CA1329203C - Esters of hexahydro-8-hydroxy-2, 6-methano-2h- quinolizin-3(4h)-one and related compounds - Google Patents
Esters of hexahydro-8-hydroxy-2, 6-methano-2h- quinolizin-3(4h)-one and related compoundsInfo
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- CA1329203C CA1329203C CA000550612A CA550612A CA1329203C CA 1329203 C CA1329203 C CA 1329203C CA 000550612 A CA000550612 A CA 000550612A CA 550612 A CA550612 A CA 550612A CA 1329203 C CA1329203 C CA 1329203C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
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- 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
- 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
- A61P25/06—Antimigraine agents
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- Neurology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention is directed to a group of esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one and related compounds. The compounds are prepared from the appro-priate carboxyllc acids and alcohols by standard procedures or, where steric factors are significant, a new process which makes use of heavy metal salts of super acids can be used. The compounds involved are useful in the treatment of migraine and similar disorders and in cytotoxic drug-induced vomiting.
The present invention is directed to a group of esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one and related compounds. The compounds are prepared from the appro-priate carboxyllc acids and alcohols by standard procedures or, where steric factors are significant, a new process which makes use of heavy metal salts of super acids can be used. The compounds involved are useful in the treatment of migraine and similar disorders and in cytotoxic drug-induced vomiting.
Description
~ 3?q203 PATENTS
ESTE~S OF HEXAHYDRO-8-HXDROXY-2,6-~THUNO-2H-QVINO7IZIN-3(4H)-ONE ~ND RELATED COMPOUNDS
:;
`` The present invention is directed to esters of hexahydro- 8-hydroxy-2,6-methano-2H-quinolizln-3(4H)-one and he~ahydro-8-10 hydroxy-2,6-methano-2H-quinollzlnes with certaln aroma~lc and hoterocyclic carboxylic aclds. The lnventlon 1~ also dlrected to novel polycyclic alcohols whiCh serve a~ lntermediates ln the preparation of the esters o~ thls invention and also to a novel process ror preparlng a group o~ esters of the present lnventlon.
Nore particularly, the present lnvention ls directed to compounds of the formula B
~ N ~ 1l ~ O-C-Rl wherein A is ~H2, =0, =(H)(OH), =(OH)2 or =N-OH; B is =H2, (H)(CH3), (H)(CH2NR3R4) or CH2 whereln R3 and R4 are C2 4 25 alkyl or are comblned t~ give tetramethylene, pontamethylene or -CH2CH2-0-CH2cH2-; Rl .
C-35,466 ~
'., 1 ;~292~3 ~ ~7 ~3 [~N-Rg or I~L
wherein Z is NRg, 0 or S; R5, R6 and R8 are each hydrogen, halogen, C1 3 alkyl or C1 3 alkoxy; R7 is hydrogen, amino, (Cl 4 alkyl)am~no, (C1 4 alkyl)2amino, alkoxy or nitro; Rg is hydrogen, 10 C~ 4 alkyl or phenyl (Cl 2 alkyl); Rlo is hydrogen, halogen, Cl 4 alkyl, C1 4 alkoxy, hydroxy, cyano or -CONH2; R11 i9 hydrogen, halogen, Cl 4 alkyl or phenyl; the wavy line lndicates that the con~iguration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and 15 quaternary ammonium salts of the aforessid compounds.
Examples of the C1 4 alkyl groups re~erred to above are methyl, ethyl, propyl, isopropyl and butyl. Examples o~ the C1 4 alkoxy groups are methoxy, ethoxy, propoxy and butoxy. The halogens re~erred to above can be fluorine, chlorlne or bromine.
20 When the wavy llne in the general structural formula is changed to a solid llne, this indicates that the con~iguration of the compounds is endo. Such endo-compounds can also be re~erred to as trans. Similarly, exo-compounds can also be referred to as cis.
Any hydrates of the present compounds are considered as 25 equivalent to the compounds themselves and this would include compounds in which the carbonyl (i.e., A is 0) exists as (OH)2.
C-35,466 1 3~9 ?~J3 A preferred group of compounds are tho~e whereln the ester is attached to the polycyclic rlng in the endo-conflguration. A
further preferred group are tho~e having the endo-configuratlon wherein A is =0 and =(OH)2. In a still further preferred group, B
5 is additionally =H2.
The pharmaceutically acceptable acid addition salts referred to above can be non-toxlc salts with suitable acids such as those with inorganic acids, for example hydrochloric, hydrobrom~c, nitric, sulfuric or phosphoric acids; or with organic acids such 10 as organic carboxylic acids, ~or example, acetic, propionic, glycolic, maleic, hydroxymaleic, malic, tartarlc, citrlc, sal~cycllc, 2-acetyloxybenzoic, nicotinic or i30nicotinic; or organic sulronic acids, ror example methanequlfonic, ethane-sulfonic, 2-hydroxyethanesul~onic, 4-toluenesulfonic or 15 2-naphthalensul~onic. Quaternary ammonium salts are formed with alkyl halldes such as methyl chlorlde, methyl bromide or ethyl bromide; or with sulfate esters such as methyl 4-toluenesulfonate or methyl 2-naphthalenesulfonate.
Some specific examples of compounds encompassed by the 20 present lnvention are the following:
endo-8-(3,5-Dimethylbenzoyloxy)hexahydro-2,6-methano-2H-qulnollzin-3(4H)-one exo-8-(3,5-Dimethylbenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one 5 endo-8-(3,5-Dichlorobenzoyloxy)hexahydro-2,6-methano-2H-qulnollzin-3(4H)-o,ne C-35,466 endo-8-(3,5-Dimethoxybenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one endo-8-(4-Aminobenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one 5 endo-8-(4-Dimethylaminobenzoyloxy)hexahydro-2,6-methano-2H-quinollzin-3(4H)-one endo-8-(3,5-Dimethylbenzoyloxy)octahydro-2,6-methano-2H-quinolizine endo-8-t3-Indolylcarbonyloxy)octahydro-2,6-methano-2H-quinolizine 10 endo-8-(~-Cyano-3-indolylcarbonyloxy)hexahydro-2,6-methano-2H-- quinollzin-3(4H)-one endo-8-(3,5-Dichlorobenzoyloxy)hexahydro-2,6-methano-4-methyl-2H-quinolizin-3(4H)-one endo-8-(3-Indolylcarbonyloxy)hexahydro-4-(diethylaminomethyl)-2,6-methano-2H-quinolizin-3(4H)-one endo-8-(3-Indolylcarbonyloxy)-3-hydroxyimino-2,6-methanooctahydro-2H-quinollzine endo-8-(2-Methyl-l-isoindolylcarbonyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one 0 endo-8-(2-Pyrrolidinylcarbonyloxy)hexahydro-2,6-methano-2H-quinollzin-3(4H)-one endo-8-(3-Indolylcarbonyloxy)-2,6-methanooctahydro-2H-quinolizin-3-ol The compounds o~ the present lnvention can be prepared by 25 reacting an alcohol or a reactlve derivative thereof, said alcohol having the formula C-35,466 ~, -..... .. . . .
1 3292a3 A' OH
~ 5 wherein A' is =0 or =H2, wlth a reactive equivalent of an acld of ;~ the formula RlCOOH
10 wherein Rl is defined as above. By a reactive equivalent of the acid is meant the corresponding acid chloride or bromide or the corresponding glyoxylyl chloride or bromide or the carboxyllc acid lmidazole obtained by the reaction of the appropriate acid halide with N,N-carbonyldiimidazole; or any similar acid 15 derivative which would yield the simple carboxylic acid ester on reaction with an alcohol or with a reactive derivative of an alcohol. More specifically, where the -OH in the alcohol is equatorial texo), then it can be reacted with the appropriate carboxylic acid imidazole obtained by the reaction of the acid 20 halide with N,N-carbonyldiimidazole. Alternatively, the acid can ~. be converted to the acid chloride by standard procedures (e.g., thionyl chloride) and then reacted with the alcohol or an alkali metal salt of the alcohol such as the lithium salt obtained by the reaction of lithium hydride with the alcohol in tetrahydro-25 furan.
_ 5 _ C-35,466 .
1 3292a3 When the -OH group in the starting alcohol is axial (endo), it can also be converted to the corresponding ester by reaction wlth the appropriate acid chloride or bromlde wlth the reaction being carried out in the presence o~ an equivalent of a suitable 5 tertiary base such as 4-dimethylamlnopyridine in a high boiling lnert solvent such as xylene. In this case, however, long heating (24-84 hours) at a temperature at or above 140C is necessary so that the procedure would not ~e suitable for use with acid halldes that are not stable under the indlcated conditions. Thus, 10 it was necessary to use an alternative for the preparation of such compounds. In this procedure, an appropriate acid chloride or bromide or a glyoxylyl chloride or bromide, in a nitroparaffin solvent, is reacted with a solution of a super acld salt of the alcohol and an equivalent amount of a heavy metal salt of the 15 same super acid. The glyoxylyl chloride can be used in the process as indicated because it decarbonylates readlly under the condltions used. The reactlon ltself can be carried out over a period of 1-24 hours at temperatures ranging from -80C to ambient temperatures tabout 23C). Examples of suitable super 20 ac~ds with M = H are MBF4, MAsF6, MSbF6, MPF6, MTaF6 or MNbF6 with examples of suitable heavy metals (M) being silver and thallium. Examples of nltroparaffln solvents are nitromethane, nitroethane, l-nitropropane and 2-nltropropane.
Actually, where the group Rl contains a primary or secondary 25 amino group, it is usually protected during the above reaction, with a benzyl group belng commonly used to protect a secondary C-35,466 l 329,~0j amine and a benzyloxycarbonyl group being used to protect a primary amine. In either case, the protecting group in the product is removed by conventional procedures, for example by hydrogenation with hydrogen and a palladium catalyst.
s Various procedures can be used to convert those compounds wherein A is =0 and whose preparation is described below, to other different bridged derivatives o~ the present invention by standard methods. Thus, the ketone group in the polycyclic system can be reduced to the corresponding alcohol using an alkali metal 10 (sodium or potassium) borohydride in a lower alkanol such as methanol or ethanol.
- The ketone group can also be reduced completely to a methylene group by a two step procedure. In the first step, the ketone ls reacted with ethylene dithiol or trimethylene dithiol 15 in the presence of a strong acid such as hydrochloric acid or BF3 to give the corresponding dithioketal. The reaction is carried out in a suitable polar solvent such as nitromethane or acetic acid. ~he dithioketal is then reduced with hydrazine in the presence of Raney nickel in a lower alkanol solvent such as 20 2-propanol at elevated temperatures (60-100C). Actually this same procedure can be used to reduce the original starting alcohol, hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one, to 8-hydroxy-2,6-methanooctahydro-2H-quinolizine which can itself be reacted with acid derivatives as described earlier to give the 25 corresponding esters.
C-35,466 , 32~2~
Compounds containing other B-groups (i.e, aminomethyl, methylene or methyl groups) can be obtained from products in which A is =0 and B is =H2 by a Mannich reaction using formal-dehyde and a secondary ~mine such as dlmethylamine, diethylamine, 5 piperidine or pyrrolidine. This reaction gives the corresponding aminomethyl compound and, when B is dimethylaminomethyl, the amino moiety is eliminated on heating at 90-110C in an inert solvent such as toluene to give the corresponding methylene compound (B is =CH2). This exocyclic methylene compound can be 10 isolated by standard methods and transformed into a methyl group by hydrogenatlon, for example, by using hydrogen and platinum oxide.
To obtain those compounds in which A is hydroxyimino (=N-OH), the ketone referred to above can be reacted with 15 hydroxylamine hydrochloride ~y standard procedures.
The alcohol used as a reactant in the above procedure can be obtained from known alkyl (C1 4) 3-cyclopentene-1-carboxylates by a multi-step procedure~ Speci~lcally, the double bond in the indicated cyclopentene is oxidized to a 1,2-diol using N-methyl-20 morpholine N-oxide in the presence of osmium tetroxide catalyst.
The diol is then cleaved to the corresponding dialdehyde using sodium metaperiodate. A Robinson-Schopf cyclization of the dialdehyde with a lower alkyl glyclne ester and acetone-dicarboxylic acid, preferably at pH4, gives a pseudopelletierine 25 derivative of the following type:
C-35,466 . ~ .
1 32'~2~3~?
N
EtOC
The ketone group is reduced to an alcohol using sodium boro-hydride and the product is reacted with dihydropyran to protect the -OH group as a tetrahydropyranyl ether, Dieckmann cycli~ation `~ Or the dlester using a strong base (e.g. potasslum t-butoxide) ~ollowed by aqueous acid hydrolysls and decarboxylation gives the ; desired alcohol. The resulting alcohols can exi~t in two conrormation~ - axlal and equatorial. The main product obtained `~ by the above procedure is the axlal alcohol and it can be separated fro~ the equatorial isomer by crystallization of the ~o camphorsulfonate or tetrafluoroborate salt.
