMRI mice weighing 18-22 g were kept under controlled conditions (0600-1800 hours of light/dark cycle, with free access to food and water) and their assignment to groups was randomized.
The groups consisted of 5-16 animals. The observation of the animals was performed between 0800 and 1300 hours.
AMPA was sprayed into the left ventricle of freely movable mice. The applicator consisted of a cannula with a device made of StAinlPf:~ steel, which limits the depth of injection to 3.2 mm. The applicator was connected to an injection pump. The hypodermic needle was inserted perpendicular to the surface of the skull according to the coordinates of Montemurro and Dukelow.
The animals were observed until the occurrence of clonic or tonic seizures up to 180 seconds. The clonic movements, which last longer than 5 seconds, were counted as seizures. The beginning of the clonic seizures was used as an end point for the determination of the seizure threshold. The dose that was nP-!PSsAry to increase or decrease the seizure threshold by 50%
tTHRDSo) was detPrm;nPd in 4-5 experiments. The THRDso limit and the confidence limit were ~1ptprm;npd in a regression analysis.
The results of these tests show that the, ' of formu a I and its acid addition salts influence functional disturbances of the AMPA receptor. They are suitable, therefore, in the production of pharmaceutical agents for symptomatic and preventive treatment of diseases, which are triggered by a change of the function of the AMPA receptor complex.
The treatment with the compounds according to the invention prevents or delays the cell damages and functional disorders that occur because of disease and reduce the symptoms that are thus produced .
The diseases which can be triggered by the dysfunction of excitatory amino acids or changed glutamatergic neurotrAn~m; ~ i on are part of, for example, neurodegenerative disturbances such as 2~86ol~
Parkinson's disease, Huntington's disease, Al~hl~ir-r's disease, senile dementia, multiinfarct dementia, AIDS dementia, AIDS
encephalopathy, amyotrophic lateral sclerosis, olivopontocerebellar degeneration, epilepsy; cell damages by hypoglycemia, hypoxia, ischemia and disturbances of the energy metabolism; neuronal damages, which are triggered by damage of the brain, such as stroke, brain trauma and asphyxia, as well as psychoses, schizophrenia, anxiety conditions, attacks of pain, migraines and vomiting. Also, functional disorders such as impaired memory (amnesia), disturbances of the learning process , vigilance symptoms and deprivation symptoms after chronic intak~
of diagnostic agents such as sedative ph~rr~ tical agents, hallucinogens, alcohol, cocaine and opiates based on the dysfunction of glutamatergic neurotransmission.
The indications can be shown by pharmacological tests that are commonly used.
The invention also comprises pharmaceutical agents, which contain the mentioned compounds, their production as well as th~
use of the _ _ullds according to the invention for the production of pharmaceutical agents, which are used for the treatment and prophylaxis of the above-mentioned diseases. The pharmaceutical agents are produced according to processes known in the art, by the active ingredient being brought with suitable vehicles, adjuvants and/or additives into the form of a pharmaceutical preparation, which is suitable for enteral or parenteral administration. The administration can be carried o7t orally or sublingually as solid in the form of capsules or ll 2~86010 tablet6 or as liquid in the ~orm of 601utions, 6u6pen6ions, elixirs or emul6ion6 or rectally in the form of 6uppo6itorie6 or in the form of optionally also subcutaneously usable injection solutions. A6 adjuvants for the desired pharmaceutical agent formulation, the inert organic and inorganic vehicles that are known to one 6killed in the art are suitable, such as, for example, water, gelatin, gum arabic, lactose, 6tarch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.
Moreover, preservative6, stabilizers, wetting agents, emulsifiers or salts optionally can be contained for changing the osmotic pres6ure or buffer.
The pharmaceutical preparation6 can be present in solid form, for example a6 tablets, coated tablets, suppositories, capsules or in liquid form, for example as solutions, suspension6 or emul6ions.
As vehicle sy6tem6, near-interface adjuvants, such as salts of bile acids or animal or plant phospholipids, but also their mixtures as well as liposomes or their components, can also be u6ed.
For oral u6e, P~ciAlly tablets, coated tablets or capsule6 with talc and/or hydrocarbon vehicles or binders, such as, for example, lacto6e, corn or potato 6tarch, are 6uitable. The u6e 1 can al60 be carried out in liquid form, 6uch as, for example, a6 juice, to which optionally a 6weetener i6 added.
For parenteral use, especially injection solutions or su6pen6ion6, e6pecially aqueou6 601utions of active compounds in polyllydL~,~Ly~thoxylated ca6tor oil, are 6uitable.
~ 12 21860~0 The dosage o~ the active ingredients can vary depending on the type of use, age and weight o~ the patient, type and severity of the disease to be treated and similar factors. The daily dose can be given as a single dose to be administered once or dividec into 2 or more daily doses. The compounds are introduced in a dosage unit of o. 05 to 100 mg of active substance into a physiologically compatible vehicle. In general, a dose of 0.1 tlo 500 ~g/day, preferably 0.1 to 50 mg/day, is used.
If the production of the starting compounds is not described, the latter are known or can be produced analogously to known compounds or processes described here.
The following examples are to explain the production of the compounds Oe eom~
, ~ 13 21860tO
Examp l e ~l-r3-(3-Dimethylaminol~henoxy)-proPYl1-4-t~ eridYl~-(4 f luorol~henyl ) -ketone 265 mg of 3-dimethylaminophenyl is introduced in 20 ml of acetone, mixed with 265 mg of potassium carbonate and 824 mg of (4-fluorophenyl)-[1-(3-methylsulfonyl~xy~lu~yl)-4-piperidyl]-ketone and ref luxed for 3 hours under argon. After the organic phase is concentrated by evaporation, it is chromatou,- a~hed on silica gel with methylene chloride and acetone = 1 + 1. 375 mg of {1-[3-(dimethylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 48-50C, is obtained.
The (4-fluorophenyl)-1-[1-(3-methylsulfonyloxy-propyl)-4-piperidyl]-ketone is obtained according to methods known in the literature by alkylation of 4-(4-fluorobenzoyl)-piperidine with 3-~ pru,uanol-l and potassium carbonate in dimethylf-rr-m;r~e and subsequent reaction with m h~n~ulfonic acid and triethylamine in methylene chloride.
Analogously, there are produced:
{1-[3-(2-Dimethylaminophenoxy) -propyl]-4-piperidyl}-(4-f luorophenyl ) -ketone {1-[3-(4-dimethylaminophenoxy) -propyl]-4-piperidyl}-(4-f luorophenyl ) -ketone {1-[3-(3-morpholinophenoxy)-propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 110-111C
{1-[3-(1-naphthyloxy) -propyl] -4-piperidyl}-(4-fluorophenyli -ketone, melting point 61-64C
* 14 2t86~tO
{1-[3-(2-naphthyloxy)-propyl]-4-piperidyl}-(4-Lluorophenyl) -ketone, melting point 114-115C
{1-[3-(3-dibutylaminophenoxy) -propyl] -4-piperidyl}-(4-f luorophenyl ~ -ketone {1-[3-t2-nitro-1-naphthyloxy) -propyl]-4-piperidyl}-(4-f luorophenyl ) -ketone {1-[3-(1-nitro-2-naphthyloxy) -propyl]-4-piperidyl}-(4-f luorophenyl ) -ketone, me lt ing po int 13 7 -13 8 C
{1-[3- (2, 4-dinitro-1-naphthyloxy) -propyl] -4-piperidyl}- (4-f luorophenyl) -ketone {1-[3-(3-anilinophenoxy) -propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 75-78C
{1-[3-(1-bromo-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 97-100C
{1-[3-(4-chloro-1-naphthyloxy)-propyl]-4-piperidyl}-(4-f luorophenyl ) -ketone {1-[3-(3-acetylaminophenoxy) -propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 108-111C
( 4 - f luoropheny 1 ) - { 1- [ 3 - ( 5 - i s oqu ino ly loxy ) -propy 1 ] -4 -piperidyl}-ketone, melting point 31-33C .