.~ The present compounds are useful for the treatment of pain, especially migralne vascular and cluster headaches and trigeminal neuralgia. They are also useful in the treatment of nausea and vomiting arising from treatment with cancer chemotherapeutic - 25 agents.
In the past, acute attacks Or migraine have been treated i with a peripheral vasoconstrictor, such as ergotamine, which may be co-administered with cafreine, and dlhydroergotamine; an C-35,466 ~ 32920 '`
antipyretic analgesic, such as acetylsalicyllc acld or p-acetyl-aminophenol; and/or an anti-emetic such as cyclizlne, metoclo-pramide and thiethylperazine~ It has also been reported (J. B.
Hughes, Med. J. A~st~ 2, No. 17, sao, 1977) that lmmediate rellef 5 o~ an acute migraine attack can be obtained by slow intravenous injection of metoclopramide (10 mg).
It i~ believed that 5-hydroxytryptamlne (5-HT) is the naturally occurring substance most likely to play a role in the pathophysiology of migraine. Increased amounts of 5-HT and its 10 metabolite 5-hydroxyindoleacetic acid are excreted in the urine durlng most attacks. Further, plasma and platelet 5-HT concen-- trations fall rapidly at the onset of an attack and remain low while the headache persists. Moreover, attac~s of migraine have been clearly associated with periods of thrombocytopaenla in 15 certain patlents. It has been proposed that compounds whlch block the actlvity of 5-HT would be of use in the symptomatic treatment of miBraine (J. R. Fozard, International Headache Congress 1980, reported in Advances in Neurology, Vol. 33, Raven Press~ New York, 1982).
The known migraine prophylactic drugs, methysergide, propranolol, amitriptyline, and chlorpromazine have widely different pharmacological activities but all are 5-HT D-receptor antagonists at the doses used cllnlcally for the prophylaxis of migralne. Metoclopramide is a potent 5-HT M-receptor antagonist 25 and it has been proposed (J. R. Fozard supra) that a blockade of the M-receptor present on afferent sensory neurones affords C-35,466 ~ 3~qL)~3 symptomatic rellef in an acute migraine attack.
The potency as 5-HT M-receptor antagonists of (-) cocaine and some related compounds, lncludlng pseudotropyl benzoate (l.e.
benzoylpseudotropine) and 3,5-dichlorobenzoyltropine has been 5 reported (J. R. Fozard e' al., Eur. J. Pharmacol., 59, 1979, 195-210; J.R. Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol., 326, 1984, 36-44). The PA2 values reported for metoclopramlde, pseudotropyl benzoate, nor(-~ cocaine and benzoyltropine are 7.2, 7.0, 7.7 and 7.2 respectively whilst the PA2 value determined for 10 3,5-dichlorobenzoyltroplne by the same procedure is 9.3 ~J. R.
Fozard et al~, Eur~ J. Pharmacol~, 49, 1978, 109-112; J.R.
Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol., 326, 1984, 36-44). In a double-bllnd clinlcal trial, 3,5-dichlorobenzoyl-tropine proved an effective treatment ~or the acute migraine 15 attack (C. Loisy et al., Cephalalgia, 5, 1985, 79-82). A further series of tropine esters, wlth PA2 values for blockade of the 5-HT M-receptors between 7.7 and 13.6 have been descrlbed by Rlchardson et al., Nature, 316, 1985, 26-131.
The compounds of the present lnvention block the M-receptors 20 for 5-hydroxytryptamlne (5-HT) on afferent sensory neurones, certain o~ which subserve the transmisslon of paln. As explalned above, the blocklng or such M-receptors appears to be a mechanism whereby the symptoms of mlgraine can be relleved. Accordingly, the present compounds are use~ul ln the treatment of migraine 25 when administered in amounts sufficient to effectively block the sald M-receptors.
C-35,466 1 32920 ~
In addltion, compounds blocking 5-HT M-receptors, includlng metoclopramide, 3,5-dichlorobenzoyltropine and (3a-tropanyl)-lH-indole-3-carboxyllc acid ester, are hlghly erfective in preventing the nausea and vomiting induced by cancer chemothera-5 peutic agents in an animal experlmental model (W.D. Miner et al.,Brit. J. Pharmacol., 88, 1986, 374P; W.D. Mlner and G.J. Sanger, Brit. J. Pharmacol., 88, 1986, 497-499, ~. Costall et al., Neuropharmacology, 25, 1986, 959-961). It is believed that cytotoxic drug-induced vomiting involves a 5-HT M-receptor 10 mechanism (W.D. Miner and G.J. Sanger, Brit. J. Pharmacol., 88, 1986, 497-499). Accordingly, the present compounds are useful ln the treatment o~ cytotoxic drug-induced vomiting when adminls-tered in amounts su~ficient to e~ectively block the said M-receptors.
lS The activity Or the compounds against 5-HT can be assessed by determining their PA2 values in the isolated rabbit heart as described by J.R. Fozard et al., Eur. J. Pharmacol., 59, 195-210 (1979). In the method descrlbed, the molar concentration of antagonist which reduces the efrects o~ twice the ED50 of 5-HT to 20 that Or the ED50 in the absence of antagonist is determined. The PA2 value is the negative logarithm of said molar concentrations.
In general terms, the higher the PA2 value the more potent is the compound. When tested in thls way, the present compounds show pA2's generally in the range of about 8 to 10.
The actlvity of these compounds against 5-HT can be assessed in vivo by measurement Or the effect o~ the compound on the Von C-35, 466 ~ 32920~
Bezold-Jarisch Reflex induced by 5-HT ln~ected intravenously into the rat (see Paintal A.S., Physlol. Rev. 53, 159-227, 1973; J.R.
Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol., 326, 1984, 36-44). The transient cardiac slowing arises from an increased 5 afferent vagus activity arising from stimulation by 5-HT of sensory afferent fibres in and around the heart. When tested against the Von Bezold-Jarlsch Reflex induced by 5-HT, compounds endo-8-(3,5-dimethylbenzoyloxy)hexahydro-2,6-methano-2H-~u~nolizln-3(4H)-one hydrochloride and endo-hexahydro-8-10 (3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one hydrochloride suppressed the response dose-dependently at doses of 0.01-0.1 mg~kg given intravenously or 0.25-1 mg/kg given orally.
The present compounds appear to be highly selective in their 15 action against 5-HT M-receptor. Thelr potency against other 5-HT
` receptors and other spasmogens, in particular carbachol, phenylephrine, histamlne and calcium, ls Xnown to be at least three orders lower ~han that against 5-HT M-receptors.
Accordingly, their use in the treatment o~ migraine or cytotoxic 20 drug-induced vomltlng should be without any side e~fects.
The present compounds can be administered in various manners to achleve the desired e~fect. The compounds can be administered alone or in the ~orm oi~ pharmaceutical preparations to the patlent belng treated elther orally or parenterally, for example, 25 subcutaneously or lntravenously. They can also be administered by inhalation or by suppository. The amount of compound administered C-35,466 1 ~'320 ~
will vary and can be any effective mlgraine-relieving amount or mount effective in cytotoxlc drug vomiting. Depending upon the patient and the mode of administration, the quantity of compound administered may vary over a wide range to provide from about 5 o.Ol mg/kg to about 10 ~.g/kg, usually 0.03 to 3.0 mg~kg, of body ` weight of the patient per dose. Unit doses o~ these compounds can contain, for example, from a~out 0.5 mg to 100 mg, usually 1 to 50 mg and pre~erably 3 to 30 m8, of the compound and may be administered, for example, from 1 to 4 times daily.
The term "unit dosage *orm" is used herein to mean a single or multlple dose form containing a quantity of the active ingredlent in admixture with or otherwise in assoclation with the diluent or carrier, said quantity being such that one or more predeterm~ned units are normally required ~or a single thera-. 15 peutic administration. In the case o~ multiple dose forms such as liquids or scored tablets, said predetermined unit will be one fraction, such as a 5 ml (teaspoon) quantity of a liquid or a half or quarter of a scored tablet, of the multiple dose form.
Specific formulations o~ the present invention are prepared - 20 in a manner well known per se in the pharmaceutical art and usually comprise at least one active compound of the invention in admixture or otherwise ln association with a pharmaceutically acceptable carrier or diluent therefor. For making those formulations the active ingredient will usually be mixed with a 25 carrier, or diluted by a diluent, or enclosed or encapsulated in a capsule, sachet, cachet, paper or other container. A carrier or C-35,466 .
1 32~
diluent may be solid, semi-solid or liquid material which serves as a vehicle, excipient or medium for the active ingredient.
Suitable carriers or diluents are well known per se. See Remington's Pharmaceutical Sclences, Mack Publishing Company, 5 Easton, Pennsylvanla, for a descriptlon of the preparation of such ~ormulat~ons.
The formulations o~ the invention may be adapted for enteral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppos~tories, solutlons, suspensions 10 or the like.
The compounds of the present inventlon can be used in migraine therapy in combination with other antimigra~ne drugs having dl~ferent modes o~ actlon, Such drugs include those used prophylactically, such as barbiturates, diazepam, chlorpromazine, 15 amitriptyline, propanolol, methyserglde, Pizotl~en, cypro-heptadine, dihydroergotamine, and clonidine, and those used in the acute attack, such as vasoconstrictor agents, e.g~, ergotamine and dihydroergotamine, analgesic/anti-inflammatory agents, e.g., aspirln, paracetamol and lndomethacln, or 20 anti-nauseants, e.g., cycllzlne, metoclopramide, and thiethyl-perazine (see Fozard, J.R., J. Pharm. Pharmacol., 27, 297-321 (1975); Saper, J.R., J. Amer. Med. Assoc. 239, 480-484 (1978);
Fozard,J.R., supra). As an example, compounds o~ the present lnvention would be bene~lclal ln comblnatlon wlth aspirin 25 300-1200 mg or methyserglde 2-6 mg given daily.
C-35,466 1 329~0:~
The following examples are presented to lllustrate the present invention but they should not be construed as limlting it in any way~
EXAMPLE I
- To a stirred solution of 160 g of diethyl malonate in 1.5 l o~ dry dimethyl~ormamide at 0C under nltrogen was slowly added ` 10 30 g o~ lithium hydride~ A~ter the evolution of hydrogen ceased (2 hours~ 143 g Or cis-1,4-dlchloro-2-butene was slowly added and t~e mixture allowed to come to room temperature~ After 72 hours, the mixture was diluted with a mixture of ether and hexane (1:4) and poured into water~ ~he organic layer was washed with water 15 and brine before drying over magneslum sul~ate. Dlstillation gave diethyl 3-cyclopentene-l,l-dlcarboxylate, bp 70-80C/0.1 mm, containing a small amount (-10X) of diethyl 2-vinylcyclopropane-~ l,l-dicarboxylate.
The impure cyclopentene dlester (148.5 g) obtained above was 20 added to a solutlon of 118 g Or potassium hydroxide in 1333 ml of 80X ethanol and the stirred solution warmed at 60-70C overnight.
The ethanol was evaporated and the residue treated with an ice cold solution of concentrated sulphuric acid (107 ml) in water (274 ml)~ Extractlon of the acid mixture with ether (3 x 400 ml) 25 followed by evaporation of the dried ether extracts gave a residue of the diacid which was decarboxylated to the monoacid by C-35,466 heating in an oil bath at 170-180C for 1 hour. The residual oil was distilled to give crude 3-cyclopentene-1-carboxylic acid, bp 68-73C (1 mm) contalning some y-vlnyl-y-butyrolactone. A
solution of 98 g o~ potassium carbonate in 300 ml of water was 5 added and the mixture extracted with ether to remove the ~-vinyl-~-butyrolactone. Acidification of the aqueous solution - and extraction with ether afforded pure 3-cyclopentene-1-~: carboxylic acid.
.:
EXAMPLE II
`i A mixture of 52 g o~ 3-cyclopentene-l-carboxyllc acid and excess thionyl chloride was stirred at room temperature ~or 15 1 hour, The excess thionyl chloride evaporated and the residue distilled to give 3-cyclopentene-1-carbonyl chloride, bp 52-58C.
The acid chloride obtained above was slowly added to an ice cooled stirred solution of 32 g of pyridine in 150 ml of ethanol.
T~e mixture was stirred for a further hour, the ethanol evaporat-20 ed and the residue treated with water and ether. The ether layerwas separated, washed several times with water and dried. Evapo-ration of the ether left a residue of ethyl 3-cyclopentene-1-carboxylate, bp 62.5-66C/14 mm.
- 17 _ C-35,466 . . .
EXAMPLE III
A solution containing 84.6 g of N-methylmorphollne N-oxide, ~`1 g of osmium tetroxide, 230 ml of water and 115 ml of acetone ~5 was allowed to stir for 30 minutes at room temperature. To this `~.stirred mixture was added very slowly over at least 8 hours, a solution o~ 80 g o~ ethyl 3-cyclopentene-1-carboxylate in 115 ml of acetone. The stirred mixture was heated at 50C for 2 hours to complete the reaction (verified by TLC examinatlon using ethyl 10 acetate/hexane 70/~0). Sodium bisulfite (~10 g) was added, the stirring continued for a further 15 minutes, and the mixture filtered through Celite. The pH of the filtrate was adJusted to 7 by the addltion of 12 N sulfuric acid (37 ml), the acetone evapo-rated, the pH of the residual solution ad~usted to 2 with 12 N
15 sulfuric acid (13 ml) and the solutlon extracted with ethyl acetate (4 x 250 ml). Evaporation of the dried ethyl acetate solutlon gave 4-ethoxycarbonyl-1,2-cyclopentanediol.
EXAMPLE IV
A solution of 85.4 g of sodium perlodate in 500 ml of water was slowly added to a s~irred solution of 69 g of 4-ethoxy-carbonyl-1,2-cyclopentanedlol ln 690 ml of tetrahydrofuran. The 25 reactlon was exothermlc and cooling was necessary. After two hours a precipitate of sodium iodate was filtered off and the C-35,466 1 3292~
solution concentrated at room temperature to remove most of the tetrahydrofuran. The resulting aqueous solution contained the desired ~-ethoxycarbonylglutaraldehyde and was used directly in t~e next reaction.
; 5 To a stirred suspension of 400 g of potassium hydrogen phthalate in 800 ml of water was added, in sequence, a solutlon ; of 80 g of acetonedicarboxylic acid in 1200 ml of water, a solution of 80 g of glycine ethyl ester hydrochloride in 400 ml of water, and finally the solution of ~-ethoxycarbonylglutaral-10 dehyde obtained above. The mixture was stlrred for 20 hours at room temperature durlng which time carbon dioxlde evolved. The mixture was basified by the addition o~ an excess of aqueous potassium carbonate and extracted with ethyl acetate several times, Evaporation of the dried ethyl acetate extracts gave a 15 syrup consisting mainly of 7-ethoxycarbonyl-9-~ethoxycarbonyl-methyl)-9-azabicyclo-r3.3.1~nonan-3-one.
EXAMPLE V
` Sodium borohydride (17 g) was added in small portions to a stirred solution of 87.6 g of 7-ethoxycarbonyl-9-(ethoxycarbonyl-methyl)-9-azabicyclo~3.3.1]nonan-3-one in 750 ml of ethanol. The mixture was stirred overnight at room temperature, the ethanol 25 evaporated and the residue treated with 200 ml of water. Hydro-chloric acid (2 M) was added until the mixture was acid and this ~ C-35,466 ~ 329,~ n3 acid solution was immediately basifled by the addition of saturated potassium carbonate solution. Extractlon with ethyl acetate and evaporation of the drled extract gave a syrup which consisted mainly of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-5 9-azabicyclo~3.3~13nonan-3-ol, The syrup can be purified by ~ column chromatography using silica and elution with hexane-ethyl -~ acetate ~30:70).
EXANPLE VI
A solutlon of 26~1 g o~ the crude 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonan-3-ol in 250 ml of methylene chloride was treated with one equivalent of methane-15 sulfonic acid (8.42 g). The methylene chloride solution wasconcentrated to about 35 ml, 9.S ml o~ dihydropyran was added together wit~ one drop o~ methanesul~onlc acid, and the mixture stirred ror 3 hours at room temperature. The mlxture was then poured into saturated potassium carbonate solution and the 20 product separated by extraction with ethyl acetate.
Evaporation o~ the dried ethyl acetate extracts gave a syrup consisting mainly of the tetrahydropyranyl ether of 7-ethoxy-carbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo~3.3.1]nonan-3-ol.
It can be purified by column chromatography using silica and 25 elution with hexane-ethyl acetate (20:80), Rf 0.7.
C-35,466 ,, 1 329~ 3 ) EXAMPLE VII
A solution of 34 g of the tetrahydropyranyl ether of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo¦3.3.1¦-5 nonan-3-ol in 800 ml of anhydrous toluene was treated with 19 g of potassium tert-butoxide and the stirred mixture heated at 100C for 2 hours. Anhydrous formic acid (7~85 g) was added to the cooled mixture, the potassium formate was ~iltered off, and the toluene solution evaporated to glve a syrup~ The syrup was 10 treated with 300 ml o~ 5 N hydrochloric acid and the stirred solution refluxed overnight. The cooled mixture was clarified by sn extraction with methylene chloride and the aqueous acid solution evaporated to dryness. The residue was dissolved in a little water and the solution treated with a large excess of 15 saturated potassium carbonate solution. Extraction of the resulting mixture with ethyl acetate and evaporatlon of the dried ethyl acetate solution gave endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H~-one as an oil which crystallized on standing. The base was converted to its camphorsulfonate salt, 20 m.p. 178C, using one equivalent of camphorsulfonic acid in ethanol.
C-35,466 .
1 32'~, ~3 ~
EXAMPLE VIII
.
A mixture of 1.8 g of endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H~-one, hydrofluoroboric acld (0.88 g; 60%
5 aqueous solution) and 20 ml of ethanol was evaporated, the residue was treated with sa ml of anhydrous toluene, and the mixture again evaporated. A stirred suspension of the anhydrous residue in 50 ml of anhydrous nitroethane at -78C was treated with 1.94 g of anhydrous silver tetrafluoroborate and a solution 10 of 1.7 g of 3,5-dimethylbenzoyl chloride ln 20 ml of anhydrous nitroethane was added slowly. The temperature of the stirred reaction was kept at -78C for 1.5 hours and then allowed to return to room temperature overnight. Triethylamlne (1 g) was added, the solution filtered and the nitroethane evaporated. A
15 solution of the residue in 20 ml of water was treated wlth an excess of a saturated aqueous solution of potasslum carbonate and the liberated oil separated by extraction with ethyl acetate. The ethyl acetate solution was washed several times with water before being dried over magneslum sulfate and evaporated~ The residue 20 obtained was endo-8-(3,5-dimethylbenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one and this was treated with methylene chloride and ethereal hydrogen chloride to give crystals of the hydrochloride salt melting at about 291C.
C-35,466 ~. ~
~ 3~92n.~., EXAMPLE IX
When the procedure of Example VIII is repeated uslng endo-hexahydro-8-hydroxy-2,6-methano-2H-qulnollzin-3(4H)-one and the 5 appropriate acid chlorlde, the corresponding e~ter~ listed below are obtalned. As necessary, the acid chlorides were obtained from the appropriate carboxylic acids by standard procedures, for example, usig thionyl chloride. To convert the ester to a corresponding acid salt, it was reacted with the appropriate acid lO with alternative solvents be~ng used as des~red.
endo-Hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinollzin-3(4H)-one methanesulfonate melting at a~out 278C.
endo-8-(3-Benzofurancarbonyloxy)hexahydro-2,6-methano-2H-15 qulnollzln-3(4H)-one endo-8-~3-Benzo[b]thiophenecarbonyloxy)hexahydro-2,6-methano-2H-quinolizin-3t4H)-one endo-8-(1-Benzyl-lH-indol-3-ylcarbonyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one endo-Hexahydro-8-(1-methyl-lH-indol-3ylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one endo 8-(4-Bromo-2-furylcarbonyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one ~ endo-Hexahydro-8-(5-phenyl-2-furylcarbonyloxy)-2,6-methano--` 25 2H-qulnollzln-3(4H)-one C-35,466 1 3292a ~
, endo-8-(3-Chloro-2-thienylcarbonyloxy)hexahydro-2,6-methano-2H-qulnolizin-3(4H)-one endo-Hexahydro-8-(5-methyl-2-thienylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one endo-Hexahydro-8-(1-methyl-lH-pyrrol-2-ylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one endo-8-(3-Chloro-4-nitrobenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one endo-8-(3-Chloro-4-dimethylaminobenzoyloxy)hexahydro-2,6-: 10 methano-2H-quinolizin-3(4H)-one endo-8-(3,5-Dichlorobenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one endo-8-(3,5-Dimethoxybenzoyloxy)hexahydro-2,6-methano-2H-` quinolizin-3~4H)-one endo-8-(2,5-Dimethylbenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one EXAMPLE X
Oxalyl chloride (0.76 ml) was slowly added to a stirred solutlon o~ 1 g of 5-methyllndole in 20 ml of anhydrous ether at 0C. The precipitate which formed was filtered off and dried at 80C to give 5-methyl-3-indolylglyoxylyl chloride.
C-35,466 292n~3 A stlrred solution of 205 mg of anhydrous sllver tetra-fluoroborate in 10 ml of anhydrous nitroethane waQ treated with a solution of 282.5 mg of endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one tetrafluoroborate (obtained by treating the 5 free amine with an equivalent of hydrofluoroboric acld) in 10 ml of anhydrous nitroethane at room temperature. A solution of 233 m~ of 5-methyl-3-indolylglyoxylyl chloride in 10 ml of anhydrous nitroethane was slowly added and the mlxture stirred at room temperature overnight. Triethylamine (101 mg) was added, the 10 solution filtered and the nitroethane evaporated. A solution of the residue in 15 ml o~ water was treated with a saturated aqueous solution o~ potassium carbonate and the liberated oil separated by extraction with ethyl acetate. The ethyl acetate solution was washed several times with water before being dried 15 over magnesium sulfate and evaporated. The residue was treated with methylene chloride and ethereal hydrogen chloride, and the solid filtered of~ and recrystallized ~rom 2-propanol to give endo-hexa~ydro-8-(5-methyl-3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one hydrochloride.
When the above procedure was repeated using the appropriate substituted indole in place of the 5-methylindole, the ~ollowing compounds were obtained:
endo-Hexahydro-8-(5-chloro-3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one hydrochloride melting at about 317-320C
- 25 (with decomposition) a~ter recrystallization from ethanol.
C-35,466 ,::
. ~ . - ..
,, . ~ ,. ,. '' .
t ~923.
endo-Hexahydro-8-(5-cyano-3-lndolylcarbonyloxy)-2,6-methano-2H-qulnolizin-3(4H)-one hydrochlorlde meltlng at about 304-305C
(with decomposition) after recrystallization from ethanol.
endo-Hexahydro-8-(5-methoxy-3-indolylcarbonyloxy)-2,6-methano-5 2H-quinolizin-3(4H)-one hydrochloride melting at about 303C
(with decomposition) after recrystallization from isopropanol.
Also obtained in the same way are endo-Hexahydro-8-(5-carbamoyl-3-lndolylcarbonyloxy)-2,6-methano-2H-quinollzin-3(4H)-one and endo-Hexahydro-8-(5-hydroxy-3-indolylcarbonyloxy)-10 2,6-methano-2H-quinolizin-3(4H)-one. In the latter case, the startlng material is 5-benzyloxyindole and the initial product is debenzylated b~ reductlon using standard procedures.
Dlmethylamine (40% solution in water, 0.68 g) and formal-dehyde (30X solution in water, 0.4g g) were successlvely added to a solutlon o~ 1.25 g o~ endo-8-(3,5-dlmethylbenzoyloxy)hexa-- ` hydro-2,6-methano-2H-qulnollzln-3(4H)-one ln a mixture of 4 ml of 20 ethanol and 2 ml of water. The stlrred mlxture was heated at 70-75C for 16 hours and concentrated. Toluene (50 ml) was added and the mlxture evaporated at 110C.
A solution of the residue [which contained endo-8-~3,5-25 dlmethylbenzoyloxy)hexahydro-4-methylene-2,6-methano-2H-quinolizin -3(4H)-one] in 30 ml of ethanol was hydrogenated at room C-35,466 1 3292n-~
temperature and atmospheric pre~ure in the presence of 0.2 g of platinum oxlde (Adams catalyQt). One equivalent of hydrogen was absorbed in one hour. The cataly~t waQ filtered off, the ethanol evaporated and the residue treated wlth one equlvalent of 5 hydrofluoroboric acld in water. Evaporation o~ the aqueous solution gave a crystalline residue which was recrystallized from et~anol to give endo-8-(3,5-dimethylbenzoyloxy)hexahydro-4-met~yl-2,6-methano-2H-quinolizin-3(4H)-one tetrafluoroborate meltlng at about 270-275C.
E~AMPLE XII
A solution Or endo-8-t3-indolylcarbonyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one (1.42 g) in ethanol (5 ml) was 15 treated with fluoboric acid ~0.64 g, 60X aqueous solutlon) and the mi~ture evaporated to glve endo-8-(~-indolylcarbonyloxy)-hexahydro-2,6-methano-2H-quinolizin-3t4H)-one tetrai~luoroborate (1.8 g).
A stlrred suspenslon Or the above salt (1.8 g) in anhydrous 20 nltroethane (30 ml) was treated with propane-1,3-dithlol (3 ml) and boron tri~luoride etherate (3 drops) and the mixture stirred overnight at room temperature. The nitroethane was removed by evaporation and the residue trlturated with ether. The solid product was filtered oi~f, washed several times wlth ether, treat-25 ed wlth water ~25 ml), saturated aqueous potassium carbonate C-35,466 ~32 ~
(3 ml) and ether (50 ml). The ether solution was separated off, dried (MgS04) and evaporated to give the propane dithioketal derivative, m.p. 226-2290C (1.6 g).