(4-f luorophenyl) -{1- [3- (3-pyridyloxy) -propyl] -4-piperidyl}-ketone, melting point 52-55C
(4-fluorophenyl)-{1-[3-(3-(N-methyl~ni~;n~)-phenoxy)-propyl]-4-piperidyl}-ketone, melting point 75-77C
4-{3-[4-(4-fluorobenzoyl) -1-piperidyl]-propoxy}-indan--1-one, melting point 126-127C
2~g6Qla 5-{3-[4-(fluoro}~enzoyl) -1-piperidyl]-propoxy}-3,4-dihydronaphthalene-1(2H)-one (oil) {1-[3-(7,8-dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(4-f luoropheny 1 ) -ketone, me lt ing po int 7 2 -7 4 C
{1-[3-(7,8-dihydro-2-naphthyloxy) -propyl]-4-piperidyl}-(3,4-difluorophenyl)-ketone {l-[3-(7~8-dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(3~4 dimethoxyphenyl ) -ketone (4-fluorophenyl) -{1-[3-(2-(lH-imidazol-1-yl) -phenoxy) -propyl]-4-piperidyl}-ketone (oil) (4-fluorophenyl) -{1-[3-(4-hydroxy-3,5-di-tert-butyl-phenoxy) -propyl] -4-piperidyl}-ketone 7-{3-[4-(4-fluorobenzoyl) -1-piperidyl]-propoxy}-2H-chroment 2-one, melting point 128-129C
7-{3-[4-(4-fluorobenzoyl) -1-piperidyl~-propoxy}-4-methyl-2H-chromen-2-one, melting point 139-140C
4-{3-[4-(4-fluorobenzoyl) -l-piperidyl] -propoxy}-2H-chromen 2-one, melting point 132-133C
{ 1- [ 3 - ( 6 -bromo-2 -naphthyloxy) -propyl ] -4 -piperidyl } - ( 4 -fluorophenyl)-ketone, melting point 126-127C
{1[3-(2-naphthyloxy) -propyl]-4-piperidyl}-(3,4-dimethoxyphenyl)-ketone, melting point 107-108C
~ 16 2 1 860 1 ~
Example 2 l-~l-r3-~3-Dimethylaminophenoxy)-proPyll-4-piperidyl~-l-(4 f luoroPhenYl ) -methano l 3 8 4 mg o f l l - [ 3 - ( 3 -d imethy l am i nophenoxy ) -propy l ] -4 -piperidyl} (4-fluorophenyl)-ketone i5 added in portions at room temperature to a solution of 15 ml of ethanol and 80 mg of sodium boLollyd, ide. After 4 hours of stirring, the reaction solution is neutralized, mixed with water and then extracted with ethyl acetate. After the organic phase i6 dried, it is concentrated by evaporation, and the residue is chromatographed on silica gel with acetone + methylene chloride = 1 + 1. 154 mg of 1-{1-[3-(3-dimethylaminophenoxy) -propyl] -4-piperidyl}-1-(4-fluorophenyl) -methanol, melting point 63-64C, is obtained.
Analogously, there are produced:
1-{1-[3-(1-Naphthyloxy) -propyl]-4-piperidyl}-1-(4-f luorophenyl) -methanol l - { 1- [ 3 - ( 2 -naphthy loxy ) -propy l ] - 4 -p iperidyl } -1- ( 4 -fluorophenyl)-methanol, melting point 136-137C
Example 3 (3-DimethYlaminoPhenYl) -~3 r4 ~4-fluorobenzY~ -Piperidyll- ¦
ProPYl~-ether , I
2 g of triethylsilane is added drop by drop to a solution of 384 mg of {1-[3-(3-dimethylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorophenyl)-ketone in 25 ml of tri~luoroacetic acid. The reaction mixture i5 stirred for 3 more days. Then, it is evaporated to dryness, and the residue is taken up in~ether and 2~86010 shaken out three times with lN HCl. The combined extracts are made basic, extracted with ether, dried and concentrated by evaporation. 197 mg of (3-dimethylaminophenyl)-{3-[4(4-fluorobenzyl)-1-piperidyl]-propyl}-ether (oil) is obtained.
Analogously, there are produced: ~
l-Naphthyl-{3-[4- (4-fluorobenzyl) -l-piperidyl] -propyl}-ether 2-naphthyl-{3-[4-(4-fluorobenzyl) -l-piperidyl]-propyl}-ether, melting point 79-80C
Example 4 ~l-rl-t3-Dimethyl~miT~oDhQrYloxY)-butYl~-4-~il~eridYl~-(4- ~=
f luoroPhenYl ) -ketone 630 mg of (4-chlorobutyl)-(3-dimethylaminophenyl)-ether is stirred in 25 ml of dimethylformamide with 950 mg of 4- (4-fluorobenzoyl)-piperidine and 0.5 ml of triethylamine at 100C
bath temperature for 8 hours under argon. After the solvent i5 distilled off, it is taken up in methylene chloride and washed once each with water and saturated common salt solution. The organic phase is dried, filtered and concentrated by evaporation.
The residue is chromatographed on silica gel with acetone +
methylene chloride = l + l. 420 mg of {1-[1-(3-dimethylaminophenoxy) -butyl] -4-piperidyl}-(4-fluorophenyl) -ketone is obtained.
The (4-chlorobutyl)-(3-dimethylaminophenyl)-ether required as starting material is obtained by etherification of 3-dimethylaminophenol with 1-bromo-4-chlorobutane and potassium carbonate in dimethylformamide.
~ 18 2t860tO
Examp 1 e 5 -rl-(3-DimethYlaminoPhenYloxy~-eth~Y11-4-PiPeri~lY11-(4-uoroPhenyl)-ketone 590 mg of {1-[1-(3-dimethylaminophenoxy)-ethyl]-4-piperidyl}-(4-fluorophenyl)-ketone (oil) is obtained from 590 mg of (2-chloroethyl)-(3-dimethyl~minr~hPnyl)-ether and 950 mg of 4l-(fluorobenzoyl)-piperidine analogously to the process according to ~xample 4.
Example 6 ~l-r3-r3-DimethylAm;~ ~ y)-2-h~dL~A~iJr~l~yll-4-piperidyll-(4 f luoroPhenYl ) -ketone 380 mg of (3-dimethyl~minorh~nyl)-(2,3-epvxy~v~y1)-ether is dissolved in 50 ml of methanol and mixed with 430 mg of 4- (4-fluorobenzoyl)-piperidine. After three hours of heating, the solvent is di6tilled off, the residue is taken up in 50 ml of lN
hydrochloric acid and extracted several times with 1 chloroform.
The aqueous phase is made ~1 k~ 1 i n~ with 2N sodium hydroxide solution and then extracted with ethyl acetate. The combined ethyl acetate phases are washed, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with acetone + methylene chloride = 1 + 1. 446 mg of {1-[3-(3-dimethylaminophenoxy) -2-hydLvxyu~vùyl] -4-piperidyl}- (4-fluorophenyl)-ketone, melting point 117-119C, is obtained. I
The ( 3 -d imethy laminopheny 1 ) - ( 2, 3 - epoxy~l v~y 1 ) -ether required as starting material is obtained by reaction of 3-I
2 ~ 86~ 1 G
dimethylaminophenol with epichlorohydrin and sodium hydride indimethylf ormamide .