Hydrazine hydrate (3 ml) was added dropwise during one hour 5 to a stirred refluxing solution of the above dithioketal tO.5 g) in isopropanol (20 ml) in the presence of Raney nickel (6 g, previously washed three times with isopropanol). The reflux was maintained for a further 30 minutes, the hot solution filtered through a triple superphosphate, the nickel washed several times 10 with hot isopropanol and the combined filtrates evaporated to give endo-8-(3-indolylcarbonyloxy)-2,6-methanooctahydro-2H-quinolizine as the free base (50 mg). Addition of methylene chloride and ethereal hydrogen chloride gave the hydrochloride (30 mg), m.p. 311-313C (from ethanol).
EXA~PLE XIII
. ~
The procedure o~ Example XII was repeated uslng endo-hexahydro-8-hydroxy-2,6-methano-2H-quinollzin-3(4H)-one in place 20 of the ester. The dithioketal obtained was reduced as described ln the final paragraph except that the hydrazine hydrate was left out. Th~s gave exo-octahydro-2,6-methano-2H-quinolizin-8-ol which was then reacted with 3,5-dimethylbenzoyl chloride to give exo-8-(3,5-dimethylbenzoyloxy)octahydro-2,6-methano-2H-quinolizine 25 which was converted to the hydrochloride, m.p. 255-256C by standard procedures.
C-35,466 '` ,.' ., ., ' - ~: ` . .
ESTE~S OF HEXAHYDRO-8-HXDROXY-2,6-~THUNO-2H-QVINO7IZIN-3(4H)-ONE ~ND RELATED COMPOUNDS
:;
`` The present invention is directed to esters of hexahydro- 8-hydroxy-2,6-methano-2H-quinolizln-3(4H)-one and he~ahydro-8-10 hydroxy-2,6-methano-2H-quinollzlnes with certaln aroma~lc and hoterocyclic carboxylic aclds. The lnventlon 1~ also dlrected to novel polycyclic alcohols whiCh serve a~ lntermediates ln the preparation of the esters o~ thls invention and also to a novel process ror preparlng a group o~ esters of the present lnventlon.
Nore particularly, the present lnvention ls directed to compounds of the formula B
~ N ~ 1l ~ O-C-Rl wherein A is ~H2, =0, =(H)(OH), =(OH)2 or =N-OH; B is =H2, (H)(CH3), (H)(CH2NR3R4) or CH2 whereln R3 and R4 are C2 4 25 alkyl or are comblned t~ give tetramethylene, pontamethylene or -CH2CH2-0-CH2cH2-; Rl .
C-35,466 ~
'., 1 ;~292~3 ~ ~7 ~3 [~N-Rg or I~L
wherein Z is NRg, 0 or S; R5, R6 and R8 are each hydrogen, halogen, C1 3 alkyl or C1 3 alkoxy; R7 is hydrogen, amino, (Cl 4 alkyl)am~no, (C1 4 alkyl)2amino, alkoxy or nitro; Rg is hydrogen, 10 C~ 4 alkyl or phenyl (Cl 2 alkyl); Rlo is hydrogen, halogen, Cl 4 alkyl, C1 4 alkoxy, hydroxy, cyano or -CONH2; R11 i9 hydrogen, halogen, Cl 4 alkyl or phenyl; the wavy line lndicates that the con~iguration of the oxygen substituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and 15 quaternary ammonium salts of the aforessid compounds.
Examples of the C1 4 alkyl groups re~erred to above are methyl, ethyl, propyl, isopropyl and butyl. Examples o~ the C1 4 alkoxy groups are methoxy, ethoxy, propoxy and butoxy. The halogens re~erred to above can be fluorine, chlorlne or bromine.
20 When the wavy llne in the general structural formula is changed to a solid llne, this indicates that the con~iguration of the compounds is endo. Such endo-compounds can also be re~erred to as trans. Similarly, exo-compounds can also be referred to as cis.
Any hydrates of the present compounds are considered as 25 equivalent to the compounds themselves and this would include compounds in which the carbonyl (i.e., A is 0) exists as (OH)2.
C-35,466 1 3~9 ?~J3 A preferred group of compounds are tho~e whereln the ester is attached to the polycyclic rlng in the endo-conflguration. A
further preferred group are tho~e having the endo-configuratlon wherein A is =0 and =(OH)2. In a still further preferred group, B
5 is additionally =H2.
The pharmaceutically acceptable acid addition salts referred to above can be non-toxlc salts with suitable acids such as those with inorganic acids, for example hydrochloric, hydrobrom~c, nitric, sulfuric or phosphoric acids; or with organic acids such 10 as organic carboxylic acids, ~or example, acetic, propionic, glycolic, maleic, hydroxymaleic, malic, tartarlc, citrlc, sal~cycllc, 2-acetyloxybenzoic, nicotinic or i30nicotinic; or organic sulronic acids, ror example methanequlfonic, ethane-sulfonic, 2-hydroxyethanesul~onic, 4-toluenesulfonic or 15 2-naphthalensul~onic. Quaternary ammonium salts are formed with alkyl halldes such as methyl chlorlde, methyl bromide or ethyl bromide; or with sulfate esters such as methyl 4-toluenesulfonate or methyl 2-naphthalenesulfonate.
Some specific examples of compounds encompassed by the 20 present lnvention are the following:
endo-8-(3,5-Dimethylbenzoyloxy)hexahydro-2,6-methano-2H-qulnollzin-3(4H)-one exo-8-(3,5-Dimethylbenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one 5 endo-8-(3,5-Dichlorobenzoyloxy)hexahydro-2,6-methano-2H-qulnollzin-3(4H)-o,ne C-35,466 endo-8-(3,5-Dimethoxybenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one endo-8-(4-Aminobenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one 5 endo-8-(4-Dimethylaminobenzoyloxy)hexahydro-2,6-methano-2H-quinollzin-3(4H)-one endo-8-(3,5-Dimethylbenzoyloxy)octahydro-2,6-methano-2H-quinolizine endo-8-t3-Indolylcarbonyloxy)octahydro-2,6-methano-2H-quinolizine 10 endo-8-(~-Cyano-3-indolylcarbonyloxy)hexahydro-2,6-methano-2H-- quinollzin-3(4H)-one endo-8-(3,5-Dichlorobenzoyloxy)hexahydro-2,6-methano-4-methyl-2H-quinolizin-3(4H)-one endo-8-(3-Indolylcarbonyloxy)hexahydro-4-(diethylaminomethyl)-2,6-methano-2H-quinolizin-3(4H)-one endo-8-(3-Indolylcarbonyloxy)-3-hydroxyimino-2,6-methanooctahydro-2H-quinollzine endo-8-(2-Methyl-l-isoindolylcarbonyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one 0 endo-8-(2-Pyrrolidinylcarbonyloxy)hexahydro-2,6-methano-2H-quinollzin-3(4H)-one endo-8-(3-Indolylcarbonyloxy)-2,6-methanooctahydro-2H-quinolizin-3-ol The compounds o~ the present lnvention can be prepared by 25 reacting an alcohol or a reactlve derivative thereof, said alcohol having the formula C-35,466 ~, -..... .. . . .
1 3292a3 A' OH
~ 5 wherein A' is =0 or =H2, wlth a reactive equivalent of an acld of ;~ the formula RlCOOH
10 wherein Rl is defined as above. By a reactive equivalent of the acid is meant the corresponding acid chloride or bromide or the corresponding glyoxylyl chloride or bromide or the carboxyllc acid lmidazole obtained by the reaction of the appropriate acid halide with N,N-carbonyldiimidazole; or any similar acid 15 derivative which would yield the simple carboxylic acid ester on reaction with an alcohol or with a reactive derivative of an alcohol. More specifically, where the -OH in the alcohol is equatorial texo), then it can be reacted with the appropriate carboxylic acid imidazole obtained by the reaction of the acid 20 halide with N,N-carbonyldiimidazole. Alternatively, the acid can ~. be converted to the acid chloride by standard procedures (e.g., thionyl chloride) and then reacted with the alcohol or an alkali metal salt of the alcohol such as the lithium salt obtained by the reaction of lithium hydride with the alcohol in tetrahydro-25 furan.
_ 5 _ C-35,466 .
1 3292a3 When the -OH group in the starting alcohol is axial (endo), it can also be converted to the corresponding ester by reaction wlth the appropriate acid chloride or bromlde wlth the reaction being carried out in the presence o~ an equivalent of a suitable 5 tertiary base such as 4-dimethylamlnopyridine in a high boiling lnert solvent such as xylene. In this case, however, long heating (24-84 hours) at a temperature at or above 140C is necessary so that the procedure would not ~e suitable for use with acid halldes that are not stable under the indlcated conditions. Thus, 10 it was necessary to use an alternative for the preparation of such compounds. In this procedure, an appropriate acid chloride or bromide or a glyoxylyl chloride or bromide, in a nitroparaffin solvent, is reacted with a solution of a super acld salt of the alcohol and an equivalent amount of a heavy metal salt of the 15 same super acid. The glyoxylyl chloride can be used in the process as indicated because it decarbonylates readlly under the condltions used. The reactlon ltself can be carried out over a period of 1-24 hours at temperatures ranging from -80C to ambient temperatures tabout 23C). Examples of suitable super 20 ac~ds with M = H are MBF4, MAsF6, MSbF6, MPF6, MTaF6 or MNbF6 with examples of suitable heavy metals (M) being silver and thallium. Examples of nltroparaffln solvents are nitromethane, nitroethane, l-nitropropane and 2-nltropropane.
Actually, where the group Rl contains a primary or secondary 25 amino group, it is usually protected during the above reaction, with a benzyl group belng commonly used to protect a secondary C-35,466 l 329,~0j amine and a benzyloxycarbonyl group being used to protect a primary amine. In either case, the protecting group in the product is removed by conventional procedures, for example by hydrogenation with hydrogen and a palladium catalyst.
s Various procedures can be used to convert those compounds wherein A is =0 and whose preparation is described below, to other different bridged derivatives o~ the present invention by standard methods. Thus, the ketone group in the polycyclic system can be reduced to the corresponding alcohol using an alkali metal 10 (sodium or potassium) borohydride in a lower alkanol such as methanol or ethanol.
- The ketone group can also be reduced completely to a methylene group by a two step procedure. In the first step, the ketone ls reacted with ethylene dithiol or trimethylene dithiol 15 in the presence of a strong acid such as hydrochloric acid or BF3 to give the corresponding dithioketal. The reaction is carried out in a suitable polar solvent such as nitromethane or acetic acid. ~he dithioketal is then reduced with hydrazine in the presence of Raney nickel in a lower alkanol solvent such as 20 2-propanol at elevated temperatures (60-100C). Actually this same procedure can be used to reduce the original starting alcohol, hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one, to 8-hydroxy-2,6-methanooctahydro-2H-quinolizine which can itself be reacted with acid derivatives as described earlier to give the 25 corresponding esters.
C-35,466 , 32~2~
Compounds containing other B-groups (i.e, aminomethyl, methylene or methyl groups) can be obtained from products in which A is =0 and B is =H2 by a Mannich reaction using formal-dehyde and a secondary ~mine such as dlmethylamine, diethylamine, 5 piperidine or pyrrolidine. This reaction gives the corresponding aminomethyl compound and, when B is dimethylaminomethyl, the amino moiety is eliminated on heating at 90-110C in an inert solvent such as toluene to give the corresponding methylene compound (B is =CH2). This exocyclic methylene compound can be 10 isolated by standard methods and transformed into a methyl group by hydrogenatlon, for example, by using hydrogen and platinum oxide.
To obtain those compounds in which A is hydroxyimino (=N-OH), the ketone referred to above can be reacted with 15 hydroxylamine hydrochloride ~y standard procedures.
The alcohol used as a reactant in the above procedure can be obtained from known alkyl (C1 4) 3-cyclopentene-1-carboxylates by a multi-step procedure~ Speci~lcally, the double bond in the indicated cyclopentene is oxidized to a 1,2-diol using N-methyl-20 morpholine N-oxide in the presence of osmium tetroxide catalyst.
The diol is then cleaved to the corresponding dialdehyde using sodium metaperiodate. A Robinson-Schopf cyclization of the dialdehyde with a lower alkyl glyclne ester and acetone-dicarboxylic acid, preferably at pH4, gives a pseudopelletierine 25 derivative of the following type:
C-35,466 . ~ .
1 32'~2~3~?
N
EtOC
The ketone group is reduced to an alcohol using sodium boro-hydride and the product is reacted with dihydropyran to protect the -OH group as a tetrahydropyranyl ether, Dieckmann cycli~ation `~ Or the dlester using a strong base (e.g. potasslum t-butoxide) ~ollowed by aqueous acid hydrolysls and decarboxylation gives the ; desired alcohol. The resulting alcohols can exi~t in two conrormation~ - axlal and equatorial. The main product obtained `~ by the above procedure is the axlal alcohol and it can be separated fro~ the equatorial isomer by crystallization of the ~o camphorsulfonate or tetrafluoroborate salt.
.~ The present compounds are useful for the treatment of pain, especially migralne vascular and cluster headaches and trigeminal neuralgia. They are also useful in the treatment of nausea and vomiting arising from treatment with cancer chemotherapeutic - 25 agents.
In the past, acute attacks Or migraine have been treated i with a peripheral vasoconstrictor, such as ergotamine, which may be co-administered with cafreine, and dlhydroergotamine; an C-35,466 ~ 32920 '`
antipyretic analgesic, such as acetylsalicyllc acld or p-acetyl-aminophenol; and/or an anti-emetic such as cyclizlne, metoclo-pramide and thiethylperazine~ It has also been reported (J. B.
Hughes, Med. J. A~st~ 2, No. 17, sao, 1977) that lmmediate rellef 5 o~ an acute migraine attack can be obtained by slow intravenous injection of metoclopramide (10 mg).
It i~ believed that 5-hydroxytryptamlne (5-HT) is the naturally occurring substance most likely to play a role in the pathophysiology of migraine. Increased amounts of 5-HT and its 10 metabolite 5-hydroxyindoleacetic acid are excreted in the urine durlng most attacks. Further, plasma and platelet 5-HT concen-- trations fall rapidly at the onset of an attack and remain low while the headache persists. Moreover, attac~s of migraine have been clearly associated with periods of thrombocytopaenla in 15 certain patlents. It has been proposed that compounds whlch block the actlvity of 5-HT would be of use in the symptomatic treatment of miBraine (J. R. Fozard, International Headache Congress 1980, reported in Advances in Neurology, Vol. 33, Raven Press~ New York, 1982).
The known migraine prophylactic drugs, methysergide, propranolol, amitriptyline, and chlorpromazine have widely different pharmacological activities but all are 5-HT D-receptor antagonists at the doses used cllnlcally for the prophylaxis of migralne. Metoclopramide is a potent 5-HT M-receptor antagonist 25 and it has been proposed (J. R. Fozard supra) that a blockade of the M-receptor present on afferent sensory neurones affords C-35,466 ~ 3~qL)~3 symptomatic rellef in an acute migraine attack.
The potency as 5-HT M-receptor antagonists of (-) cocaine and some related compounds, lncludlng pseudotropyl benzoate (l.e.
benzoylpseudotropine) and 3,5-dichlorobenzoyltropine has been 5 reported (J. R. Fozard e' al., Eur. J. Pharmacol., 59, 1979, 195-210; J.R. Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol., 326, 1984, 36-44). The PA2 values reported for metoclopramlde, pseudotropyl benzoate, nor(-~ cocaine and benzoyltropine are 7.2, 7.0, 7.7 and 7.2 respectively whilst the PA2 value determined for 10 3,5-dichlorobenzoyltroplne by the same procedure is 9.3 ~J. R.
Fozard et al~, Eur~ J. Pharmacol~, 49, 1978, 109-112; J.R.
Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol., 326, 1984, 36-44). In a double-bllnd clinlcal trial, 3,5-dichlorobenzoyl-tropine proved an effective treatment ~or the acute migraine 15 attack (C. Loisy et al., Cephalalgia, 5, 1985, 79-82). A further series of tropine esters, wlth PA2 values for blockade of the 5-HT M-receptors between 7.7 and 13.6 have been descrlbed by Rlchardson et al., Nature, 316, 1985, 26-131.
The compounds of the present lnvention block the M-receptors 20 for 5-hydroxytryptamlne (5-HT) on afferent sensory neurones, certain o~ which subserve the transmisslon of paln. As explalned above, the blocklng or such M-receptors appears to be a mechanism whereby the symptoms of mlgraine can be relleved. Accordingly, the present compounds are use~ul ln the treatment of migraine 25 when administered in amounts sufficient to effectively block the sald M-receptors.
C-35,466 1 32920 ~
In addltion, compounds blocking 5-HT M-receptors, includlng metoclopramide, 3,5-dichlorobenzoyltropine and (3a-tropanyl)-lH-indole-3-carboxyllc acid ester, are hlghly erfective in preventing the nausea and vomiting induced by cancer chemothera-5 peutic agents in an animal experlmental model (W.D. Miner et al.,Brit. J. Pharmacol., 88, 1986, 374P; W.D. Mlner and G.J. Sanger, Brit. J. Pharmacol., 88, 1986, 497-499, ~. Costall et al., Neuropharmacology, 25, 1986, 959-961). It is believed that cytotoxic drug-induced vomiting involves a 5-HT M-receptor 10 mechanism (W.D. Miner and G.J. Sanger, Brit. J. Pharmacol., 88, 1986, 497-499). Accordingly, the present compounds are useful ln the treatment o~ cytotoxic drug-induced vomiting when adminls-tered in amounts su~ficient to e~ectively block the said M-receptors.
lS The activity Or the compounds against 5-HT can be assessed by determining their PA2 values in the isolated rabbit heart as described by J.R. Fozard et al., Eur. J. Pharmacol., 59, 195-210 (1979). In the method descrlbed, the molar concentration of antagonist which reduces the efrects o~ twice the ED50 of 5-HT to 20 that Or the ED50 in the absence of antagonist is determined. The PA2 value is the negative logarithm of said molar concentrations.
In general terms, the higher the PA2 value the more potent is the compound. When tested in thls way, the present compounds show pA2's generally in the range of about 8 to 10.
The actlvity of these compounds against 5-HT can be assessed in vivo by measurement Or the effect o~ the compound on the Von C-35, 466 ~ 32920~
Bezold-Jarisch Reflex induced by 5-HT ln~ected intravenously into the rat (see Paintal A.S., Physlol. Rev. 53, 159-227, 1973; J.R.
Fozard, Naunyn-Schmiedeberg's Arch. Pharmacol., 326, 1984, 36-44). The transient cardiac slowing arises from an increased 5 afferent vagus activity arising from stimulation by 5-HT of sensory afferent fibres in and around the heart. When tested against the Von Bezold-Jarlsch Reflex induced by 5-HT, compounds endo-8-(3,5-dimethylbenzoyloxy)hexahydro-2,6-methano-2H-~u~nolizln-3(4H)-one hydrochloride and endo-hexahydro-8-10 (3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one hydrochloride suppressed the response dose-dependently at doses of 0.01-0.1 mg~kg given intravenously or 0.25-1 mg/kg given orally.
The present compounds appear to be highly selective in their 15 action against 5-HT M-receptor. Thelr potency against other 5-HT
` receptors and other spasmogens, in particular carbachol, phenylephrine, histamlne and calcium, ls Xnown to be at least three orders lower ~han that against 5-HT M-receptors.
Accordingly, their use in the treatment o~ migraine or cytotoxic 20 drug-induced vomltlng should be without any side e~fects.
The present compounds can be administered in various manners to achleve the desired e~fect. The compounds can be administered alone or in the ~orm oi~ pharmaceutical preparations to the patlent belng treated elther orally or parenterally, for example, 25 subcutaneously or lntravenously. They can also be administered by inhalation or by suppository. The amount of compound administered C-35,466 1 ~'320 ~
will vary and can be any effective mlgraine-relieving amount or mount effective in cytotoxlc drug vomiting. Depending upon the patient and the mode of administration, the quantity of compound administered may vary over a wide range to provide from about 5 o.Ol mg/kg to about 10 ~.g/kg, usually 0.03 to 3.0 mg~kg, of body ` weight of the patient per dose. Unit doses o~ these compounds can contain, for example, from a~out 0.5 mg to 100 mg, usually 1 to 50 mg and pre~erably 3 to 30 m8, of the compound and may be administered, for example, from 1 to 4 times daily.
The term "unit dosage *orm" is used herein to mean a single or multlple dose form containing a quantity of the active ingredlent in admixture with or otherwise in assoclation with the diluent or carrier, said quantity being such that one or more predeterm~ned units are normally required ~or a single thera-. 15 peutic administration. In the case o~ multiple dose forms such as liquids or scored tablets, said predetermined unit will be one fraction, such as a 5 ml (teaspoon) quantity of a liquid or a half or quarter of a scored tablet, of the multiple dose form.
Specific formulations o~ the present invention are prepared - 20 in a manner well known per se in the pharmaceutical art and usually comprise at least one active compound of the invention in admixture or otherwise ln association with a pharmaceutically acceptable carrier or diluent therefor. For making those formulations the active ingredient will usually be mixed with a 25 carrier, or diluted by a diluent, or enclosed or encapsulated in a capsule, sachet, cachet, paper or other container. A carrier or C-35,466 .
1 32~
diluent may be solid, semi-solid or liquid material which serves as a vehicle, excipient or medium for the active ingredient.
Suitable carriers or diluents are well known per se. See Remington's Pharmaceutical Sclences, Mack Publishing Company, 5 Easton, Pennsylvanla, for a descriptlon of the preparation of such ~ormulat~ons.
The formulations o~ the invention may be adapted for enteral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppos~tories, solutlons, suspensions 10 or the like.
The compounds of the present inventlon can be used in migraine therapy in combination with other antimigra~ne drugs having dl~ferent modes o~ actlon, Such drugs include those used prophylactically, such as barbiturates, diazepam, chlorpromazine, 15 amitriptyline, propanolol, methyserglde, Pizotl~en, cypro-heptadine, dihydroergotamine, and clonidine, and those used in the acute attack, such as vasoconstrictor agents, e.g~, ergotamine and dihydroergotamine, analgesic/anti-inflammatory agents, e.g., aspirln, paracetamol and lndomethacln, or 20 anti-nauseants, e.g., cycllzlne, metoclopramide, and thiethyl-perazine (see Fozard, J.R., J. Pharm. Pharmacol., 27, 297-321 (1975); Saper, J.R., J. Amer. Med. Assoc. 239, 480-484 (1978);
Fozard,J.R., supra). As an example, compounds o~ the present lnvention would be bene~lclal ln comblnatlon wlth aspirin 25 300-1200 mg or methyserglde 2-6 mg given daily.
C-35,466 1 329~0:~
The following examples are presented to lllustrate the present invention but they should not be construed as limlting it in any way~
EXAMPLE I
- To a stirred solution of 160 g of diethyl malonate in 1.5 l o~ dry dimethyl~ormamide at 0C under nltrogen was slowly added ` 10 30 g o~ lithium hydride~ A~ter the evolution of hydrogen ceased (2 hours~ 143 g Or cis-1,4-dlchloro-2-butene was slowly added and t~e mixture allowed to come to room temperature~ After 72 hours, the mixture was diluted with a mixture of ether and hexane (1:4) and poured into water~ ~he organic layer was washed with water 15 and brine before drying over magneslum sul~ate. Dlstillation gave diethyl 3-cyclopentene-l,l-dlcarboxylate, bp 70-80C/0.1 mm, containing a small amount (-10X) of diethyl 2-vinylcyclopropane-~ l,l-dicarboxylate.
The impure cyclopentene dlester (148.5 g) obtained above was 20 added to a solutlon of 118 g Or potassium hydroxide in 1333 ml of 80X ethanol and the stirred solution warmed at 60-70C overnight.
The ethanol was evaporated and the residue treated with an ice cold solution of concentrated sulphuric acid (107 ml) in water (274 ml)~ Extractlon of the acid mixture with ether (3 x 400 ml) 25 followed by evaporation of the dried ether extracts gave a residue of the diacid which was decarboxylated to the monoacid by C-35,466 heating in an oil bath at 170-180C for 1 hour. The residual oil was distilled to give crude 3-cyclopentene-1-carboxylic acid, bp 68-73C (1 mm) contalning some y-vlnyl-y-butyrolactone. A
solution of 98 g o~ potassium carbonate in 300 ml of water was 5 added and the mixture extracted with ether to remove the ~-vinyl-~-butyrolactone. Acidification of the aqueous solution - and extraction with ether afforded pure 3-cyclopentene-1-~: carboxylic acid.
.:
EXAMPLE II
`i A mixture of 52 g o~ 3-cyclopentene-l-carboxyllc acid and excess thionyl chloride was stirred at room temperature ~or 15 1 hour, The excess thionyl chloride evaporated and the residue distilled to give 3-cyclopentene-1-carbonyl chloride, bp 52-58C.
The acid chloride obtained above was slowly added to an ice cooled stirred solution of 32 g of pyridine in 150 ml of ethanol.
T~e mixture was stirred for a further hour, the ethanol evaporat-20 ed and the residue treated with water and ether. The ether layerwas separated, washed several times with water and dried. Evapo-ration of the ether left a residue of ethyl 3-cyclopentene-1-carboxylate, bp 62.5-66C/14 mm.
- 17 _ C-35,466 . . .