Analogously, there are produced:
3-t4-(4-Fluorobenzyl) -piperidino) -2-hydL~xy~L~IJoxy]-dimethyl~m;nn~nilin~, melting point 85-87C
{l-[3--(3-morE~hnl innrhonnYy)-2-~lydLoxy~Luyyl]--4-piperid (4-fluorophenyl) -ketone 2-[4-(4-fluorobenzyl) -piperidino) -2-lly-lL~xy~ropoxy] -naphthalene, melting point 89-90C
1- [ 4 - ( 4 - f luorobenz yl ) -p iperid i no ) - 2 -1IYdL ".y ~r ~,~oxy ] -naphthalene,, melting point 104-105C
{ 1- ( 3 - ( l-naphthyloxy) -2 -1IYdL JXy~L ~ yy 1 ] -4 -piperidyl } -4 -fluorophenyl) -ketone {1-[3-(2-naphthyloxy) -2-hy.lL."~y~r~,pyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 136-137C
( 4 -f luorophenyl ) - { 1- [ 3 - ( 1 -oxo-1, 2, 3, 4 -tetrahydro-5 -naphthyloxy)-2-~ydL.,xypL.,~yl]-4-piperidyl}-ketone, melting point {1-[3-tl-naphthyloxy) -2-hydL~Jxy~)Lupyl]-4-piperidyl}-(3,4-h n-~yphenyl ) -ketone {1-[3-(1-naphthyloxy) -2-hydroxypropyl]-4-piperidyl}-(3,4-f luorophenyl ) -ketone {1-[3-(2-naphthyloxy)-2-hydL~xy~L~yl]-4-piperidyl}-(3,4- ¦
f luoropheny 1 ) -ketone 218601Vn Example 7 ~1- ,r3-(3-DimethYlaminophenoxy) -2-acetoxYProPYll -4-Piperidyl~-(4-f luoroPhenY l ) -ketone 250 mg of {1-[3-(3-dimethylAm;norh~n-~y)-2-hydroxypropyl]-4' piperidyl}-(4-fluorophenyl)-ketone is dissolved in 10 ml of dry pyridine. After 0.15 ml of acetic anhydride is added, it is heated under reflux for 3 hours. After cooling, the reaction mixture is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with methylene chloride +
ethanol = 1800 + 75. 125 mg of {1-[3-(3-dimethylAmin~h~n~y)-2 acetoxy-propyl]-4-piperidyl}-(4-fluorophenyl)-ketone (oil) is obta ined .
Analogously, there are produced:
2 - t 4- ( 4 -Fluorobenzyl) -piperidino) -2-acetuxy~- v~o..y ] -naphthalene {1-[3-(1-naphthyloxy) -2-acetoxypropyl]-4-piperidyl}-(4-f luorophenyl ) -ketone { 1- [ 3 - ( 2 -naphthyloxy ) - 2 -acetuxy 1~ ~ v~y 1 ] - 4--p iper idyl } - ( 4 -f luorophenyl ) -ketone { 1- [ 3 - ( 1 -naphthyloxy ) - 2 -a cetoxy ~L U~y l ~ -4 -p iperidyl } - ( 3, 4 -dif luorophenyl ) -ketone Example 8 ~l-r3-(3-DimethYlamino~henoxy) -2-methoxYl~Lvuyl~-4-piperidyl~-(4 f luoroPhenYl ) -ketone 250 mg of {1-~3-(3-dimethylaminophenoxy)-2-lly-lLuxy~Lu~yl]-4 piperidyl}- (4-fluorophenyl) -ketone is dissolved in 10 ml of 2~860~
ethylene glycol dimethyl ether, mixed with 20 mg of sodium hydride (90%) and cooled in an ice bath. After 106 mg of methyl iodide i8 added, the reaction mixture is stirred for 4 hours cold and for 1 hour at room temperature. After the organic phase is concentrated by evaporation, it is chromatographed on silica gel with methylene chloride + ethanol = 1800 + 75. 150 mg of {1-[3-( 3 -dimethylaminophenoxy) -2 -methu.~y~u~ u,uy 1 ] -4-piperidyl } - ( 4 -fluorophenyl)-ketone (oil) is obtained.
Analogously, there are produced:
2- [ 4 - ( 4 -Fluorobenzyl) -piperidino) -2 -methuxy,uL v~v~y ] -naphtha lene, {l-t3-(l-naPhthyloxy)-2-methoxy~uLupyl]-4-piperidyl}-(4 f luorophenyl ) -ketone, {l-t3- (2-naphthyloxy) -2-methoxypropyl] -4-piperidyl}- (4-f luorophenyl ) -ketone, { 1- t 3 - ( l-naphthyloxy) -2 -methvxy~L u~y 1 ] -4 -piperidyl } - ( 3, 4 -dimethoxyphenyl ) -ketone Example 9 (4-FluQro~henYl)- r1-r 3-(1,2,3 4-tetrAI ydLu ., naPhthYloXy)-~ropyl 1 -4-1~i~eridYl ~ -ketone A solution of 200 mg of 1,2,3,4-tetrahydro-5-naphthol in 25' ml of tetrahydrofuran p.A. is mixed with 700 mg of (4-fluorophenyl)-1-tl-(3-hyd~vxy~u~u~yl)-4-piperidyl]-ketone, 700 mg of triphenylphosphine and 0 . 45 ml of azodicarboxylic acid diethy ester, and it is heated f or 2 0 minutes to 8 0C bath temperature while being stirred. The reaction solution is mixed with 50 ml of water and then extracted with ethyl acetate . Af ter the organic phase is dried, it is concentrated by evaporation, and the residue is chromatographed on silica gel with methylene chloride + ethanol = 9 + 1. 264 mg of (4-fluorophenyl)-{1-[3-(1,2,3,4-tetrallydLu 5 naphthyloxy)-propyl]-4-piperidyl}-ketone is obtained .
The (4-fluorophenyl)-1-[1-(3-llydLoxy~Lu~yl)-4-piperidyl]-ketone is obtained according to methods known in the literature ¦
by alkylation of 4-(4-fluorobenzoyl)-piperidine with 3-bL' L ~,~anol-1 and potassium carbonate in dimethylformamide.