EXAMPLE III
A solution containing 84.6 g of N-methylmorphollne N-oxide, ~`1 g of osmium tetroxide, 230 ml of water and 115 ml of acetone ~5 was allowed to stir for 30 minutes at room temperature. To this `~.stirred mixture was added very slowly over at least 8 hours, a solution o~ 80 g o~ ethyl 3-cyclopentene-1-carboxylate in 115 ml of acetone. The stirred mixture was heated at 50C for 2 hours to complete the reaction (verified by TLC examinatlon using ethyl 10 acetate/hexane 70/~0). Sodium bisulfite (~10 g) was added, the stirring continued for a further 15 minutes, and the mixture filtered through Celite. The pH of the filtrate was adJusted to 7 by the addltion of 12 N sulfuric acid (37 ml), the acetone evapo-rated, the pH of the residual solution ad~usted to 2 with 12 N
15 sulfuric acid (13 ml) and the solutlon extracted with ethyl acetate (4 x 250 ml). Evaporation of the dried ethyl acetate solutlon gave 4-ethoxycarbonyl-1,2-cyclopentanediol.
EXAMPLE IV
A solution of 85.4 g of sodium perlodate in 500 ml of water was slowly added to a s~irred solution of 69 g of 4-ethoxy-carbonyl-1,2-cyclopentanedlol ln 690 ml of tetrahydrofuran. The 25 reactlon was exothermlc and cooling was necessary. After two hours a precipitate of sodium iodate was filtered off and the C-35,466 1 3292~
solution concentrated at room temperature to remove most of the tetrahydrofuran. The resulting aqueous solution contained the desired ~-ethoxycarbonylglutaraldehyde and was used directly in t~e next reaction.
; 5 To a stirred suspension of 400 g of potassium hydrogen phthalate in 800 ml of water was added, in sequence, a solutlon ; of 80 g of acetonedicarboxylic acid in 1200 ml of water, a solution of 80 g of glycine ethyl ester hydrochloride in 400 ml of water, and finally the solution of ~-ethoxycarbonylglutaral-10 dehyde obtained above. The mixture was stlrred for 20 hours at room temperature durlng which time carbon dioxlde evolved. The mixture was basified by the addition o~ an excess of aqueous potassium carbonate and extracted with ethyl acetate several times, Evaporation of the dried ethyl acetate extracts gave a 15 syrup consisting mainly of 7-ethoxycarbonyl-9-~ethoxycarbonyl-methyl)-9-azabicyclo-r3.3.1~nonan-3-one.
EXAMPLE V
` Sodium borohydride (17 g) was added in small portions to a stirred solution of 87.6 g of 7-ethoxycarbonyl-9-(ethoxycarbonyl-methyl)-9-azabicyclo~3.3.1]nonan-3-one in 750 ml of ethanol. The mixture was stirred overnight at room temperature, the ethanol 25 evaporated and the residue treated with 200 ml of water. Hydro-chloric acid (2 M) was added until the mixture was acid and this ~ C-35,466 ~ 329,~ n3 acid solution was immediately basifled by the addition of saturated potassium carbonate solution. Extractlon with ethyl acetate and evaporation of the drled extract gave a syrup which consisted mainly of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-5 9-azabicyclo~3.3~13nonan-3-ol, The syrup can be purified by ~ column chromatography using silica and elution with hexane-ethyl -~ acetate ~30:70).
EXANPLE VI
A solutlon of 26~1 g o~ the crude 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonan-3-ol in 250 ml of methylene chloride was treated with one equivalent of methane-15 sulfonic acid (8.42 g). The methylene chloride solution wasconcentrated to about 35 ml, 9.S ml o~ dihydropyran was added together wit~ one drop o~ methanesul~onlc acid, and the mixture stirred ror 3 hours at room temperature. The mlxture was then poured into saturated potassium carbonate solution and the 20 product separated by extraction with ethyl acetate.
Evaporation o~ the dried ethyl acetate extracts gave a syrup consisting mainly of the tetrahydropyranyl ether of 7-ethoxy-carbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo~3.3.1]nonan-3-ol.
It can be purified by column chromatography using silica and 25 elution with hexane-ethyl acetate (20:80), Rf 0.7.
C-35,466 ,, 1 329~ 3 ) EXAMPLE VII
A solution of 34 g of the tetrahydropyranyl ether of 7-ethoxycarbonyl-9-(ethoxycarbonylmethyl)-9-azabicyclo¦3.3.1¦-5 nonan-3-ol in 800 ml of anhydrous toluene was treated with 19 g of potassium tert-butoxide and the stirred mixture heated at 100C for 2 hours. Anhydrous formic acid (7~85 g) was added to the cooled mixture, the potassium formate was ~iltered off, and the toluene solution evaporated to glve a syrup~ The syrup was 10 treated with 300 ml o~ 5 N hydrochloric acid and the stirred solution refluxed overnight. The cooled mixture was clarified by sn extraction with methylene chloride and the aqueous acid solution evaporated to dryness. The residue was dissolved in a little water and the solution treated with a large excess of 15 saturated potassium carbonate solution. Extraction of the resulting mixture with ethyl acetate and evaporatlon of the dried ethyl acetate solution gave endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H~-one as an oil which crystallized on standing. The base was converted to its camphorsulfonate salt, 20 m.p. 178C, using one equivalent of camphorsulfonic acid in ethanol.
C-35,466 .
1 32'~, ~3 ~
EXAMPLE VIII
.
A mixture of 1.8 g of endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H~-one, hydrofluoroboric acld (0.88 g; 60%
5 aqueous solution) and 20 ml of ethanol was evaporated, the residue was treated with sa ml of anhydrous toluene, and the mixture again evaporated. A stirred suspension of the anhydrous residue in 50 ml of anhydrous nitroethane at -78C was treated with 1.94 g of anhydrous silver tetrafluoroborate and a solution 10 of 1.7 g of 3,5-dimethylbenzoyl chloride ln 20 ml of anhydrous nitroethane was added slowly. The temperature of the stirred reaction was kept at -78C for 1.5 hours and then allowed to return to room temperature overnight. Triethylamlne (1 g) was added, the solution filtered and the nitroethane evaporated. A
15 solution of the residue in 20 ml of water was treated wlth an excess of a saturated aqueous solution of potasslum carbonate and the liberated oil separated by extraction with ethyl acetate. The ethyl acetate solution was washed several times with water before being dried over magneslum sulfate and evaporated~ The residue 20 obtained was endo-8-(3,5-dimethylbenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one and this was treated with methylene chloride and ethereal hydrogen chloride to give crystals of the hydrochloride salt melting at about 291C.
C-35,466 ~. ~
~ 3~92n.~., EXAMPLE IX
When the procedure of Example VIII is repeated uslng endo-hexahydro-8-hydroxy-2,6-methano-2H-qulnollzin-3(4H)-one and the 5 appropriate acid chlorlde, the corresponding e~ter~ listed below are obtalned. As necessary, the acid chlorides were obtained from the appropriate carboxylic acids by standard procedures, for example, usig thionyl chloride. To convert the ester to a corresponding acid salt, it was reacted with the appropriate acid lO with alternative solvents be~ng used as des~red.
endo-Hexahydro-8-(3-indolylcarbonyloxy)-2,6-methano-2H-quinollzin-3(4H)-one methanesulfonate melting at a~out 278C.
endo-8-(3-Benzofurancarbonyloxy)hexahydro-2,6-methano-2H-15 qulnollzln-3(4H)-one endo-8-~3-Benzo[b]thiophenecarbonyloxy)hexahydro-2,6-methano-2H-quinolizin-3t4H)-one endo-8-(1-Benzyl-lH-indol-3-ylcarbonyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one endo-Hexahydro-8-(1-methyl-lH-indol-3ylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one endo 8-(4-Bromo-2-furylcarbonyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one ~ endo-Hexahydro-8-(5-phenyl-2-furylcarbonyloxy)-2,6-methano--` 25 2H-qulnollzln-3(4H)-one C-35,466 1 3292a ~
, endo-8-(3-Chloro-2-thienylcarbonyloxy)hexahydro-2,6-methano-2H-qulnolizin-3(4H)-one endo-Hexahydro-8-(5-methyl-2-thienylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one endo-Hexahydro-8-(1-methyl-lH-pyrrol-2-ylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one endo-8-(3-Chloro-4-nitrobenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one endo-8-(3-Chloro-4-dimethylaminobenzoyloxy)hexahydro-2,6-: 10 methano-2H-quinolizin-3(4H)-one endo-8-(3,5-Dichlorobenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one endo-8-(3,5-Dimethoxybenzoyloxy)hexahydro-2,6-methano-2H-` quinolizin-3~4H)-one endo-8-(2,5-Dimethylbenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one EXAMPLE X
Oxalyl chloride (0.76 ml) was slowly added to a stirred solutlon o~ 1 g of 5-methyllndole in 20 ml of anhydrous ether at 0C. The precipitate which formed was filtered off and dried at 80C to give 5-methyl-3-indolylglyoxylyl chloride.
C-35,466 292n~3 A stlrred solution of 205 mg of anhydrous sllver tetra-fluoroborate in 10 ml of anhydrous nitroethane waQ treated with a solution of 282.5 mg of endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one tetrafluoroborate (obtained by treating the 5 free amine with an equivalent of hydrofluoroboric acld) in 10 ml of anhydrous nitroethane at room temperature. A solution of 233 m~ of 5-methyl-3-indolylglyoxylyl chloride in 10 ml of anhydrous nitroethane was slowly added and the mlxture stirred at room temperature overnight. Triethylamine (101 mg) was added, the 10 solution filtered and the nitroethane evaporated. A solution of the residue in 15 ml o~ water was treated with a saturated aqueous solution o~ potassium carbonate and the liberated oil separated by extraction with ethyl acetate. The ethyl acetate solution was washed several times with water before being dried 15 over magnesium sulfate and evaporated. The residue was treated with methylene chloride and ethereal hydrogen chloride, and the solid filtered of~ and recrystallized ~rom 2-propanol to give endo-hexa~ydro-8-(5-methyl-3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one hydrochloride.
When the above procedure was repeated using the appropriate substituted indole in place of the 5-methylindole, the ~ollowing compounds were obtained:
endo-Hexahydro-8-(5-chloro-3-indolylcarbonyloxy)-2,6-methano-2H-quinolizin-3(4H)-one hydrochloride melting at about 317-320C
- 25 (with decomposition) a~ter recrystallization from ethanol.
C-35,466 ,::
. ~ . - ..
,, . ~ ,. ,. '' .
t ~923.
endo-Hexahydro-8-(5-cyano-3-lndolylcarbonyloxy)-2,6-methano-2H-qulnolizin-3(4H)-one hydrochlorlde meltlng at about 304-305C
(with decomposition) after recrystallization from ethanol.
endo-Hexahydro-8-(5-methoxy-3-indolylcarbonyloxy)-2,6-methano-5 2H-quinolizin-3(4H)-one hydrochloride melting at about 303C
(with decomposition) after recrystallization from isopropanol.
Also obtained in the same way are endo-Hexahydro-8-(5-carbamoyl-3-lndolylcarbonyloxy)-2,6-methano-2H-quinollzin-3(4H)-one and endo-Hexahydro-8-(5-hydroxy-3-indolylcarbonyloxy)-10 2,6-methano-2H-quinolizin-3(4H)-one. In the latter case, the startlng material is 5-benzyloxyindole and the initial product is debenzylated b~ reductlon using standard procedures.
Dlmethylamine (40% solution in water, 0.68 g) and formal-dehyde (30X solution in water, 0.4g g) were successlvely added to a solutlon o~ 1.25 g o~ endo-8-(3,5-dlmethylbenzoyloxy)hexa-- ` hydro-2,6-methano-2H-qulnollzln-3(4H)-one ln a mixture of 4 ml of 20 ethanol and 2 ml of water. The stlrred mlxture was heated at 70-75C for 16 hours and concentrated. Toluene (50 ml) was added and the mlxture evaporated at 110C.
A solution of the residue [which contained endo-8-~3,5-25 dlmethylbenzoyloxy)hexahydro-4-methylene-2,6-methano-2H-quinolizin -3(4H)-one] in 30 ml of ethanol was hydrogenated at room C-35,466 1 3292n-~
temperature and atmospheric pre~ure in the presence of 0.2 g of platinum oxlde (Adams catalyQt). One equivalent of hydrogen was absorbed in one hour. The cataly~t waQ filtered off, the ethanol evaporated and the residue treated wlth one equlvalent of 5 hydrofluoroboric acld in water. Evaporation o~ the aqueous solution gave a crystalline residue which was recrystallized from et~anol to give endo-8-(3,5-dimethylbenzoyloxy)hexahydro-4-met~yl-2,6-methano-2H-quinolizin-3(4H)-one tetrafluoroborate meltlng at about 270-275C.
E~AMPLE XII
A solution Or endo-8-t3-indolylcarbonyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one (1.42 g) in ethanol (5 ml) was 15 treated with fluoboric acid ~0.64 g, 60X aqueous solutlon) and the mi~ture evaporated to glve endo-8-(~-indolylcarbonyloxy)-hexahydro-2,6-methano-2H-quinolizin-3t4H)-one tetrai~luoroborate (1.8 g).
A stlrred suspenslon Or the above salt (1.8 g) in anhydrous 20 nltroethane (30 ml) was treated with propane-1,3-dithlol (3 ml) and boron tri~luoride etherate (3 drops) and the mixture stirred overnight at room temperature. The nitroethane was removed by evaporation and the residue trlturated with ether. The solid product was filtered oi~f, washed several times wlth ether, treat-25 ed wlth water ~25 ml), saturated aqueous potassium carbonate C-35,466 ~32 ~
(3 ml) and ether (50 ml). The ether solution was separated off, dried (MgS04) and evaporated to give the propane dithioketal derivative, m.p. 226-2290C (1.6 g).
Hydrazine hydrate (3 ml) was added dropwise during one hour 5 to a stirred refluxing solution of the above dithioketal tO.5 g) in isopropanol (20 ml) in the presence of Raney nickel (6 g, previously washed three times with isopropanol). The reflux was maintained for a further 30 minutes, the hot solution filtered through a triple superphosphate, the nickel washed several times 10 with hot isopropanol and the combined filtrates evaporated to give endo-8-(3-indolylcarbonyloxy)-2,6-methanooctahydro-2H-quinolizine as the free base (50 mg). Addition of methylene chloride and ethereal hydrogen chloride gave the hydrochloride (30 mg), m.p. 311-313C (from ethanol).
EXA~PLE XIII
. ~
The procedure o~ Example XII was repeated uslng endo-hexahydro-8-hydroxy-2,6-methano-2H-quinollzin-3(4H)-one in place 20 of the ester. The dithioketal obtained was reduced as described ln the final paragraph except that the hydrazine hydrate was left out. Th~s gave exo-octahydro-2,6-methano-2H-quinolizin-8-ol which was then reacted with 3,5-dimethylbenzoyl chloride to give exo-8-(3,5-dimethylbenzoyloxy)octahydro-2,6-methano-2H-quinolizine 25 which was converted to the hydrochloride, m.p. 255-256C by standard procedures.
C-35,466 '` ,.' ., ., ' - ~: ` . .
Claims (33)
1. A process for preparing a compound of the formula:
wherein A is =H2, =O, =(H)(OH) or =N-OH; B is =H2, =(H)(CH3), =(H)(CH2NR3R4) or =CH2 wherein R3 and R4 are C2-4 alkyl or are combined to give tetramethylene, pentameth-ylene or -CH2CH2-O-CH2CH2-; R1 is , , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hydro-gen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2;
R11 is hydrogen, halogen, C1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen sub-stituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds, which comprises reacting an alcohol or a reactive derivative thereof, said alcohol having the formula:
wherein A' is =H2 or =O, with a reactive equivalent of an acid of the formula:
wherein R1 is defined as above, to give those compounds wherein A is =H2 or =O, optionally followed by (a) reduction of the product ketone with an alkali metal borohydride to give those compounds in which A is =(H)(OH), or (b) conversion of the product ketone to a dithio-ketal with ethylene dithiol or trimethylene dithiol followed by reduction with hydrazine in the presence of Raney nickel to give those compounds in which A is =H2, or (c) reaction of the product ketone with hydrox-ylamine hydrochloride to give those compounds in which A is =N-OH, or (d) reaction of the product ketone with form-aldehyde and an appropriate secondary amine to give those compounds in which B is =(H)(CH2NR3R4), followed by, when B is dimethylaminomethyl, heating to give those compounds in which B is =CH2, further followed by hydrogenation to give those compounds in which B is =(H)(CH3).
wherein A is =H2, =O, =(H)(OH) or =N-OH; B is =H2, =(H)(CH3), =(H)(CH2NR3R4) or =CH2 wherein R3 and R4 are C2-4 alkyl or are combined to give tetramethylene, pentameth-ylene or -CH2CH2-O-CH2CH2-; R1 is , , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hydro-gen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2;
R11 is hydrogen, halogen, C1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen sub-stituent on the ring can be endo or exo; and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds, which comprises reacting an alcohol or a reactive derivative thereof, said alcohol having the formula:
wherein A' is =H2 or =O, with a reactive equivalent of an acid of the formula:
wherein R1 is defined as above, to give those compounds wherein A is =H2 or =O, optionally followed by (a) reduction of the product ketone with an alkali metal borohydride to give those compounds in which A is =(H)(OH), or (b) conversion of the product ketone to a dithio-ketal with ethylene dithiol or trimethylene dithiol followed by reduction with hydrazine in the presence of Raney nickel to give those compounds in which A is =H2, or (c) reaction of the product ketone with hydrox-ylamine hydrochloride to give those compounds in which A is =N-OH, or (d) reaction of the product ketone with form-aldehyde and an appropriate secondary amine to give those compounds in which B is =(H)(CH2NR3R4), followed by, when B is dimethylaminomethyl, heating to give those compounds in which B is =CH2, further followed by hydrogenation to give those compounds in which B is =(H)(CH3).
2. A process according to Claim 1 for preparing a compound of the formula:
wherein A' is =H2 or =O, R1 is , , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hydro-gen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2;
R11 is hydrogen, halogen, C1-4 alkyl or phenyl; and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds, which comprises reacting an alcohol or a reactive derivative thereof, said alcohol having the formula:
wherein A' is defined as above, with a reactive equivalent of an acid of the formula:
wherein R1 is defined as above.
wherein A' is =H2 or =O, R1 is , , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hydro-gen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2;
R11 is hydrogen, halogen, C1-4 alkyl or phenyl; and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds, which comprises reacting an alcohol or a reactive derivative thereof, said alcohol having the formula:
wherein A' is defined as above, with a reactive equivalent of an acid of the formula:
wherein R1 is defined as above.
3. A process according to Claim 1 for preparing a compound of the formula:
wherein A' is =H2 or =0, R1 is , or wherein R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)-amino, (C1-4 alkyl)2amino or nitro; R10 is hydrogen, halo-gen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; Z is NR9, O or S; R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); and the pharmaceutically acceptable acid addition and quater-nary ammonium salts of the aforesaid compounds, which comprises reacting an alcohol of the formula:
with an acid of the formula:
wherein A' and R1 are defined as above; said alcohol being used in the form of a super acid salt of the alcohol and in the presence of an equivalent of a heavy metal salt of the same super acid; said acid being used in the form of the corresponding acid chloride or bromide or the corresponding glyoxylyl chloride or bromide; with the reaction carried out in a nitroparaffin solvent at a temperature between -80°C and ambient temperature for a period up to about 24 hours.
wherein A' is =H2 or =0, R1 is , or wherein R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)-amino, (C1-4 alkyl)2amino or nitro; R10 is hydrogen, halo-gen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; Z is NR9, O or S; R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); and the pharmaceutically acceptable acid addition and quater-nary ammonium salts of the aforesaid compounds, which comprises reacting an alcohol of the formula:
with an acid of the formula:
wherein A' and R1 are defined as above; said alcohol being used in the form of a super acid salt of the alcohol and in the presence of an equivalent of a heavy metal salt of the same super acid; said acid being used in the form of the corresponding acid chloride or bromide or the corresponding glyoxylyl chloride or bromide; with the reaction carried out in a nitroparaffin solvent at a temperature between -80°C and ambient temperature for a period up to about 24 hours.
4. A process according to Claim 1 for preparing a compound which has the formula:
wherein R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydro-gen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; and the pharmaceutically acceptable acid addition and quater-nary ammonium salts of the aforesaid compounds, which comprises reacting an alcohol of the formula:
with an acid of the formula:
wherein R1 is defined as above; said alcohol being used in the form of a super acid salt of the alcohol and in the presence of an equivalent of a heavy metal salt of the same super acid; said acid being used in the form of the corresponding acid chloride or bromide or the corres-ponding glyoxylyl chloride or bromide; with the reaction carried out in a nitroparaffin solvent at a temperature between -80°C and ambient temperature for a period up to about 24 hours.
wherein R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydro-gen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; and the pharmaceutically acceptable acid addition and quater-nary ammonium salts of the aforesaid compounds, which comprises reacting an alcohol of the formula:
with an acid of the formula:
wherein R1 is defined as above; said alcohol being used in the form of a super acid salt of the alcohol and in the presence of an equivalent of a heavy metal salt of the same super acid; said acid being used in the form of the corresponding acid chloride or bromide or the corres-ponding glyoxylyl chloride or bromide; with the reaction carried out in a nitroparaffin solvent at a temperature between -80°C and ambient temperature for a period up to about 24 hours.
5. A process according to Claim 1 for preparing a compound which has the formula:
wherein R1 is or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hy-drogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2, and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds, which comprises reacting an alcohol of the formula:
with an acid of the formula:
wherein R1 is defined as above; said alcohol being used in the form of a super acid salt of the alcohol and in the presence of an equivalent of a heavy metal salt of the same super acid; said acid being used in the form of the corresponding acid chloride or bromide or the corres-ponding glyoxylyl chloride or bromide; with the reaction carried out in a nitroparaffin solvent at a temperature between -80°C and ambient temperature for a period up to about 24 hours.
wherein R1 is or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hy-drogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2, and the pharmaceutically acceptable acid addition and quaternary ammonium salts of the aforesaid compounds, which comprises reacting an alcohol of the formula:
with an acid of the formula:
wherein R1 is defined as above; said alcohol being used in the form of a super acid salt of the alcohol and in the presence of an equivalent of a heavy metal salt of the same super acid; said acid being used in the form of the corresponding acid chloride or bromide or the corres-ponding glyoxylyl chloride or bromide; with the reaction carried out in a nitroparaffin solvent at a temperature between -80°C and ambient temperature for a period up to about 24 hours.
6. A process according to Claim 1 for preparing endo-8-(3,5-dimethylbenzoyloxy)hexahydro-2,6-methano-2H-quino-lizin-3(4H)-one which comprises reacting endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one first with hydrofluoroboric acid, then with silver tetrafluoroborate, and finally with 3,5-dimethylbenzoyl chloride.
7. A process according to Claim 1 for preparing endo-
8-(3-indolylcarbonyloxy)hexahydro-2,6-methano-2H-quinoli-zin-3(4H)-one which comprises reacting endo-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one first with hydrofluoroboric acid, then with silver tetrafluoroborate, and finally with indole-3-carboxylic acid chloride.
8. A compound of the formula:
wherein A is =H2, =O, =(H) (OH) or =N-OH; B is =H2, =(H)(CH3), =(H)(CH2NR3R4) or =CH2 wherein R3 and R4 are C2-4 alkyl or are combined to give tetramethylene, pentameth-ylene or -CH2CH2-O-CH2CH2-; R1 is , , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hy-drogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2:
R11 is hydrogen, halogen, C1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; or a pharmaceutically acceptable acid addition salt or a quat-ernary ammonium salt of the aforesaid compound, whenever prepared by the process of Claim 1.
8. A compound of the formula:
wherein A is =H2, =O, =(H) (OH) or =N-OH; B is =H2, =(H)(CH3), =(H)(CH2NR3R4) or =CH2 wherein R3 and R4 are C2-4 alkyl or are combined to give tetramethylene, pentameth-ylene or -CH2CH2-O-CH2CH2-; R1 is , , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hy-drogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2:
R11 is hydrogen, halogen, C1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo; or a pharmaceutically acceptable acid addition salt or a quat-ernary ammonium salt of the aforesaid compound, whenever prepared by the process of Claim 1.
9. A compound of the formula:
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl, or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid compound, whenever prepared by the process of Claim 2.
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl, or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid compound, whenever prepared by the process of Claim 2.
10. A compound of the formula:
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hy-drogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2;
R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quat-ernary ammonium salt of the aforesaid compound, whenever prepared by the process of Claim 3.
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hy-drogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2;
R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quat-ernary ammonium salt of the aforesaid compound, whenever prepared by the process of Claim 3.
11. A compound of the formula:
wherein R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hy-drogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2;
R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quat-ernary ammonium salt of the aforesaid compound, whenever prepared by the process of Claim 4.
wherein R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydrogen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro; R9 is hy-drogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2;
R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quat-ernary ammonium salt of the aforesaid compound, whenever prepared by the process of Claim 4.
12. A compound of the formula:
wherein R1 is or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2, or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the afore-said compound, whenever prepared by the process of Claim 5.
wherein R1 is or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2, or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the afore-said compound, whenever prepared by the process of Claim 5.
13. The compound which is endo-8-(3,5-dimethylbenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one, whenever prepared by the process of Claim 6.
14. The compound which is endo-8-(3-indolylcarbonyloxy)hexahydro-2,6-methano-2H-quino-lizin-3(4H)-one, whenever prepared by the process of Claim 7.
15. A compound of the formula:
wherein A is =H2, =O, =(H)(OH) or =N-OH; B is =H2, =(H)(CH3), =(H)(CH2NR3R4) or =CH2 wherein R3 and R4 are C2-4 alkyl or are combined to give tetramethylene, pen-tamethylene or -CH2CH2-O-CH2CH2-; R1 is , , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo;
or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid compound.
wherein A is =H2, =O, =(H)(OH) or =N-OH; B is =H2, =(H)(CH3), =(H)(CH2NR3R4) or =CH2 wherein R3 and R4 are C2-4 alkyl or are combined to give tetramethylene, pen-tamethylene or -CH2CH2-O-CH2CH2-; R1 is , , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo;
or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid compound.