Analogously, there are produced: I
( 4 -Fluorophenyl ) - { 1- [ 3 - ( indan-4 -yloxy) -propyl ] -4 -piperidyl } -ketone, melting point 70-72C
(4-fluorophenyl) -{1-[3-(indan-5-yloxy) -propyl]-4-piperidyl}-ketone, melting point 49-52C
( 3, 4 -di f luorophenyl ) - { 1- [ 3 - ( indan-4 -yloxy) -propyl ] -4-piperidyl } -ketone {1-[3-(4-benzylphenoxy) -propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 105-107C
(4-fluorophenyl)-{1-[3-(1,2,3,4-tetrahydro-6-naphthyloxy)-propyl ] -4 -piperidyl } -ketone
2~g6Qla 5-{3-[4-(fluoro}~enzoyl) -1-piperidyl]-propoxy}-3,4-dihydronaphthalene-1(2H)-one (oil) {1-[3-(7,8-dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(4-f luoropheny 1 ) -ketone, me lt ing po int 7 2 -7 4 C
{1-[3-(7,8-dihydro-2-naphthyloxy) -propyl]-4-piperidyl}-(3,4-difluorophenyl)-ketone {l-[3-(7~8-dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(3~4 dimethoxyphenyl ) -ketone (4-fluorophenyl) -{1-[3-(2-(lH-imidazol-1-yl) -phenoxy) -propyl]-4-piperidyl}-ketone (oil) (4-fluorophenyl) -{1-[3-(4-hydroxy-3,5-di-tert-butyl-phenoxy) -propyl] -4-piperidyl}-ketone 7-{3-[4-(4-fluorobenzoyl) -1-piperidyl]-propoxy}-2H-chroment 2-one, melting point 128-129C
7-{3-[4-(4-fluorobenzoyl) -1-piperidyl~-propoxy}-4-methyl-2H-chromen-2-one, melting point 139-140C
4-{3-[4-(4-fluorobenzoyl) -l-piperidyl] -propoxy}-2H-chromen 2-one, melting point 132-133C
{ 1- [ 3 - ( 6 -bromo-2 -naphthyloxy) -propyl ] -4 -piperidyl } - ( 4 -fluorophenyl)-ketone, melting point 126-127C
{1[3-(2-naphthyloxy) -propyl]-4-piperidyl}-(3,4-dimethoxyphenyl)-ketone, melting point 107-108C
~ 16 2 1 860 1 ~
Example 2 l-~l-r3-~3-Dimethylaminophenoxy)-proPyll-4-piperidyl~-l-(4 f luoroPhenYl ) -methano l 3 8 4 mg o f l l - [ 3 - ( 3 -d imethy l am i nophenoxy ) -propy l ] -4 -piperidyl} (4-fluorophenyl)-ketone i5 added in portions at room temperature to a solution of 15 ml of ethanol and 80 mg of sodium boLollyd, ide. After 4 hours of stirring, the reaction solution is neutralized, mixed with water and then extracted with ethyl acetate. After the organic phase i6 dried, it is concentrated by evaporation, and the residue is chromatographed on silica gel with acetone + methylene chloride = 1 + 1. 154 mg of 1-{1-[3-(3-dimethylaminophenoxy) -propyl] -4-piperidyl}-1-(4-fluorophenyl) -methanol, melting point 63-64C, is obtained.
Analogously, there are produced:
1-{1-[3-(1-Naphthyloxy) -propyl]-4-piperidyl}-1-(4-f luorophenyl) -methanol l - { 1- [ 3 - ( 2 -naphthy loxy ) -propy l ] - 4 -p iperidyl } -1- ( 4 -fluorophenyl)-methanol, melting point 136-137C
Example 3 (3-DimethYlaminoPhenYl) -~3 r4 ~4-fluorobenzY~ -Piperidyll- ¦
ProPYl~-ether , I
2 g of triethylsilane is added drop by drop to a solution of 384 mg of {1-[3-(3-dimethylaminophenoxy)-propyl]-4-piperidyl}-(4-fluorophenyl)-ketone in 25 ml of tri~luoroacetic acid. The reaction mixture i5 stirred for 3 more days. Then, it is evaporated to dryness, and the residue is taken up in~ether and 2~86010 shaken out three times with lN HCl. The combined extracts are made basic, extracted with ether, dried and concentrated by evaporation. 197 mg of (3-dimethylaminophenyl)-{3-[4(4-fluorobenzyl)-1-piperidyl]-propyl}-ether (oil) is obtained.
Analogously, there are produced: ~
l-Naphthyl-{3-[4- (4-fluorobenzyl) -l-piperidyl] -propyl}-ether 2-naphthyl-{3-[4-(4-fluorobenzyl) -l-piperidyl]-propyl}-ether, melting point 79-80C
Example 4 ~l-rl-t3-Dimethyl~miT~oDhQrYloxY)-butYl~-4-~il~eridYl~-(4- ~=
f luoroPhenYl ) -ketone 630 mg of (4-chlorobutyl)-(3-dimethylaminophenyl)-ether is stirred in 25 ml of dimethylformamide with 950 mg of 4- (4-fluorobenzoyl)-piperidine and 0.5 ml of triethylamine at 100C
bath temperature for 8 hours under argon. After the solvent i5 distilled off, it is taken up in methylene chloride and washed once each with water and saturated common salt solution. The organic phase is dried, filtered and concentrated by evaporation.
The residue is chromatographed on silica gel with acetone +
methylene chloride = l + l. 420 mg of {1-[1-(3-dimethylaminophenoxy) -butyl] -4-piperidyl}-(4-fluorophenyl) -ketone is obtained.
The (4-chlorobutyl)-(3-dimethylaminophenyl)-ether required as starting material is obtained by etherification of 3-dimethylaminophenol with 1-bromo-4-chlorobutane and potassium carbonate in dimethylformamide.
~ 18 2t860tO
Examp 1 e 5 -rl-(3-DimethYlaminoPhenYloxy~-eth~Y11-4-PiPeri~lY11-(4-uoroPhenyl)-ketone 590 mg of {1-[1-(3-dimethylaminophenoxy)-ethyl]-4-piperidyl}-(4-fluorophenyl)-ketone (oil) is obtained from 590 mg of (2-chloroethyl)-(3-dimethyl~minr~hPnyl)-ether and 950 mg of 4l-(fluorobenzoyl)-piperidine analogously to the process according to ~xample 4.
Example 6 ~l-r3-r3-DimethylAm;~ ~ y)-2-h~dL~A~iJr~l~yll-4-piperidyll-(4 f luoroPhenYl ) -ketone 380 mg of (3-dimethyl~minorh~nyl)-(2,3-epvxy~v~y1)-ether is dissolved in 50 ml of methanol and mixed with 430 mg of 4- (4-fluorobenzoyl)-piperidine. After three hours of heating, the solvent is di6tilled off, the residue is taken up in 50 ml of lN
hydrochloric acid and extracted several times with 1 chloroform.
The aqueous phase is made ~1 k~ 1 i n~ with 2N sodium hydroxide solution and then extracted with ethyl acetate. The combined ethyl acetate phases are washed, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with acetone + methylene chloride = 1 + 1. 446 mg of {1-[3-(3-dimethylaminophenoxy) -2-hydLvxyu~vùyl] -4-piperidyl}- (4-fluorophenyl)-ketone, melting point 117-119C, is obtained. I
The ( 3 -d imethy laminopheny 1 ) - ( 2, 3 - epoxy~l v~y 1 ) -ether required as starting material is obtained by reaction of 3-I
2 ~ 86~ 1 G
dimethylaminophenol with epichlorohydrin and sodium hydride indimethylf ormamide .
Analogously, there are produced:
3-t4-(4-Fluorobenzyl) -piperidino) -2-hydL~xy~L~IJoxy]-dimethyl~m;nn~nilin~, melting point 85-87C
{l-[3--(3-morE~hnl innrhonnYy)-2-~lydLoxy~Luyyl]--4-piperid (4-fluorophenyl) -ketone 2-[4-(4-fluorobenzyl) -piperidino) -2-lly-lL~xy~ropoxy] -naphthalene, melting point 89-90C
1- [ 4 - ( 4 - f luorobenz yl ) -p iperid i no ) - 2 -1IYdL ".y ~r ~,~oxy ] -naphthalene,, melting point 104-105C
{ 1- ( 3 - ( l-naphthyloxy) -2 -1IYdL JXy~L ~ yy 1 ] -4 -piperidyl } -4 -fluorophenyl) -ketone {1-[3-(2-naphthyloxy) -2-hy.lL."~y~r~,pyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 136-137C
( 4 -f luorophenyl ) - { 1- [ 3 - ( 1 -oxo-1, 2, 3, 4 -tetrahydro-5 -naphthyloxy)-2-~ydL.,xypL.,~yl]-4-piperidyl}-ketone, melting point {1-[3-tl-naphthyloxy) -2-hydL~Jxy~)Lupyl]-4-piperidyl}-(3,4-h n-~yphenyl ) -ketone {1-[3-(1-naphthyloxy) -2-hydroxypropyl]-4-piperidyl}-(3,4-f luorophenyl ) -ketone {1-[3-(2-naphthyloxy)-2-hydL~xy~L~yl]-4-piperidyl}-(3,4- ¦
f luoropheny 1 ) -ketone 218601Vn Example 7 ~1- ,r3-(3-DimethYlaminophenoxy) -2-acetoxYProPYll -4-Piperidyl~-(4-f luoroPhenY l ) -ketone 250 mg of {1-[3-(3-dimethylAm;norh~n-~y)-2-hydroxypropyl]-4' piperidyl}-(4-fluorophenyl)-ketone is dissolved in 10 ml of dry pyridine. After 0.15 ml of acetic anhydride is added, it is heated under reflux for 3 hours. After cooling, the reaction mixture is concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with methylene chloride +
ethanol = 1800 + 75. 125 mg of {1-[3-(3-dimethylAmin~h~n~y)-2 acetoxy-propyl]-4-piperidyl}-(4-fluorophenyl)-ketone (oil) is obta ined .
Analogously, there are produced:
2 - t 4- ( 4 -Fluorobenzyl) -piperidino) -2-acetuxy~- v~o..y ] -naphthalene {1-[3-(1-naphthyloxy) -2-acetoxypropyl]-4-piperidyl}-(4-f luorophenyl ) -ketone { 1- [ 3 - ( 2 -naphthyloxy ) - 2 -acetuxy 1~ ~ v~y 1 ] - 4--p iper idyl } - ( 4 -f luorophenyl ) -ketone { 1- [ 3 - ( 1 -naphthyloxy ) - 2 -a cetoxy ~L U~y l ~ -4 -p iperidyl } - ( 3, 4 -dif luorophenyl ) -ketone Example 8 ~l-r3-(3-DimethYlamino~henoxy) -2-methoxYl~Lvuyl~-4-piperidyl~-(4 f luoroPhenYl ) -ketone 250 mg of {1-~3-(3-dimethylaminophenoxy)-2-lly-lLuxy~Lu~yl]-4 piperidyl}- (4-fluorophenyl) -ketone is dissolved in 10 ml of 2~860~
ethylene glycol dimethyl ether, mixed with 20 mg of sodium hydride (90%) and cooled in an ice bath. After 106 mg of methyl iodide i8 added, the reaction mixture is stirred for 4 hours cold and for 1 hour at room temperature. After the organic phase is concentrated by evaporation, it is chromatographed on silica gel with methylene chloride + ethanol = 1800 + 75. 150 mg of {1-[3-( 3 -dimethylaminophenoxy) -2 -methu.~y~u~ u,uy 1 ] -4-piperidyl } - ( 4 -fluorophenyl)-ketone (oil) is obtained.
Analogously, there are produced:
2- [ 4 - ( 4 -Fluorobenzyl) -piperidino) -2 -methuxy,uL v~v~y ] -naphtha lene, {l-t3-(l-naPhthyloxy)-2-methoxy~uLupyl]-4-piperidyl}-(4 f luorophenyl ) -ketone, {l-t3- (2-naphthyloxy) -2-methoxypropyl] -4-piperidyl}- (4-f luorophenyl ) -ketone, { 1- t 3 - ( l-naphthyloxy) -2 -methvxy~L u~y 1 ] -4 -piperidyl } - ( 3, 4 -dimethoxyphenyl ) -ketone Example 9 (4-FluQro~henYl)- r1-r 3-(1,2,3 4-tetrAI ydLu ., naPhthYloXy)-~ropyl 1 -4-1~i~eridYl ~ -ketone A solution of 200 mg of 1,2,3,4-tetrahydro-5-naphthol in 25' ml of tetrahydrofuran p.A. is mixed with 700 mg of (4-fluorophenyl)-1-tl-(3-hyd~vxy~u~u~yl)-4-piperidyl]-ketone, 700 mg of triphenylphosphine and 0 . 45 ml of azodicarboxylic acid diethy ester, and it is heated f or 2 0 minutes to 8 0C bath temperature while being stirred. The reaction solution is mixed with 50 ml of water and then extracted with ethyl acetate . Af ter the organic phase is dried, it is concentrated by evaporation, and the residue is chromatographed on silica gel with methylene chloride + ethanol = 9 + 1. 264 mg of (4-fluorophenyl)-{1-[3-(1,2,3,4-tetrallydLu 5 naphthyloxy)-propyl]-4-piperidyl}-ketone is obtained .
The (4-fluorophenyl)-1-[1-(3-llydLoxy~Lu~yl)-4-piperidyl]-ketone is obtained according to methods known in the literature ¦
by alkylation of 4-(4-fluorobenzoyl)-piperidine with 3-bL' L ~,~anol-1 and potassium carbonate in dimethylformamide.
Analogously, there are produced: I
( 4 -Fluorophenyl ) - { 1- [ 3 - ( indan-4 -yloxy) -propyl ] -4 -piperidyl } -ketone, melting point 70-72C
(4-fluorophenyl) -{1-[3-(indan-5-yloxy) -propyl]-4-piperidyl}-ketone, melting point 49-52C
( 3, 4 -di f luorophenyl ) - { 1- [ 3 - ( indan-4 -yloxy) -propyl ] -4-piperidyl } -ketone {1-[3-(4-benzylphenoxy) -propyl]-4-piperidyl}-(4-fluorophenyl)-ketone, melting point 105-107C
(4-fluorophenyl)-{1-[3-(1,2,3,4-tetrahydro-6-naphthyloxy)-propyl ] -4 -piperidyl } -ketone
Claims (4)
1. Compounds of formula I
(I), (I), in which R1 means phenyl substituted with C1-4 alkyl, CF3, -OCF3, hydroxy, carboxyl C1-4 alkoxycarbonyl, formyl, phenoxy, benzyl, -NR5R6 or SO2NR5R6, substituted or unsubstituted pyridine, substituted or unsubstituted naphthalene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted indole, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzofuran, substituted or unsubstituted tetrahydroquinoline, substituted or unsubstituted tetrahydroisoquinoline, substituted or unsubstituted tetralin, substituted or unsubstituted dihydronaphthalene, substituted or unsubstituted indan substituted or unsubstituted indanone, substituted or unsubstituted tetralone, substituted or unsubstituted chromen-2-one, substituted or unsubstituted naphthoquinone, R5 and R6 are the same or different and mean hydrogen, C1-4 alkyl, phenyl, C1-6 alkanoyl or together with the nitrogen atom a 5- or 6-membered saturated or unsaturated heterocycle, which can be substituted in one or more places with C1-4 alkyl or phenyl and can contain another O, N or S atom, Z means oxygen, X means --(CH2) m--CR2R3--(CH2)p or --(CH2) m--CHR2--(CH2)9--CHR3--(CH2)p--, B means , and m, p, g each mean 0, 1, 2 or 3, R2 and R3 are the same or different and mean hydrogen, hydroxy, C1-4 alkyl, C1-4 alkoxy or C1-6 alkanoyloxy, R4 means straight-chain or branched, C1-6 alkyl, or a phenyl, benzyl, benzoyl, .alpha.-hydroxy-benzyl, pyridinyl or naphthoyl radical optionally substituted with C1-4 alkyl, C1-4 alkoxy, halogen, hydroxy, --CF3 or --O--CF3, whereby the substituent can be the same or different in one to three places, and Y means oxygen, sulfur or ---NH--, as well as their physiologically compatible salts and isomers.