16. A compound according to Claim 15 which has the formula:
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R8, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl, or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid com-pound.
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R8, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl, or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid com-pound.
17. A compound according to Claim 15 which has the formula:
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid com-pound.
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid com-pound.
18. A compound according to Claim 15 which has the formula:
wherein R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid com-pound.
wherein R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid com-pound.
19. A compound according to Claim 15 which has the formula:
wherein R1 is or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the afore-said compound.
wherein R1 is or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the afore-said compound.
20. A compound according to Claim 15 which is endo-8-(3,5-dimethylbenzoyloxy)hexahydro-2,6-methano-2H-quino-lizin-3(4H)-one.
21. A compound according to Claim 15 which is endo-8-(3-indolylcarbonyloxy)hexahydro-2,6-methano-2H-quino-lizin-3(4H)-one.
22. A pharmaceutical composition comprising a com-pound of the formula:
in admixture with a pharmaceutically acceptable carrier therefor, wherein A is =H2, =O, =(H)(OH) or =N-OH; B is =H2, =(H)(CH3), -(H)(CH2NR3R4) or =CH2 wherein R3 and R4 are C2-4 alkyl or are combined to give tetramethylene, pentamethylene or -CH2CH2-O-CH2CH2-; R1 is , , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo;
or a pharmaceutically acceptable acid addition salt, or a quaternary ammonium salt, of the aforesaid compound.
in admixture with a pharmaceutically acceptable carrier therefor, wherein A is =H2, =O, =(H)(OH) or =N-OH; B is =H2, =(H)(CH3), -(H)(CH2NR3R4) or =CH2 wherein R3 and R4 are C2-4 alkyl or are combined to give tetramethylene, pentamethylene or -CH2CH2-O-CH2CH2-; R1 is , , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; the wavy line indicates that the configuration of the oxygen substituent on the ring can be endo or exo;
or a pharmaceutically acceptable acid addition salt, or a quaternary ammonium salt, of the aforesaid compound.
23. A composition according to claim 22 wherein the compound has the formula:
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl, or a pharmaceutically acceptable acid addition salt, or a quaternary ammonium salt, of the aforesaid compound.
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl, or a pharmaceutically acceptable acid addition salt, or a quaternary ammonium salt, of the aforesaid compound.
24. A composition according to claim 22 wherein the compound has the formula:
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid compound.
wherein A' is =H2 or =O, R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid compound.
25. A composition according to claim 22 wherein the compound has the formula:
wherein R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid compound.
wherein R1 is , or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2; R11 is hydrogen, halogen, C1-4 alkyl or phenyl; or a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt of the aforesaid compound.
26. A composition according to claim 22 wherein the compound has the formula:
wherein R1 is or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2, or a pharmaceutically acceptable acid addition salt, or a quaternary ammonium salt, of the aforesaid compound.
wherein R1 is or wherein Z is NR9, O or S; R5, R6 and R8 are each hydro-gen, halogen, C1-3 alkyl or C1-3 alkoxy; R7 is hydrogen, amino, (C1-4 alkyl)amino, (C1-4 alkyl)2amino or nitro;
R9 is hydrogen, C1-4 alkyl or phenyl (C1-2 alkyl); R10 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, cyano or -CONH2, or a pharmaceutically acceptable acid addition salt, or a quaternary ammonium salt, of the aforesaid compound.
27. A composition according to claim 22 wherein the compound is endo-8-(3,5-dimethylbenzoyloxy)hexahydro-2,6-methano-2H-quinolizin-3(4H)-one.
28. A composition according to claim 22 wherein the compound is endo-8-(3-indolylcarbonyloxy)hexahydro-2,6-methano-2H-quinolizine-3(4H)-one.
29. A composition according to claim 22 which is in a form suitable for oral administration.
30. A composition according to claim 22 which is in a form suitable for parenteral administration.
31. A composition according to claim 22 which is in a form suitable for intravenous or subcutaneous administ-ration.
32. A composition according to claim 22 which is in a form suitable for administration by inhalation.
33. A composition according to claim 22 which is in a form suitable for administration as a suppository.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US92661986A | 1986-11-03 | 1986-11-03 | |
| US926,619 | 1986-11-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1329203C true CA1329203C (en) | 1994-05-03 |
Family
ID=25453460
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000550612A Expired - Lifetime CA1329203C (en) | 1986-11-03 | 1987-10-29 | Esters of hexahydro-8-hydroxy-2, 6-methano-2h- quinolizin-3(4h)-one and related compounds |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0266730B1 (en) |
| JP (2) | JP2542225B2 (en) |
| KR (1) | KR950011737B1 (en) |
| CN (1) | CN1021654C (en) |
| AR (1) | AR246264A1 (en) |
| AT (1) | ATE109779T1 (en) |
| AU (1) | AU600318B2 (en) |
| CA (1) | CA1329203C (en) |
| DE (2) | DE19775092I2 (en) |
| DK (1) | DK171116B1 (en) |
| ES (1) | ES2061469T3 (en) |
| FI (1) | FI87786C (en) |
| HU (1) | HU197008B (en) |
| IE (1) | IE63670B1 (en) |
| IL (1) | IL84309A (en) |
| NL (1) | NL970043I2 (en) |
| NO (2) | NO165922C (en) |
| NZ (1) | NZ222349A (en) |
| PH (2) | PH24664A (en) |
| PT (1) | PT86060B (en) |
| ZA (1) | ZA878096B (en) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0329932B1 (en) * | 1988-02-23 | 1995-10-18 | Merrell Pharmaceuticals Inc. | Use of quinolizine and quinolizinone derivatives in the manufacture of medicaments |
| EP0329905A1 (en) * | 1988-02-23 | 1989-08-30 | Merrell Dow Pharmaceuticals Inc. | Use of quinolizine and quinolizinone derivatives in the manufacture of medicaments for increasing gastric motility |
| EP0329903A1 (en) * | 1988-02-23 | 1989-08-30 | Merrell Dow Pharmaceuticals Inc. | Use of quinolizinone and quinolizine derivatives in the manufacture of medicaments for the treatment of glaucoma |
| EP0329902A1 (en) * | 1988-02-23 | 1989-08-30 | Merrell Dow Pharmaceuticals Inc. | Use of quinolizinone and quinolizine derivatives in the manufacture of medicaments for the treatment of psychosis |
| US5011846A (en) * | 1988-02-23 | 1991-04-30 | Merrell Dow Pharmaceuticals Inc. | Medicament compositions derived from quinolizine and quinolizinone and methods of use thereof |
| EP0329904A1 (en) * | 1988-02-23 | 1989-08-30 | Merrell Dow Pharmaceuticals Inc. | Use of quinolizine and quinolizinone derivatives in the manufacture of medicaments for the treatment of anxiety |
| EP0330788A1 (en) * | 1988-03-01 | 1989-09-06 | Merrell Dow Pharmaceuticals Inc. | Use of quinolizine and quinolizinone derivatives in the manufacture of medicaments for the treatment of cardiac arrhythmia |
| ZA893008B (en) * | 1988-04-29 | 1989-12-27 | Merrell Dow Pharma | Process for preparing indole-3-carboxylic acid esters of transhexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3(4h)-one |
| GB8928837D0 (en) * | 1989-12-21 | 1990-02-28 | Beecham Group Plc | Pharmaceuticals |
| EP0492020A1 (en) * | 1990-12-21 | 1992-07-01 | Merrell Dow Pharmaceuticals Inc. | Use of certain esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one and related compounds for treating cognitive disorders |
| DK1040094T3 (en) * | 1997-12-17 | 2009-06-02 | Biocryst Pharm Inc | Substituted cyclopentane and cyclopenten compounds useful as neuraminidase inhibitors |
| CN100390172C (en) * | 2004-09-10 | 2008-05-28 | 成都欣捷高新技术开发有限公司 | A kind of crystal form of dolasetron mesylate and preparation method thereof |
| US20070299260A1 (en) * | 2004-11-25 | 2007-12-27 | Cilag Ltd. | Method for Preparing Hexahydro-8-Hydroxy-2, 6-Methano-2H-Chinolizin-3 (4H) -One Esters |
| DE602006003227D1 (en) * | 2005-07-06 | 2008-11-27 | Inke Sa | PROCESS FOR OBTAINING THE PHARMACEUTICALLY ACTIVE DAVON AND METHOD FOR THEIR OBTAINMENT |
| ES2264901B1 (en) | 2005-07-06 | 2007-12-01 | Inke, S.A. | PROCEDURE FOR OBTAINING A PHARMACEUTICALLY ACTIVE COMPOUND, ITS SYNTHESIS INTERMEDIATES AND PROCEDURE FOR OBTAINING THEMSELVES. |
| US20070203177A1 (en) * | 2006-01-05 | 2007-08-30 | Janos Hajko | Forms of dolasetron mesylate and processes for their preparation |
| EP2060557B1 (en) | 2007-11-13 | 2012-06-06 | Inke, S.A. | Intermediate compounds useful to prepare dolasetron |
| CN102458400B (en) | 2009-05-20 | 2014-10-08 | 国立健康与医学研究所 | Serotonin 5-HT3 receptor antagonists for the treatment of focal vestibular dysfunction |
| EP2253316B1 (en) | 2009-05-20 | 2013-08-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Serotonin 5-HT3 receptor antagonists for use in the treatment or prevention of an inner ear pathology with vestibular deficits |
| EP3347011A4 (en) | 2015-09-11 | 2019-06-19 | Chase Pharmaceuticals Corporation | Muscarinic combination and its use for combating hypocholinergic disorders of the central nervous system |
| CN108976230A (en) * | 2018-06-18 | 2018-12-11 | 东莞市联洲知识产权运营管理有限公司 | A method of dolasetron mesilate key intermediate is prepared based on graphene activation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI74707C (en) * | 1982-06-29 | 1988-03-10 | Sandoz Ag | FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA ALKYLENOEVERBRYGGADE PIPERIDYLESTRAR ELLER -AMIDER AV BICYKLISKA KARBOXYLSYROR. |
| WO1985001048A1 (en) * | 1983-08-26 | 1985-03-14 | Sandoz Ag | Aromatic esters or amides of carboxylic acid and sulfonic acid |
| EP0189002B1 (en) * | 1984-12-20 | 1993-03-03 | Sandoz Ag | Treatment of gastrointestinal disorders using 5-ht3 antagonists |
-
1987
- 1987-10-28 ZA ZA878096A patent/ZA878096B/en unknown
- 1987-10-29 FI FI874768A patent/FI87786C/en not_active IP Right Cessation
- 1987-10-29 NZ NZ222349A patent/NZ222349A/en unknown
- 1987-10-29 IL IL84309A patent/IL84309A/en not_active IP Right Cessation
- 1987-10-29 CA CA000550612A patent/CA1329203C/en not_active Expired - Lifetime
- 1987-10-30 AR AR87309166A patent/AR246264A1/en active
- 1987-10-30 PH PH36006A patent/PH24664A/en unknown
- 1987-11-02 AT AT87116119T patent/ATE109779T1/en not_active IP Right Cessation
- 1987-11-02 DK DK572887A patent/DK171116B1/en not_active IP Right Cessation
- 1987-11-02 HU HU874918A patent/HU197008B/en unknown
- 1987-11-02 NO NO874550A patent/NO165922C/en not_active IP Right Cessation
- 1987-11-02 EP EP87116119A patent/EP0266730B1/en not_active Expired - Lifetime
- 1987-11-02 PT PT86060A patent/PT86060B/en unknown
- 1987-11-02 DE DE1997175092 patent/DE19775092I2/en active Active
- 1987-11-02 DE DE3750359T patent/DE3750359T2/en not_active Expired - Lifetime
- 1987-11-02 CN CN87107629A patent/CN1021654C/en not_active Expired - Lifetime
- 1987-11-02 AU AU80596/87A patent/AU600318B2/en not_active Expired
- 1987-11-02 JP JP62275894A patent/JP2542225B2/en not_active Expired - Lifetime
- 1987-11-02 ES ES87116119T patent/ES2061469T3/en not_active Expired - Lifetime
- 1987-11-02 IE IE295587A patent/IE63670B1/en not_active IP Right Cessation
- 1987-11-03 KR KR1019870012286A patent/KR950011737B1/en not_active Expired - Lifetime
-
1990
- 1990-01-02 PH PH39830A patent/PH26261A/en unknown
-
1996
- 1996-02-27 JP JP8065408A patent/JP2657267B2/en not_active Expired - Lifetime
-
1997
- 1997-12-17 NL NL970043C patent/NL970043I2/en unknown
-
1999
- 1999-08-26 NO NO1999020C patent/NO1999020I1/en unknown
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