(I), (I), in which R1 means phenyl substituted with C1-4 alkyl, CF3, -OCF3, hydroxy, carboxyl C1-4 alkoxycarbonyl, formyl, phenoxy, benzyl, -NR5R6 or SO2NR5R6, substituted or unsubstituted pyridine, substituted or unsubstituted naphthalene, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted indole, substituted or unsubstituted benzothiophene, substituted or unsubstituted benzofuran, substituted or unsubstituted tetrahydroquinoline, substituted or unsubstituted tetrahydroisoquinoline, substituted or unsubstituted tetralin, substituted or unsubstituted dihydronaphthalene, substituted or unsubstituted indan substituted or unsubstituted indanone, substituted or unsubstituted tetralone, substituted or unsubstituted chromen-2-one, substituted or unsubstituted naphthoquinone, R5 and R6 are the same or different and mean hydrogen, C1-4 alkyl, phenyl, C1-6 alkanoyl or together with the nitrogen atom a 5- or 6-membered saturated or unsaturated heterocycle, which can be substituted in one or more places with C1-4 alkyl or phenyl and can contain another O, N or S atom, Z means oxygen, X means --(CH2) m--CR2R3--(CH2)p or --(CH2) m--CHR2--(CH2)9--CHR3--(CH2)p--, B means , and m, p, g each mean 0, 1, 2 or 3, R2 and R3 are the same or different and mean hydrogen, hydroxy, C1-4 alkyl, C1-4 alkoxy or C1-6 alkanoyloxy, R4 means straight-chain or branched, C1-6 alkyl, or a phenyl, benzyl, benzoyl, .alpha.-hydroxy-benzyl, pyridinyl or naphthoyl radical optionally substituted with C1-4 alkyl, C1-4 alkoxy, halogen, hydroxy, --CF3 or --O--CF3, whereby the substituent can be the same or different in one to three places, and Y means oxygen, sulfur or ---NH--, as well as their physiologically compatible salts and isomers.
2. {1-[3-(1-Naphthyloxy)-propyl]-4-piperidyl}-(4-fluorophenyl) -ketone {1-[3-(2-naphthyloxy) -propyl]-4-piperidyl}-(4-fluorophenyl) -ketone {1-[3-(2-nitro-1-naphthyloxy) -propyl]-4-piperidyl}-(4-fluorophenyl) -ketone {1-[3-(1-nitro-2-naphthyloxy) -propyl]-4-piperidyl}-(4-fluorophenyl) -ketone {1-[3-(2,4-dinitro-1-naphthyloxy) -propyl]-4-piperidyl}-(4-fluorophenyl) -ketone (4-fluorophenyl)-{1-[3-(5-isoquinolyloxy) -propyl]-4-piperidyl}-ketone {1-[ 3-(1-bromo-2-naphthyloxy) -propyl ] -4-piperidyl } -(4-fluorophenyl) -ketone {1-[3-(4-chloro-2-naphthyloxy) -propyl]-4-piperidyl}-(4-fluorophenyl) -ketone {1-(3-(1-naphthyloxy) -2-hydroxypropyl] -4-piperidyl} -4-fluorophenyl) -ketone {1-[3-(2-naphthyloxy) -2-hydroxypropyl]-4-piperidyl}-(4-fluorophenyl) -ketone 1-{1-[3-(1-naphthyloxy) -propyl]-4-piperidyl}-1-(4-fluorophenyl) -methanol 1-{1-[3-(2-naphthyloxy) -propyl] -4-piperidyl}-1-(4-fluorophenyl) -methanol 1-naphthyl-{3-[4-(4-fluorobenzyl) -1-piperidyl]-propyl}-ether 2-naphthyl-{3- [4-(4-fluorobenzyl) -1-piperidyl] -propyl} -ether {1-[3-(1-bromo-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorophenyl) -ketone {1-[3- (4-chloro-2-naphthyloxy) -propyl] -4-piperidyl}-(4-fluorophenyl) -ketone 4-{3-[4-(4-fluorobenzoyl) -1-piperidyl] -propoxy}-indan-1-one 5-{3-[4-(fluorobenzoyl) -1-piperidyl]-propoxy}-3,4-dihydronaphthalene-1 (2H) -one {1-[3-(7,8-dihydro-2-naphthyloxy) -propyl] -4-piperidyl} -(4-fluorophenyl) -ketone {1-[3-(7,8-dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(3,4-difluorophenyl) -ketone {1-[3-(7,8-dihydro-2-naphthyloxy)-propyl]-4-piperidyl}-(3,4-dimethoxyphenyl) -ketone 7-{3-[4 -(4-fluorobenzoyl)-1-piperidyl]-propoxy}-2H-chromen-2-one 7-{3-[4-(4-fluorobenzoyl)-1-piperidyl]-propoxy}-4-methyl-2H-chromen-2-one 4-{3-[4-(4-fluorobenzoyl)-1-piperidyl]-propoxy}-2H-chromen-2-one {1-[3-(6-bromo-2-naphthyloxy)-propyl]-4-piperidyl}-(4-fluorophenyl)-ketone {1-[3-(2-naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(4-fluorophenyl)-ketone (4-fluorophenyl)-{1-[3-(1-oxo-1,2,3,4-tetrahydro-5-naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-ketone {1-[3-(1-naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(3,4-dimethoxyphenyl)-ketone {1-[3-(1-naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(3,4-fluorophenyl)-ketone {1-[3-(2-naphthyloxy)-2-hydroxypropyl]-4-piperidyl}-(3,4-fluorophenyl)-ketone 2-[4-(4-fluorobenzyl)-piperidino)-2-methoxypropoxy]-naphthalene {1-[3-(1-naphthyloxy)-2-methoxypropyl]-4-piperidyl}-(4-fluorophenyl)-ketone {1-[3-(2-naphthyloxy)-2-methoxypropyl]-4-piperidyl}-(4-fluorophenyl)-ketone {1-[3-(1-naphthyloxy)-2-methoxypropyl]-4-piperidyl}-(3,4-dimethoxyphenyl)-ketone (4-fluorophenyl)-{1-[3-(1,2,3,4-tetrahydro-5-naphthyloxy)-propyl]-4-piperidyl}-ketone (4-fluorophenyl)-{1-[3-(indan-4-yloxy)-propyl]-4-piperidyl}-ketone (4-fluorophenyl)-{1-[3-(indan-5-yloxy)-propyl]-4-piperidyl}-ketone (3,4-difluorophenyl) -{1-[3-(indan-4-yloxy)-propyl]-4-piperidyl } -ketone (4-fluorophenyl) -{1-[3-(1,2,3,4-tetrahydro-6-naphthyloxy) -propyl ] -4-piperidyl } -ketone according to claim 1.
3. Pharmaceutical agents based on compounds according to claims 1 and 2.
4. Process for the production of compounds according to claim 1, wherein a) a compound of formula II
R1 Z--H (II), in which R1 and Z have the above meaning, is reacted with a compound of formula III
(III), in which X and B have the above meaning and A represents a leaving group, or b) a compound of formula IV
A--X--Z--R1 (IV), in which X, Z and R1 have the above meaning and A represents a leaving group, is reacted with an amine of formula V
(V), in which B has the above meaning, or c) an epoxide of formula VI
(VI), in which R1, Z and m have the above meaning, is reacted with an amine of formula V
(V), or d) a compound of formula VII
(VII) in which X and B have the above meaning, is reacted with a compound of formula R1-OH according to Mitsunobu and then optionally a carbonyl group is reduced or a hydroxy group is esterified or etherified or the physiologically compatible salts are formed or the isomers are separated.
R1 Z--H (II), in which R1 and Z have the above meaning, is reacted with a compound of formula III
(III), in which X and B have the above meaning and A represents a leaving group, or b) a compound of formula IV
A--X--Z--R1 (IV), in which X, Z and R1 have the above meaning and A represents a leaving group, is reacted with an amine of formula V
(V), in which B has the above meaning, or c) an epoxide of formula VI
(VI), in which R1, Z and m have the above meaning, is reacted with an amine of formula V
(V), or d) a compound of formula VII
(VII) in which X and B have the above meaning, is reacted with a compound of formula R1-OH according to Mitsunobu and then optionally a carbonyl group is reduced or a hydroxy group is esterified or etherified or the physiologically compatible salts are formed or the isomers are separated.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4410822.2 | 1994-03-24 | ||
| DE4410822A DE4410822A1 (en) | 1994-03-24 | 1994-03-24 | New piperidine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2186010A1 true CA2186010A1 (en) | 1995-09-28 |
Family
ID=6514110
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002186010A Abandoned CA2186010A1 (en) | 1994-03-24 | 1995-03-23 | New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptor |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0751936A1 (en) |
| JP (1) | JPH09510460A (en) |
| KR (1) | KR970701695A (en) |
| CN (1) | CN1145618A (en) |
| AU (1) | AU2212595A (en) |
| CA (1) | CA2186010A1 (en) |
| CZ (1) | CZ277096A3 (en) |
| DE (1) | DE4410822A1 (en) |
| FI (1) | FI963786A (en) |
| HU (1) | HUT75653A (en) |
| IL (1) | IL113103A0 (en) |
| NO (1) | NO963984L (en) |
| PL (1) | PL316382A1 (en) |
| SK (1) | SK120196A3 (en) |
| WO (1) | WO1995025721A1 (en) |
| ZA (1) | ZA952431B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10556013B2 (en) | 2017-06-20 | 2020-02-11 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
| US11530184B2 (en) | 2020-06-30 | 2022-12-20 | Imbria Pharmaceuticals, Inc. | Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
| US11780811B2 (en) | 2020-06-30 | 2023-10-10 | Imbria Pharmaceuticals, Inc. | Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
| US11883396B2 (en) | 2021-05-03 | 2024-01-30 | Imbria Pharmaceuticals, Inc. | Methods of treating kidney conditions using modified forms of trimetazidine |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA9610741B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | 4-Substituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
| ZA9610736B (en) | 1995-12-22 | 1997-06-27 | Warner Lambert Co | 2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists |
| ZA9610738B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | Subtype selective nmda receptor ligands and the use thereof |
| ZA9610745B (en) * | 1995-12-22 | 1997-06-24 | Warner Lambert Co | 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
| DK0885004T3 (en) * | 1996-03-08 | 2002-08-19 | Hoffmann La Roche | Use of 4-phenyl-3,6-dihydro-2H-pyridyl derivatives as NMDA receptor subtype blockers |
| US5824662A (en) | 1996-09-27 | 1998-10-20 | Guilford Pharmaceuticals Inc. | Treatment of global and focal ischemia using naaladase inhibitors |
| US6017903A (en) | 1996-09-27 | 2000-01-25 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of treating a glutamate abnormality and effecting a neuronal activity in an animal using NAALADase inhibitors |
| TR199901173T2 (en) | 1996-09-27 | 1999-07-21 | Guilford Pharmaceuticals, Inc. | Methods and compositions of NAALADase for the treatment of glutamate abnormality and regulation of neuronal activity in vivo. |
| US6242450B1 (en) * | 1998-07-27 | 2001-06-05 | Eli Lilly And Company | 5-HT1F antagonists |
| US6358982B1 (en) * | 1998-07-31 | 2002-03-19 | Eli Lilly And Company | Heterocyclyl sulphonamide derivatives |
| CA2372715A1 (en) * | 1999-05-13 | 2001-04-12 | Shionogi & Co., Ltd. | Preventive or therapeutic drugs for diabetes |
| TWI254043B (en) * | 1999-06-08 | 2006-05-01 | Hoffmann La Roche | Ethanesulfonyl-piperidine derivatives having good affinity to N-methyl-D-aspartate (NMDA) receptor |
| DE60104923T2 (en) * | 2000-03-22 | 2005-08-25 | F. Hoffmann-La Roche Ag | Piperidine and pirazine compounds for use in the treatment of Alzheimer's disease |
| PA8525601A1 (en) | 2000-08-21 | 2002-04-25 | Hoffmann La Roche | PROPHARMS OF (3S, 4S) -4-BENCIL-1- [2- (4-HIDROXI-BENCENOSULFONIL) -ETIL] -PIPERIDIN-3-OL |
| US6770659B2 (en) * | 2002-08-26 | 2004-08-03 | Sk Corporation | Benzoyl piperidine compounds |
| GB0224084D0 (en) | 2002-10-16 | 2002-11-27 | Glaxo Group Ltd | Novel compounds |
| CN110437136A (en) * | 2019-07-30 | 2019-11-12 | 东南大学 | 1- virtue oxygen ethyl piperidine -4- base methanone derivatives and its preparation method and application |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3576810A (en) * | 1968-06-20 | 1971-04-27 | Robins Co Inc A H | 1-substituted-3-(-4)-aroylpiperidines |
| DE2827566A1 (en) * | 1978-06-23 | 1980-01-10 | Boehringer Mannheim Gmbh | 1,2-DIHYDRO-CHINOLIN-2-ON DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| WO1982003861A1 (en) * | 1981-05-08 | 1982-11-11 | Tominaga Michiaki | Aniline derivatives,process for their preparation,and cardiotonics |
| PH19166A (en) * | 1982-09-04 | 1986-01-16 | Pfizer | Dihydropyridined,pharmaceutical compositions and method of use |
| FR2534580A1 (en) * | 1982-10-13 | 1984-04-20 | Synthelabo | PHENYL-1 PIPERIDINO-2 PROPANOL DERIVATIVES, THEIR PREPARATION, AND MEDICINES THAT CONTAIN THEM |
| DK623586A (en) * | 1985-12-27 | 1987-06-28 | Eisai Co Ltd | PIPERIDE INGREDIENTS OR SALTS THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE COMPOUNDS |
| US4868181A (en) * | 1986-08-04 | 1989-09-19 | E. I. Du Pont De Nemours And Company | 1,4-dihydropyridine derivatives with calcium agonist and alpha1 -antagonist activity |
| KR910006138B1 (en) * | 1986-09-30 | 1991-08-16 | 에자이 가부시끼가이샤 | Cyclic amine derivatives |
| EP0294183B1 (en) * | 1987-06-02 | 1994-03-30 | Ajinomoto Co., Inc. | Use of ethylamine derivatives as antihypertensive agents |
| HUT58275A (en) * | 1987-12-11 | 1992-02-28 | Mitsui Petrochemical Ind | Process for producing amines and pharmaceutical compositions containing them |
| SU1731048A3 (en) * | 1988-05-27 | 1992-04-30 | Эйсай Ко., Лтд (Фирма) | Process for preparing piperidine derivatives of pharmacolocically acceptable salts thereof |
| FR2632641B1 (en) * | 1988-06-13 | 1990-10-12 | Irceba | ((ARYL-4-PIPERAZINYL-1) -2 ETHOXY) -3 P-CYMENE, ORTHO DERIVATIVES, META, PARA MONOSUBSTITUTED OR DISUBSTITUTED ON THE PHENYL CORE OF THIS PRODUCT, THE PROCESS FOR THE PREPARATION OF SUCH DERIVATIVES, AND THE MEDICINAL PRODUCTS AS ACTIVE PRINCIPLE |
| US5153198A (en) * | 1989-03-15 | 1992-10-06 | Santen Pharmaceutical Co., Ltd. | Agent for treatment of disorders of the cerebro-neural transmission system |
| US5116846A (en) * | 1990-03-28 | 1992-05-26 | Du Pont Merck Pharmaceutical Company | N-aralkyl piperidine derivatives as psychotropic drugs |
| FR2681319B1 (en) * | 1991-09-12 | 1995-02-17 | Synthelabo | 1- (PHENOXYALKYL) PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| ES2060547B1 (en) * | 1992-06-04 | 1995-06-16 | Ferrer Int | IMPROVEMENTS IN THE PURPOSE OF THE INVENTION PATENT N / 9201158 THAT REFERS TO "PROCEDURE FOR OBTAINING NEW DERIVATIVES OF 4-BENCILPIPERIDINE". |
| FR2705343B1 (en) * | 1993-05-17 | 1995-07-21 | Fournier Ind & Sante | Beta, beta-dimethyl-4-piperidineethanamine derivatives, process for their preparation and their use in therapy. |
-
1994
- 1994-03-24 DE DE4410822A patent/DE4410822A1/en not_active Withdrawn
-
1995
- 1995-03-23 WO PCT/DE1995/000442 patent/WO1995025721A1/en not_active Application Discontinuation
- 1995-03-23 EP EP95915116A patent/EP0751936A1/en not_active Withdrawn
- 1995-03-23 IL IL11310395A patent/IL113103A0/en unknown
- 1995-03-23 JP JP7524306A patent/JPH09510460A/en active Pending
- 1995-03-23 PL PL95316382A patent/PL316382A1/en unknown
- 1995-03-23 SK SK1201-96A patent/SK120196A3/en unknown
- 1995-03-23 CZ CZ962770A patent/CZ277096A3/en unknown
- 1995-03-23 HU HU9602607A patent/HUT75653A/en unknown
- 1995-03-23 KR KR1019960705269A patent/KR970701695A/en not_active Application Discontinuation
- 1995-03-23 AU AU22125/95A patent/AU2212595A/en not_active Abandoned
- 1995-03-23 CN CN95192230A patent/CN1145618A/en active Pending
- 1995-03-23 CA CA002186010A patent/CA2186010A1/en not_active Abandoned
- 1995-03-25 ZA ZA952431A patent/ZA952431B/en unknown
-
1996
- 1996-09-23 FI FI963786A patent/FI963786A/en not_active Application Discontinuation
- 1996-09-23 NO NO963984A patent/NO963984L/en unknown
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10556013B2 (en) | 2017-06-20 | 2020-02-11 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
| US10918728B2 (en) | 2017-06-20 | 2021-02-16 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
| US10953102B2 (en) | 2017-06-20 | 2021-03-23 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
| US11376330B2 (en) | 2017-06-20 | 2022-07-05 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
| US11844840B2 (en) | 2017-06-20 | 2023-12-19 | Imbria Pharmaceuticals, Inc. | Compositions and methods for increasing efficiency of cardiac metabolism |
| US11530184B2 (en) | 2020-06-30 | 2022-12-20 | Imbria Pharmaceuticals, Inc. | Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
| US11746090B2 (en) | 2020-06-30 | 2023-09-05 | Imbria Pharmaceuticals, Inc. | Crystal forms of 2-[4-[(2,3,4- trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
| US11780811B2 (en) | 2020-06-30 | 2023-10-10 | Imbria Pharmaceuticals, Inc. | Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
| US12065410B2 (en) | 2020-06-30 | 2024-08-20 | Imbria Pharmaceuticals, Inc. | Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
| US12110275B2 (en) | 2020-06-30 | 2024-10-08 | Imbria Pharmaceuticals, Inc. | Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl] piperazin-1-yl]ethyl pyridine-3-carboxylate |
| US11883396B2 (en) | 2021-05-03 | 2024-01-30 | Imbria Pharmaceuticals, Inc. | Methods of treating kidney conditions using modified forms of trimetazidine |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0751936A1 (en) | 1997-01-08 |
| KR970701695A (en) | 1997-04-12 |
| PL316382A1 (en) | 1997-01-06 |
| FI963786A0 (en) | 1996-09-23 |
| FI963786A (en) | 1996-09-23 |
| MX9604201A (en) | 1997-12-31 |
| HU9602607D0 (en) | 1996-11-28 |
| AU2212595A (en) | 1995-10-09 |
| DE4410822A1 (en) | 1995-09-28 |
| CN1145618A (en) | 1997-03-19 |
| WO1995025721A1 (en) | 1995-09-28 |
| NO963984D0 (en) | 1996-09-23 |
| CZ277096A3 (en) | 1997-01-15 |
| IL113103A0 (en) | 1995-06-29 |
| ZA952431B (en) | 1995-12-19 |
| JPH09510460A (en) | 1997-10-21 |
| SK120196A3 (en) | 1997-10-08 |
| HUT75653A (en) | 1997-05-28 |
| NO963984L (en) | 1996-09-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2186010A1 (en) | New 1,4-disubstituted piperidine derivatives useful as medicaments acting on the glutamate receptor | |
| US5877187A (en) | Benzimidazole derivatives with antihistaminic activity | |
| WO1993014084A2 (en) | Piperidine derivatives | |
| JP5360605B2 (en) | Acid addition salt of optically active piperidine derivative and process for producing the same | |
| US5409931A (en) | 1,3-substituted cycloalkenes and cycloalkanes as central nervous system agents | |
| KR100563867B1 (en) | Indazole amide compounds as serotoninergic agents | |
| JPH02223551A (en) | New n-substituted aza heterocyclic carboxylic acids | |
| US4983607A (en) | Quinolinone derivatives and their preparation in therapy | |
| DE3522579C2 (en) | Novel 1,4-dihydropyridine derivatives and salts thereof, processes for their preparation and pharmaceutical compositions containing the same | |
| US5314887A (en) | 2-amino-1, 4-dihydropyridine derivatives with calcium agonist and alpha.sub. -antagonist activity | |
| DK168291B1 (en) | N-substituted diphenylpiperidines, process for their preparation, drug containing the compounds and use of the compounds and use of the compounds for the preparation of a drug for use in the prevention or treatment of obesity | |
| DE69736890T2 (en) | CONDENSED HETEROCYCLIC COMPOUNDS AND ITS PHARMACEUTICAL USE | |
| US4460594A (en) | Bicyclo-hetero-alkylene-1-piperidines, pharmaceutical compositions thereof and methods of use thereof | |
| US4560692A (en) | 4-Piperidino-2-phenylquinolines | |
| US5604242A (en) | Heterocyclic chemistry | |
| FI97131C (en) | Process for the preparation of therapeutically active piperidine derivatives | |
| US5118691A (en) | Substituted tetrahydropyridines as central nervous system agents | |
| US5045550A (en) | Substituted tetrahydropyridines as central nervous system agents | |
| US5089497A (en) | Substituted piperazines as central nervous system agents | |
| EP0505465B1 (en) | 4-Heterocyclyl-piperidine derivatives, their preparation and their use as inhibitors of calcium overload in brain cells | |
| JPS63130581A (en) | Production of 2-substituted-1, 4- dihydropyridines | |
| MXPA96004201A (en) | New piperid derivatives | |
| US4518713A (en) | Analgesic substituted-1-aminoalkylamino-4-aryloxypiperidines | |
| CA2170615A1 (en) | Alkoxy-substituted .beta.-carbolines acting on the ampa-receptor | |
| AU691468B2 (en) | Ring-closed dihydropyridines and their use in the preparation of pharmaceutical compositions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |