NZ205509A - Propylamine derivatives and pharmaceutical compositions - Google Patents
Propylamine derivatives and pharmaceutical compositionsInfo
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- NZ205509A NZ205509A NZ205509A NZ20550983A NZ205509A NZ 205509 A NZ205509 A NZ 205509A NZ 205509 A NZ205509 A NZ 205509A NZ 20550983 A NZ20550983 A NZ 20550983A NZ 205509 A NZ205509 A NZ 205509A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
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- 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
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- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A compound of the general formula I see diagramm : EP0102929,P33,F1 Wherein each of R1 and R2 independently of the other represents hydrogen or lower alkyl ; or R1 and R2 together with the adjacent nitrogen atom represent piperidino or pyrrolidino or a five- or six-membered saturated heterocyclic ring containing NH, N-lower alkyl, O or S ; R3 represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl ; Ar represents phenyl or phenyl substituted by one to three substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl, or by on lower alkylenedioxy ; and X represents O, S or N-lower alkyl ; and n represents an integer 1, 2 or 3 ; or an N-oxide thereof ; an acid addition salt thereof ; of an N-lower alkyl or N-benzyl quaternary salt thereof ; with the exception of the compound of formula I wherein R1 and R2 represent ethyl, R3 represents hydrogen, Ar represents phenyl, X represents O, and n is 3, or a salt thereof ; with the groups qualified by the term "lower" containing at most 7 carbon atoms. For the Contracting State : AT 1. A process for the preparation of a novel propylamine derivative of the general formula I see diagramm : EP0102929,P37,F1 Wherein each of R1 and R2 independently of the other represents hydrogen or lower alkyl ; or R1 and R2 together with the adjacent nitrogen atom represent piperidono or pyrrodino or a five- or six-membered saturated heterocyclic ring containing NH, N-lower alkyl, O or S ; R3 represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl ; Ar represents phenyl or phenyl substituted by one to three substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl, or by on lower alkylenedioxy ; and X represents O, S or N-lower alkyl ; and n represents an integer 1, 2 or 3 ; or of an N-oxide thereof ; an acid addition salt thereof ; of an N-lower alkyl or N-benzyl quaternary salt thereof ; with the exception of the compound of formula I wherein R1 and R2 represent ethyl, R3 represents hydrogen, Ar represents phenyl, X represents O, and n is 3, or a salt thereof ; with the groups qualified by the term "lower" containing at most 7 carbon atoms ; which process comprises a) condensing a compound of the formula II see diagramm : EP0102929,P37,F2 or an acid addition salt thereof, with a compound of the formula III AR-Y(III) wherein R1 , R2 , R3 , n and Ar are as defined above, one of the symbols W and Y represents a group XH or XH in a metal salt from, in which X is as defined above, and the other one represents the group XH in a reactive esterified form thereof or as an N,N'-disubstituted isourea or isothiourea derivative ; or b) alkylating an amine of the formula IV see diagramm : EP0102929,P37,F3 or an acid addition salt thereof, with a compound of the formula V see diagramm : EP0102929,P38,F4 in which Z is a hydrogen atom together with a reactive esterified hydroxyl group of the oxo group and Ar, X, R3 and n are as defined above, and if Z is the oxo group, said alkylation is carried out under reductive conditions ; or c) reducing a compound structurally analogous to a compound of formula I as defined above, wherein an oxo group is present on at least one carbon atom adjacent to the amino nitrogen ; or d) saturating with hydrogen a multiple bond or multiple bonds in a compound structurally analogous to the compound of formula I as defined above and wherein one or two double bonds are present in the aliphatic moiety of the molecule inclusive of the amino group ; or e) removing the radial R0 from a compound of the formula VI see diagramm : EP0102929,P38,F5 wherein R2 , R3 , X, n and Ar are as defined above and R0 is an amino proctective group, to obtain a compound of formula in which R1 is hyrogen ; or f) reducing a compound of the formula VII see diagramm : EP0102929,P38,F5 wherein T represents cyano or azidomethyl ; and R3 , X, n and Ar are as defined above to obtain a compound of formula I wherein R1 and R2 are hydrogen ; or g) condensing a compound of the formula VIIA see diagramm : EP0102929,P39,F6 with a compound of the formula VIIB see diagramm : EP0102929,P39,F6 wherein one of the groups Q and M represents a removable group, and the other represents a metal or halometal radical, and Ar, X, R1 to R3 and n are as defined above, if necesseray while temporarily protecting any interfering reactive group in all these processes, and isolating the resultant compound of formula ; and/or, if required, converting a resultant compound of formula I into another compound of formula I, and/or, if require, converting a resultant free compound into a salt or a resultant salt into the free compound or into another salt, and/or, if required, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if required, resolving a racemate obtained into the optical antipodes.
Description
New Zealand Paient Spedficaiion for Paient Number £05509
Patents Form No. 5
NEW ZEALAND
PATENTS ACT 1953
COMPLETE SPECIFICATION "PROPYLAMINE DERIVATIVES"
WE, CIBA-GEIGY AG, a Swiss Corporation of Klybeckstrasse 141, 4002 Basle, Switzerland,
hereby declare the invention, for which we pray that a patent may be granted to us,and the method by which it is to be performed, to be particularly described in and by the following statement:~
(follcwetJ I v i
®°550#
- iA
4-1^082/CGC 988/+
Propylamine derivatives
British patent application 1,343,527 is directed to compounds claimed to be certain 2-(aryl, aralkynyl, or aralkyl)-3-(aryl or alk)-oxy-propylamines active on the cardiovascular system. Example 60 therein is indicated to have a structure corresponding to 2-benzyl-3-phenoxy-N,N-diethyl-propylamine. By repeating the preparation of example 60 of British patent application 1,343,527 using methodology given therein, it has now been found that the product of example 60 actually consists essentially of a compound not having the alleged structure. This compound has instead been assigned the 3-phenoxy-methyl-3-phenyl-N,N-diethyl-propylamine structure.
The present invention concerns nev compounds of the general formula I
\ >"CH2X
CH-CH_-h
Ar-X-CH2
(I)
wherein R^ and R^ independently of the other represent hydrogen or lover alkyl; or and Rj together vith the adjacent nitrogen atom represent piperidino or pyrrolidino or a five- or six-membered saturated heterocyclic ring containing NH, N-lover alkyl, 0 or S;
represents hydrogen, lover alkyl, lover alkoxy, halogen or tri-fluoronethyl; Ar represents phenyl or phenyl substituted by one to
' V* ■'
J U u U J
three substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl, or by one lower alkylenedioxy; and X represents 0, S or N-lover alkyl, and o ropfeoente aw integer 1, 2 -or-3;- acid addition salts thereof, particularly pharmaceutically acceptable salts; N-oxides thereof; and N-lower alkyl or N-benzyl quaternary salts thereof; except the compound of formula X wherein R^ and R2 represent ethyl, R3 represents hydrogen, Ar represents phenyl, and X represents 0, and n io 3j and salts thereof; process for their t>-s\ manufacture, pharmaceutical preparations containing these compounds t and their therapeutic application.
In particular the present invention concerns compounds of the general formula I wherein and R^ independently of the other represent hydrogen or lover alkyl; or and Rj together with the adjacent nitrogen atom represent piperidino or pyrrolidino or a five- or six-membered saturatfed heterocyclic ring containing NH, N-lower alkyl, 0 or S; Rj represents hydrogen, lower alkyl, lover alkoxy, halogen or trifluoromethyl; Ar represents phenyl or phenyl substituted by one to three substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkyl-mercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trif luoromethyl, or by one lower alkylenedioxy; X represents S or N-lower alkyl; and a reprcsenta the integer 1, 2 or 3; acid addition salts thereof, especially pharmaceutically acceptable salts; N-oxides thereof; and N-lower alkyl or N-benzyl quaternary salts thereof.
^, Preferred are the compounds of general formula I, wherein R^ and R^
independently represent hydrogen or lower alkyl; or R^ and R2 together with the adjacent nitrogen atom represent pyrrolidino or jiperidino; R^i Ar -«-and X have the meanings given above; and acid
ZUbL-u J
- 3
addition sales thereof, especially pharmaceutically acceptable salts thereof, except the catpound of formula I wherein Rj and R2 represent ethyl, R3 represents hydrogen, Ar represents phenyl, and X represents O, and n io 3/ and salts thereof.
Illustrative of the above-cited preferred compounds are conpounds represented by general formula I wherein and R^ independently represent hydrogen, methyl or ethyl; R^ represents hydrogen, chloro or trifluoromethyl; Ar represents phenyl substituted by one or two substituents selected from the group consisting of methyl, methoxy, allyloxy, methylthio, methylsulfinyl, chloro, bromo and trifluoromethyl, or by one methylenedioxy, n represents the integer 1 or 2, X represents 0 or S; and acid addition salts thereof, especially pharmaceutically acceptable salts thereof,.except the compound of formula I wherein Rj and R2 represent-ethyl, Rj represents hydrogen, Ar represents phenyl; and X represents O, and salts thereof.
Preferred are the compounds of formula I wherein R^ and R^
independently of the other represent hydrogen or lower alkyl;
or R^ and Rj together with the adjacent nitrogen atom represent pyrrolidino or piperidino or a five- or six—membered saturated heterocyclic ring containing NH, N-lower alkyl, 0 or S, R^ represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;. n represents the iutegei 1 ui 2,' X represents 0, S or N-lower alkyl; Ar represents phenyl substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylmercapto, lower alkyl-sulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl, or by one lower alkylenedioxy; and acid addition salts, especially pharmaceutically acceptable acid addition salts thereof.
A specific embodiment of the invention relates to compounds of the general formula IA
2055 0
3y-% \
/ _CH2\
CH-CH
Ar-X-CH2 ~2
(IA)
wherein and R2 independently of the other represent hydrogen or lower alkyl; or R^ and R^ together with the adjacent nitrogen atom represent pyrrolidino or piperidino or a five- or six-meiabered saturated heterocyclic ring containing NH, N-lower alkyl, 0 or S; R^ represents hydrogen, lower alkyl, lower alkoxy, halogen or tri-fluoromethyl; Ar represents phenyl substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl, or by one lower alkylenedioxy; and X represents 0 or S; acid addition salts thereof, particularly pharmaceutically acceptable salts; N-oxides thereof; and N-lower alkyl or N-benzyl quaternary salts thereof.
Preferred in turn are the compounds of general formula IA, wherein R^ and R2 independently represent hydrogen or lower alkyl; or R^ and R2 together with the adjacent nitrogen atom represent pyrrolidino or piperidino; R^, Ar and X have the meanings given above; and acid addition salts, especially pharmaceutically acceptable salts thereof.
Preferred are compounds of formula IA wherein R^ and R2 independently represent hydrogen or lower alkyl; or R^ and R2 together with the adjacent nitrogen represent piperidino; R^ represents hydrogen, halogen or trifluoromethyl; Ar represents phenyl monosubstituted or disubstituted by identical or different substituents selected from lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl; or Ar represents phenyl monosubstituted by lower alkylene-
20550
dioxy; and X represents 0 or S; and acid-addition salts, especially pharmaceutically useful salts thereof.
Illustrative of the above-cited preferred compounds are compounds represented by general formula IA wherein and independently represent hydrogen, methyl or ethyl; represents hydrogen, chloro or trifluoromethyl; Ar represents phenyl substituted by one or two substituents selected from the group consisting of methyl, methoxy, allyloxy, methylmercapto, methylsulfinyl, chloro, bromo and trifluoro-methyl, or by one methylenedioxy; X represents 0 or S; and acid addition salts, especially pharmaceutically acceptable salts thereof.
Of particular interest are the compounds of formula IB
wherein and R£ independently represent hydrogen or lower alkyl; R.j represents hydrogen, halogen or trifluoromethyl; Ar represents phenyl monosubstituted or disubstituted by identical or different substituents selected from lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl,
halogen and trifluoromethyl; and the acid addition salts, especially pharmaceutically useful salts thereof.
Highly preferred are the compounds of formula IB wherein R^
represents hydrogen or alkyl of 1-4 carbons; R2 represents alkyl of 1-4 carbons; R^ represents hydrogen or chloro; Ar represents phenyl mono-substituted by alkoxy of 1-4 carbons, alkyl of 1-4 carbons, alkylmercapto of 1-4 carbons, chloro, or trifluoromethyl; and the acid addition salts, especially the pharmaceutically acceptable salts thereof.
(IB)
2055
Another preferred embodiment of the invention is represented by compounds of formula IB wherein represents hydrogen; Rg represents alkyl of 1-4 carbons; R^ represents hydrogen or chloro; Ar represents phenyl monosubstituted by alkoxy of 1-4 carbons, alkyl of 1-4 carbons, alkylmercapto of 1-4 carbons, chloro or trifluoromethyl; and the acid addition salts, especially the pharmaceutically acceptable salts thereof.
For the compounds of formula IB within all the embodiments described above, Ar advantageously represents phenyl di- or mono-substituted at the 3- and/or 4-position of the phenyl ring by groups listed above.
Illustrative of the preferred compounds of formula IB are said compounds wherein represents hydrogen or methyl; R^ represents methyl; R^ represents hydrogen or chloro at the 3- or 4-position; Ar represents phenyl mono-substituted by methoxy, methyl, methyl-thio, chloro or trifluoromethyl; or an acid addition salt, especially a pharmaceutically acceptable salt thereof. Preferred in turn are the said compounds wherein Ar represents phenyl substituted at the 3- or 4-position, advantageously at the 4-position, by methoxy, methylthio or trifluorophenyl; and the acid addition salts, especially pharmaceutically acceptable salts thereof.
A specific group of compounds are those of formula I, wherein R^ represents hydrogen or methyl and R£ is methyl; represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; n is the integer 1 or 2, X represents 0 and Ar is unsubstituted phenyl, and acid addition salts thereof, especially pharmaceutically acceptable salts thereof.
The general definitions used herein have the following meanings within the scope of the present invention.
•20550
The term "lower" referred to above and hereinafter in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up to and including 4 and advantageously one or two carbon atoms.
A lower alkyl group preferably contains 1-4 carbon atoms and represents for example ethyl, propyl, butyl or advantageously methyl.
Lower alkoxy is preferably ethoxy, propoxy, isopropoxy or advantageously methoxy.
Lower alkylthio is preferably ethylthio, propylthio or advantageously methylthio.
•
Lower alkylsulfinyl is preferably ethylsulfinyl, propylsulfinyl or advantageously methylsulfinyl.
Lower alkylsulfonyl is preferably ethylsulfonyl, propylsulfonyl or advantageously methylsulfonyl.
An alkenyl group, as such or as present in e.g. alkenyloxy, represents straight chain or branched alkenyl preferably up to 7 carbon atoms, advantageously up to and including 4 carbon atoms, e.g., 2-propenyl (allyl, 2-butenyl, 2-methyl-2-propenyl or 2-methyl-2-butenyl.
An alkynyl group, as such or as present in e.g. alkynyloxy, represents straight chain or branched alkynyl preferably up to 7 carbon atoms, advantageously up to and including 4 carbon atoms, e.g., 2-propynyl (propargyl), 2-butynyl or 2-pentynyl.
Halogen is preferably chloro, but may also be bromo, iodo or fluoro.
, V-y-:...'' •_ -.w, .... . ( ..... . ...
20550
When R^ and combined with the adjacent nitrogen to which they are attached in formula I represent a five- or six-membered saturated heterocyclic ring, the ring may be devoid of or may contain an additional hetero atom. Five- and six-membered saturated heterocyclic ring moieties devoid of an additional hetero atom are preferably pyrrolidino and piperidino. Five- and six-membered saturated heterocyclic ring moieties containing an additional hetero group is NH, N-lower alkyl, 0 or S. Representative moieties are preferably pyrazolidino, isooxazolidino, and advantageously morpholino, thio-morpholino, piperazino and N-lower alkylpiperazino.
Said compounds of formula X form acid addition salts, which are preferably such of therapeutically acceptable inorganic or organic acids, such as strong mineral acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic,
acetic, propionic, oxalic, succinic, glycolic, lactic, malic,
tartaric, gluconic, citric, maleic, fumaric, pyruvic, phenylacetic,
benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic; methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic, cyclohexylsulfamic acid, or ascorbic acid.
Acid addition salts, such as of other strong inorganic or organic acids, e.g., perchloric or picric acid can also be used for the isolation, purification and characterization of the compounds of formula I.
The compounds of the invention exhibit valuable pharmacological properties, e.g. particularly central nervous system regulatory,
specifically effects indicative of antidepressant acitivity, by inter alia selectively inhibiting brain neuronal serotonin (also
2055 C
designated as 5-hydroxytryptamine or 5-HT) uptake. Compounds of the invention are also inhibitors of neuronal uptake of norepinephrine (NE).
Said effects are demonstrable by in vitro and in vivo tests using advantageously mammals, e.g. mice, rats, guinea pigs, rabbits or monkeys as test subjects. Said compounds can be applied to them enterally or parenterally, advantageously orally, or subcutaneously, intravenously or intraperitoneally, for example, within gelatin capsules or in the form of starchy suspensions or aqueous solutions or suspensions respectively. The applied dosage may range between about 0.1 and 100 mg/kg/day, preferably between about 1 and 50 rag/ kg/day, advantageously between about 5 and 30 mg/kg/day.
The inhibition of serotonin (5-HT) uptake indicative of potential antidepressant activity is determined in rat midbrain synaptosomes in vitro as follows:
Synaptosomes from the rat midbrain-diencephalon region are
3
prepared and the uptake of H-5-HT measured as described by Baumann and Maitre, Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 31 (1977).
-9
The concentration of 5-HT in the incubation medium is 2.5 x 10 M, and the incubation period is 10 minutes. The concentration of a compound of this invention required to inhibit serotonin uptake by 50 %, i.e. the is determined.
Illustrative of the invention, N,N-dimethyl-2-benzyl-3-(4-methyl-
thiophenoxy)-propylamine oxalate, N,N-dimethyl-2-benzyl-3-(4-tri-
fluoromethylphenoxy)-propylamine oxalate and N-methyl-2-benzyl-3-
(4-trifluoromethylphenoxy)-propylamine oxalate inhibit the uptake 3
of H-5-HT into rat midbrain synaptosomes with IC,- values of
—8 —8 —0
about 3 x 10 M, 1.5 x 10 M and 1 x 10 M respectively.
20550
The inhibition of norepinephrine (NE) uptake is determined in rat midbrain synaptosomes in vitro as follows:
Synaptosomes from the rat midbrain-diencephalon region are prepared 3
and the uptake of H-NE is measured as described by Bauotann and
Maitre, Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 31 (1977). The
—8
concentration of NE in the incubation medium is 1 x 10 M, and the incubation period is 20 minutes. The concentration of a new compound required to inhibit norepinephrine uptake by 50 Z, i.e. the is determined.
Illustrative of the invention, N,N-dimethyl-2-benzyl-3-(4-methyl-
thiophenoxy)-propylamine oxalate, N,N-diraethyl-2-benzyl-3-(4-trifluoro-
methylphenoxy)-propylamine oxalate and N-methyl-2-benzyl-3-(4-
trifluoromethylphenoxy)-propylamine oxalate inhibit the uptake 3
of H-NE into rat midbrain synaptosomes with IC,Q values of about
•■7 —6 —6
x 10 M, 3 x 10 M and 2 x 10 M respectively.
Serotonin (5-HT) uptake inhibition is also determined in rats pretreated with compounds of the instant invention.
Illustrative of the invention, N,N-dimethyl-2-benzyl-3-(4-methyl-
thiophenoxy)-propylamine oxalate and N,N-dimethyl-2-benzyl-3-(4-
trifluoromethylphenoxy)-propylamine oxylate at an oral dose of
mg/kg p.o. show about 80 % and 60 % inhibition respectively of 3
H-5HT uptake. N-Methyl-2-benzyl-3-(4-trifluoromethylphenoxy)-
... 3
propylamine oxalate gives about a 50 % inhibition of H-5HT uptake at a dose of 10 mg/kg p.o.
The serotonin uptake inhibiting or serotonin activating properties of the compounds of the invention are indicative of antidepressant properties as determined by the reversal of reserpine-induced ptosis (i.e. contraction of the eyelid) in the rabbit.
2055
- n -
Rabbits are injected intravenously with 2 rag/kg reserpine 90 minutes before the i.v. infusion of 0.2 % drug solution into the ear vein according to the method of J. Mizoule et al. [J.Pharmacol., 3, 269 - 285, (1977)]. The complete opening of the eye-lids is taken as a criterion for reversal of the reserpine-induced ptosis. The results are expressed in terms of the mean dose of test compound inducing complete opening of the eye-lids in reserpine treated rabbits.
Illustrative of the invention, N,N-dimethyl-2-benzyl-3-(4-niethylthio-phenoxy)-propylamine oxalate, N,N-diraethyl-2-benzyl-3-(4~trifluoro-methylphenoxy)—propylamine oxalate and N-methyl-2—benzyl-3-(4-trifluoromethylphenoxy)-propylamine oxalate which show the described effect at a dose of about 7.7, 12.6 and 12.9 mg/kg i.v. respectively.
The compounds of the invention also inhibit the serotonin-depleting effect of 3-hydroxy-4-methyl-a-ethylphenethylamine (H 75/12) in rat brain. The test is performed essentially according to the method described by Carlsson, Corrodi, Fuxe and Hoekfelt, Europ. J. Pharmacol. .5, 357, (1969).
The compound to be tested is administered orally 30 minutes before H 75/12 (25 mg/kg s.c.) and the animals are decapitated 4 hours thereafter. The brains are immediately taken out, the serotonin content is determined as described above, and the of the compound is determined.
The potency of a compound of the invention in inhibiting the serotonin-depleting effect of H 75/12 represents an indirect measure of its serotonin-uptake inhibitory potency.
Illustrative of the serotonin uptake inhibiting effect of the compounds of the invention, the values in the above H 75/12 test for N,N-
205509
dimethy1-2-(3-chlorobenzyl)-3-(A-methylthiophenoxy)-propylamine oxalate and N-methyl-2-benzyl-3-(A-trifluoromethylphenoxy)-propyl-amine oxalate are about l.A and 1.8 mg/kg p.o. respectively. The EDjq values for N,N-dimethyl-2-benzyl-3-(4-methylthiophenoxy)-propyl-amine oxalate and N,N-dimethyl-2-benzyl-3-(A-trifluoromethylphenoxy)-propylamine oxalate are about 2.3 and A.5 mg/kg p.o. respectively.
Accordingly the compounds of this invention are particularly useful when administered alone or in combination to mammals for the treatment of psychotropic disorders, especially depression. The compounds of the invention may also be useful for the treatment of other central nervous system disorders responsive to brain serotonin modulation, e.g. minimal brain dysfunction, excessive appetite, anxiety, schizophrenia and dementia. They are also useful as analgesics, furthermore as intermediates in the preparation of other valuable products, especially of pharmacologically active compositions.
Compounds of formula I according to the invention can be prepared by synthetic procedues which are per se known to those skilled in the art.
In particular, compounds of formula I are prepared by a) condensing a compound of the formula or an acid addition salt thereof, with a compound of the formula III
2
'2
(II)
Ar-Y
(III)
205509
wherein R^, R^, R^f—wand Ar have the meanings given hereinabove, one of the symbols W and Y represents a group XH or XH in a metal salt form, in which X has the meaning given hereinabove and the other one represents the group XH in a reactive esterified form thereof or as an N,N'-disubstituted isourea or isothiourea derivative ; or b) condensing an amine of the formula IV
(IV)
■c or an acid addition salt thereof, with a compound of the formula V
r-3
>"CH2X
... CH-CH-Z (V)
Ar-X-CH2
in which Z is a hydrogen atom together with a reactive esterified hydroxy1 group or the oxo group and Ar, X and R^ have the meaning given hereinabove; or c) reducing a compound structurally analogous to a compound of formula I defined hereinabove, wherein an oxo group is present on at least one carbon atom adjacent to the amino nitrogen; or d) saturating (a) multiple bond(s) in a compound structurally analogous to the compound of formula I defined hereinabove, wherein one or two double bonds is (are) present in the aliphatic portion of the molecule inclusive of the amino group; or e) removing the radTcafTT "from-a compound of the formula VI
205509
*3v
V"\
\__V■CH2Sm. ...
(VI)
2
Ar-X-CH0' \2
wherein R., R,, X -n-and Ar have Che meanings given hereinabove and R Z J o is an amino protecting group, to obtain a compound of formula I in which R^ is hydrogen;
f) reducing a compound of che formula
V"%
N )-CH2\
—• CH-T (VII)
Ar-X-CH2
wherein T represents cyano or azidomechyl; R^, X «■ and Ar have the meanings given hereinabove to obtain a compound of formula I vherein R^ and R^ are hydrogen; or g) condensing a compound of the formula VIIA
Q
I
Ar-X-CH2-CH-CH2-Nf (VIIA)
\2
with a compound of the formula VIIB
R3\.
I II (VIIB)
XCH2M
.... .rT. + ..-A±.
205503
-IS -
wherein one of the groups Q and M represents a leaving group, and the other represents a metal or halometal radical, Ar, X, Rj to R3 have meaning as defined hereinabove, while temporarily protecting any interfering reactive group and isolating the resulting compound of formula 1; and/or if required, converting a resulting compound of formula I into another compound of the invention, and/or if required, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt, and/or, if required, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if required, resolving a racemate obtained into the optical antipodes.
The condensation according to process a) is carried out as described below. The group XH is a hydroxyl or a mercapto (thiol) group. A metal salt form of this group is derived preferably from an alkali metal (e.g. potassium, lithium or, especially, sodium) or, in the case of mercapto, also from uni- or bivalent copper.
The condensation according to process a) is carried out advantageously by making use of a reactive functionalized hydroxyl or thiol group derived from a carbodiimide, i.e., that being represented as an 0-(or S—)derivative of an N,N'-disubstituted isourea (or isothiourea) and having the characteristic grouping b-N/
in which X has the meanings given hereinabove and a and b are optionally substituted hydrocarbyl radicals e.g. especially cyclo-hexyl. Advantageously, the reactive esters of this type are obtained and reacted in situ, e.g. by heating a mixture of an esterifying react^nt, especially an N,N'-disubstituted derivative of carbodiimide,
^EN^^e. g. Especially N,N'-dicyclohexyl carbodiimide and the starting o\ ;
"^materials of formulae II and III, in which both W and Y are in the
2 4 MAR 1987
—I
I
... m*'<—v «
20f509
form of a free hydroxyl or thiol group respectively. Alternatively,
one of the starting materials may be heated advantageously at a temperature ranging from 50° to 200"C, with the N,N'-substituted carbodiimide, preferably in the presence of cuprous chloride to form the isourea or isothiourea derivative. Subsequently the second starting material is added and heating is continued to form the product.
The condensation according to process a) may also be carried out in a more conventional manner. A reactive esterified form of the group XH is thus preferably one in which the hydroxyl or thiol group, respectively, is esterified with a strong organic acid, e.g. an aliphatic or aromatic sulfonic acid (such as a lower alkanesulfonic acid, especially methanesulfonic, trifluoromethanesulfonic and ethanesulfonic acid, or an arylsulfonic acid, especially benzene-sulfonic, p-toluenesulfonic, p-bromobenzenesulfonic and p-nitro-benzenesulfonic acid) or with a strong inorganic acid, such as,
especially, sulfuric acid or a hydrohalic acid, e.g., hydrobromic,
hydriodic or, preferably, hydrochloric, and if attached to the residue Ar, most preferably hydrofluoric acid. If the symbol W or Y specifically represents the group XH reactively esterified with a hydrohalic acid, it represents, in fact, the corresponding halogen atom, i.e. a bromine, iodine or, preferably chlorine or,
especially in connection with the residue Ar a fluorine atom.
In the case of a starting material ArY wherein Y represents halogen, especially fluorine, an activating group, e.g. a trifluoromethyl, alkylsulfonyl or alkylsulfinyl group, is advantageously located ortho or para to the halogen atom. An especially suitable starting material is p-fluorobenzotrifluoride (p-trifluoromethyl-fluorobenzene).
When the condensation according to process a) is carried out as described above, temperatures ranging between about 0°C up to the boiling temperature of the reaction mixture, preferably
7 0 n ~ p e
temperatures between room temperature and about 100°C are employed. The reaction takes place advantageously in the presence of a solvent which is inert with respect to the reactants, such as especially an acyclic or cyclic ether (e.g. diethyl ether, 1,2-dimethoxyethane,
dioxane or tetrahydrofuran) and, in particular, a low-molecular-weight tertiary amide (e.g. N,N-dimethylformamide, N,N-dimethyl-acetamide, N-methylpyrrolidone, N-ethylpiperidone and hexamethyl-phosphoric acid triamide). Advantageously, if a strong acid is liberated during the condensation, it is bound by the addition of an acid-binding agent, e.g. an alkali metal carbonate or hydroxide or preferably, of a very strong base, such as an alkali metal hydride (e.g. sodium or potassium hydride), alkoxide (e.g. sodium methoxide or ethoxide, potassium tert-butoxide) or amide (e.g. lithium di-isopropylamide). Starting with a compound of formula II, wherein W is halogen (preferably chlorine), it is advantageous to convert first the corresponding reactant of formula III, i.e. in this case a phenol, into a corresponding metal phenoxide, especially an alkali metal phenoxide (e.g. a sodium phenoxide) by the action of an equivalent amount of sodium hydride in a polar aprotic solvent, e.g. one of those mentioned above, and to carry out the condensation with this salt. In carrying out the condensation with starting materials of formulae II and III, in which the reactive esterified hydroxyl group is formed in situ by the action of an N,N'-disubstituted carbodiimide such as N,N'—dicyclohexylcarbodiimide, conventional conditions for this condensation are used as well-known in the art.
Starting materials of formula III are, in general, known compounds, or if unknown, they are easily accessible in a manner which is analogous to the preparation of known compounds.
Starting materials of formula II, which are generally new, are accessible by conventional, in temselves known processes of organic synthesis. For example, a lower alkyl a-benzylacrylate of the formula VIII
^ 0 L/ U U li
18 -
*3
v-%
(VIII)
II 0
wherein and n has the meaning given hereinabove and R is a lower alkyl [for preparation, see R.B. Miller and B.F. Smith, Synth. Connnun. 3^ 359 (1973)], is condensed with a secondary amine of formula IV as defined hereinabove in a lower alkanol under the general conditions of a Michael addition, and the resulting lower alkyl a-benzyl-p-aminopropionate of the formula is a lower alkyl, is reduced with a complex hydride, preferably lithium aluminium hydride or an equivalent carbonyl-reducing agent, to the corresponding alcohol, i.e. a compound of formula II, in which W is hydroxyl. If desired, this hydroxyl can be converted into a reactive esterified form thereof by conventional means,
e.g. for the preparation of a preferred chloride (W=C1) by treatment with thionyl chloride, phosphorus trichloride, phosphorus oxychloride or a similar reagent.
The intermediates of formula IX may also be prepared by a) converting e.g. a lower alkyl ester of ^-(NRj^^substituted-propionic acid to an a-metallated derivative thereof, e.g. to the a-lithio derivative with lithium diisopropylamide, and b) subsequently a-metallated derivative with a compound of formula IXA
- 1 APR 1937
L -j u
19 -
II
(ixa)
the wherein and w has/meaning as defined above and P represents reactive esterified hydroxy as defined hereinabove, particularly halogen such as chloro, in a suitable solvent such as tetrahydrofuran optionally in the presence of another solvating compound such as hexamethylphosphoramide.
Process b) is carried out in the conventional manner well-known in the art as alkylation of amines. In the starting materials of formula V, the group 2 (replaceable by amino) can represent especially a hydrogen atom together with a reactive esterified hydroxyl group, or the oxo group. In the first case, the amine alkylation proceeds under the general conditions of substitutive alkylation of amines, in the second case general conditions of reductive alkylation of amines are applicable.
In the case of substitutive alkylation of the amine of formula IV, the reactive esterified hydroxyl group in a compound of formula V is similar to that used in process a), especially a hydroxyl group esterified with a strong organic acid, e.g. an aliphatic or aromatic sulfonic acid, especially methanesulfonic, trifluoromethanesulfonic acid, benzenesulfonic, p-toluenesulfonic, p-bromobenzenesulfonic and p-nitrobenzenesulfonic acid) or esterified with a strong inorganic acid, such as, especially, sulfuric acid, or a hydrohalic acid, such as hydrochloric or, most preferably, hydriodic or hydrobromic acid. The alkylation is carried out preferably under similar conditions and with the same solvents as in process a) , however, halogenated alkanes, e.g. chloroform and methylene"chloride, are also useful solvents. Usually also milder acid-scavengers in process a) are employed, especially organic quaternary bases
- t APR 1967.
2 C
(e.g. a tetrabutylamraonium sale) or organic tertiary bases, e.g. triethylamine, N-ethylpiperidine, benzyldiethylamine, pyridine or quinoline.
The condensation according to process b) can also be carried out under the conditions of reductive alkylation of amines in the manner generally known and used in the art. A compound of formula V, in which Z represents oxo and X, Ar, and n have the meanings given herinabove, is used as the alkylating agent and is reacted with the starting amine IV and simultaneously or in a subsequent step, with a reducing agent. Among reducing agents which are used simultaneously with the alkylating agent, mention should be made of complex metal hydrides such as sodium cyanoborohydride; among reducing agents used predominatly in a separate subsequent operation, mention should be made of diborane and complex metal hydrides, such as sodium borohydride and sodium cyanoborohydride, which are applied advantageously to the primary reaction mixture without isolating an intermediate. In this case, the alkylation is carried out advantageously in an organic solvent inert to the reducing agent,
such as an aliphatic or cyclic ether (e.g. diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran) or an aliphatic alcohol (such as methanol, ethanol, isopropyl alcohol, glycol, glycol monomethyl ether or diethyleneglycol), preferably at about 0° - 80°C. However, a principal reducing agent which can be used both simultaneously and subsequently, is hydrogen, especially catalytically activated hydrogen. The catalysts are those conventionally used as hydrogenation catalysts, i.e. preferably those of the class of precious metal (such as palladium, platinum and rhodium) on a carrier (such as carbon black, calcium carbonate, aluminium oxide or barium sulfate), in a finely dispersed suspension without carrier or, in form of complexes, in a homogeneous phase. Also, finely dispersed transition metals such as Raney nickel, are very suitable catalysts for the reductive alkylation. The specific reaction conditions depend,
..v.: i m
205509
to a large extent, on the particular hydrogenation catalyst and its specific activity, and do not differ from those generally known for hydrogenation. Temperatures ranging from room temperature to about 150°C, and pressures of hydrogen ranging from atmospheric pressure to about 300 atmospheres are applicable according to the standard procedures of the art. In addition to the inert solvents which were mentioned above in connection with the hydride reduction, low-molecular amides, especially tertiary amides (such as N,N-dimethyl-formaxnide, N,N-dimethylacetamide, N-methylpyrrolidone, N-ethyl-piperidone, and hexamethylphosphoric acid triamide), also formamide and acetamide can be used as suitable solvents. Special measures have to be taken with starting materials of formula V in which X respresents S; since most hydrogenation catalysts are deactivated by sulfur compounds, other reducing agents (such as complex metal hydrides mentioned hereinabove, especially sodium cyanoborohydride) are preferred in this case.
The starting amines of formula IV are known compounds. The novel starting materials of formula V can be obtained according to conventional synthetic methods, e.g. from a compound of formula X
wherein R^, -B-r X and Ar have the meanings given hereinabove, and R represents hydrogen or lower alkyl, to give compounds of formula V wherein Z represents oxo or Z represents hydrogen together with reactive esterified hydroxy.
y~\-cn
\ / 2\
CH-COOR
Ar-X-CH2
(X)
Intermediates of formula X are advantageous1]
205539
a compound of formula VIII with a compound of formula Ar-XH vherein X represents 0, S or N-lower alkyl or e.g. an alkali metal salt thereof, under standard conditions of Michael addition. Compounds of formula X are reduced to compounds of formula V vherein Z represents hydrogen together with a hydroxyl group according to well-known conventional procedures, especially with compolex metal hydrides under standard conditions. Reduction of compounds of formula X with e.g. diisobutyl aluminium hydride also yields the aldehydes having formula V wherein Z represents oxo. Alternatively, the aldehydes may also be obtained by oxidation of the above compounds of formula V, wherein Z represents hydrogen together with a hydroxyl group, with pyridinium dichromate in methylene chloride. If starting materials are required in which Z is hydrogen together with a reactive esterified hydroxyl group, the free hydroxyl group is converted into its reactive esterified form by conventional processes used for the esterification with strong acids, e.g. for the halides, by reacting with conventional halogenating agents mentioned hereinabove in connection with the preparation of analogous starting materials of formula II.
Process c) can also be carried out in the manner generally known for the reduction of amides to amines. In the starting materials, one or two carbon atoms adjacent to the nitrogen atom can carry an oxo group forming an amide or imide grouping. Starting materials for this process are represented by the formula XI
205509
- 23
in which X, Ar, and R3 have the meanings given hereinabove,
and the other one represents oxo or two hydrogen atoms. The reduction is carried out with a conventional appropriate reducing agent, e.g. preferably, a complex metal hydride such lithium aluminium hydride or borane.
Starting materials of formula XI are new and can be prepared by processes which are in themselves known. Thus, compounds of formula
XI wherein X is oxo and X represents two hydrogens are prepared a b by the simple amidation of an intermediate of formula X specified hereinabove with an amine of formula IV specified hereinabove. Starting materials of formula XI, in which X represents two hydrogens and a
X^ is oxo, can be obtained e.g. by acylation of a compound of formula I in which at least one of and R2 represents hydrogen,
with a reactive derivative of an alkanoic acid, e.g. acetyl chloride.
Process d) can also be performed in a manner per se known, and under conventional conditions. The double bond in the starting materials for process d) can be located either between the nitrogen atom and one adjacent carbon atom or between two carbon atoms. Thus, a carbon bond may be positioned between the nitrogen atom and any one of the neighbouring carbon atoms, and an additional carbon-to-carbon double bond can be placed on the central carbon atom. Also, starting materials can be used having solely a carbon-to-carbon double bond, which joins the central carbon atom to any of the three adjacent carbon atoms. Starting materials for process d) ar- —-— —<—J 1—
R^ is hydrogen or lower alkyl of one less carbon atom than Rp or R^ and R^ are joined together to form a five- or six-membered heterocyclic ring; and one of the symbols X^ and X^ represents oxo
L'■ u o I
- 21* -
*3
V~\
\ >_CHv
^C-CH-N-Rj (XIla)
Ar-X-CtT
wherein R^, R^» i*t Ar and X have the meanings given hereinabove, and the dotted lines indicate one optionally present double bond, or by the formula Xllb
R3
^ )-c\
«"• \«L , . . ,
^^-^CH-N-R (Xllb)
Ar-X-CK
wherein R^, Ar and X have the meanings given hereinabove, R^ represents a lower alkylidene residue and the dotted lines indicate one optionally present double bond, or by the formula XIII
Rv-\
A
• c~—ch-nf (XIII)
Ar-X-Cli 2
wherein R^, R2> R^» Ar and X have the meanings given hereinabove and the dotted lines indicate one double bond.
Process e) can be carried out in a manner generally known in the art, especially under conditions for removing amino-protecting groups. Suitable protecting groups, as well as procedures for their introduction and removal are well known in the art, being elaborated in great detail in particular as general methods for the synthesis of peptides; e.g., see Houben-Weyl: Methoden der Organischen
2n5'3 9
4th edition, vol. 15/1 and II, E. Wunsch (editor): Synthese von Peptiden (Ceorg Thieme Verlag, Stuttgart, 1974).
Suitable as amino-protecting groups (Rq) are especially amino-protecting groups that can be removed by reduction, for example, especially the benzyl or benzyloxycarbonyl groups which may be substituted in the aromatic moiety by halogen, lower alkoxy, lower alkyl radicals and, especially, by nitro groups, or alternatively the amino protecting group is isonicotinyloxycarbonyl.
The benzyl, the benzyloxycarbonyl and isonicotinyloxycarbonyl protecting groups are in general smoothly removed by hydrogenolysis, especially by hydrogenation over a precious metal catalyst in a well-established manner. Those groups that contain isonicotinyl radicals (for example isonicotinyloxycarbonyl) and, especially, substituted benzyl radicals especially 4-nitrobenzyl radicals of any kind, are preferably removed by reduction with zinc, usually in the presence of an acid, preferably acetic acid, and with or without the addition of an inert organic solvent, usually at room temperature.
It is also possible to use groups that can be removed by acidolysis, such as cyano, the tert-butoxycarbonyl groups and analogous groups as well as those of the aralkyl type, such as benzhydryl, di-(4-methoxy)-benzhydryl and triphenylmethyl (trityl), or certain aralkoxycarbonyl groups of the 2-(p-biphenylyl)-2-propoxycarbonyl type, which are described in British Patent Specification No. 1,218,251. The removal of a protecting group by acid hydrolysis (acidolysis) is carried out in the case of groups of the tert-butyl type by means of such acids as hydrogen chloride, hydrogen fluoride or trifluoro-acetic acid, and in the case of acid-sensitive protecting groups chiefly by means of a lower aliphatic carboxylic acid, such as formic acid and/or acetic acid, in the presence of water, and, --'-'"V
, ; F «
optionally, a polyhalogenated lower alkanol or lower alkanone, suply' as l,l,l,3,3,3-hexafluoropropan-2-ol or hexafluoroacetone. In /.
205308
26
this manner it is possible, for example, for an N-trityl group to be removed by an organic acid, such as foroiic acid, acetic acid, chloroacetic acid or trifluoroacetic acid, in aqueous or absolute trifluoroethanol as solvenc (cf. Bricish Patent No.1,448,371)
or bv aqueoues acetic acid; for the tert-butoxycarbonyl group to be removed by trifluoroacetic acid or hydrochlorid acid; and for the 2-(j>-biphenylyL)-isopropoxycarbonyl group to be removed by aqueous acetic acid or, for example, by a mixture of glacial acetic acid, formic acid (82.8 Z strength) and water (7:1:2), or in accordance with the process in GB P. No. 1,448,371. An advantageous amino-protecting group R^ is also the ethoxycarbonyl group which carries in the (3-position a silyl group substituted by three hydrocarbon radicals, such as triphenylsilyl, dimethylbutylsilyl or especially, trimethylsilyl. A p-(trihydrocarbylsilyl)-ethoxycarbonyl group of this type, such as a (3-(tri-lower alkylsilyU-ethoxycarbonyl group, for example, especially /3-(trimethylsilyl)-ethoscycarbonyl,
forms with the amino group to be protected a corresponding (B-tri-hydrocarbylsilyl-ethoxycarbonylamino group (for example the (3-tri-methylsilylethoxycarbonylamino group), and is preferably removed by fluoride ion-yielding reagents, for example fluorides of quaternary organic bases, such as tetraethylamraonium fluoride. The cyano group is preferably removed by hydrolysis with a strong mineral acid, e.g. concencrated hydrochloric acid according to Chem. Ber. 68. 2291 (1935).
The starting materials for process e), i.e. the compounds of formula VI specified above, are new. They are prepared in a manner described in particular hereinabove in previous processes, advantageously process a) the only difference being that starting materials are used in which the nitrogen of the group —NR^R^ bears the amino-
protecting group R in place of the radical R, .
o I
Process f) is carried out by well-known hydrogenation procedures for the reduction of nitriles and azides, e.g. in the presence /■ t i •' 3
of ammonia, or by treatment with a simple or complex metal hydride, such as alane.
The starting materials are advantageously accessible, e.g. for compounds wherein T represents cyano, by condensation of an a-benzyl-acrylonitrile of formula XIV
wherein has the meaning as previously defined, with a compound of formula ArXH wherein X represents 0, S or N-lower alkyl or e.g. an alkali metal derivative thereof, under standard condition of a Michael addition.
Process g) can be carried out by well-known organometallic coupling procedures starting with an organometallic compounds of formula VIIA VIIB wherein M or Q is a metal radical, e.g. aluminium, magnesium, an alkali metal such as lithium, zinc, zirconium or copper or wherein M or Q is a halometal radical e.g. halomagnesium such as chloromagnesium, optionally in the presence of a transition metal catalyst, especially a salt, e.g. a halide of chromium, manganese, iron, cobalt or nickel, e.g. as described in Comprehensive Organometallic Chemistry Vol. 2_, 754, ibid Vol. 8^ 738, Tetrahedron 31, 2735 (1975). In the organometallic compounds VIIA and VIIB the number of organic radicals attached to the metal group M or Q corresponds to the valency of the metal used.
(XIV)
R
3
The condensation of the organometallic reagent with a compound of formula VIIA or VIIB wherein M or Q represents a leaving group, e.g. a reactive esterified hydroxyl group [as described for process
2 055 0
a)] is carried ouc advantageously in an inert solvent such as ethers, e.g. diethyl ether, tetrahydrofuran or dimethoxyethane or hydrocarbons, e.g. toluene at a temperature ranging from about -75°C to about +50°C, in an inert atmosphere and under anhydrous conditions.
The organometallic reagent is preferably prepared in situ by methods known in the art, e.g. that of formula VII B wherein M is e.g.
lithium can be obtained by treatnent of the appropriate optionally substituted toluene with e.g. lithium diisopropylamide. The organometallic reagent of formula VIIB wherein M is halomagnesium (a Grignard reagent) can be obtained by treatment of the optionally substituted benzyl halide with magnesium, e.g. as described in Organic Synthesis coll. Vol. I. 471 (1941).
The isolation of the desired compound of formula I is carried out using standard separation procedures, e.g. fractional distillation or crystallization, thin-layer chromatography and high-pressure liquid chromatography.
The compounds of the invention obtained by any of the methods described above can be converted into each other according to conventional methods known to the art, and e.g. as illustrated herein.
Compounds of formula I wherein R^ and/or represent(s) hydrogen, may be converted to the compound of formula I wherein R^ and/or represent(s) lower alkyl, by reaction with a reactive esterified lower alkanol, e.g. with a lower alkyl halide, thereby preferably isolating the resulting compound of formula I as the corresponding acid-addition salt, or by reductive alkylation, e.g. with formaldehyde and formic acid to yield the compound of formula I wherein R^ and/ or R^ represents methyl.
2 0 550?
Compounds of formula I wherein and represent lower alkyl, advantageously methyl, can be converted to compounds of formula I wherein or R2 represent hydrogen by catalytic air oxidation, e.g. with palladium on charcoal using an alcohol such as methanol as the solvent, preferably at room temperature, or by reacting with lower alkyl haloforraates, e.g. ethyl chloroformate, to yield N-acyl derivatives which, in turn may be hydrolyzed to said unsubstituted compounds, those with R^ or R2 " H, for example with a base, such as an alkali metal hydroxide, e.g. an aqueous or hydroalcoholic solution of sodium hydroxide.
Compounds of formula I wherein R^ and/or R2 is methyl can be prepared by reacting the corresponding compounds of formula I wherein and/or R^ represents hydrogen with lower alkyl- or phenyl lower alkyl-haloformates, such as ethyl chloroformate, to obtain compounds of formula I wherein R^ or R2 is alkoxycarbonyl or phenylalkoxy-carbonyl, and reducing said acyl derivatives with simple or complex light metal hydrides such as lithium aluminium hydride, sodium tri-t-butoxyaluminium hydride or sodium bis-(2-methoxyethoxy) aluminium hydride.
Unsaturated compounds, such as those bearing an alkenyl or alkynyl radical, may be hydrogenated with catalytically activated hydrogen to obtain compounds of formula I or intermediates bearing the corresponding alkyl radical.
With reference to the above reactions, it may be advantageous to appropriately protect the potentially reactive, e.g. amine, carboxy or other interfering substituents in accordance with protective techniques well known to the art, e.g. as illustrated below, such that interfering reactions are avoided, by protecting such substituents prior to the desired reaction and subsequently, if necessary removing the protective groups to obtain the desired compounds, e.g. of
205509
formula I, or intermediates.
For instance, a free basic amino group, the group -NR^R^ bearing at least one hydrogen on nitrogen, may be protected in the form of easily cleaved amides, e.g. as acyl derivatives such as the benzyloxycarbonyl (carbobenzyloxy) or the t-butyloxycarbonyl derivatives, or any other easily removable N-protecting group as previously described.
Similarly a carboxy group may be protected in the form of an easily cleaved ester, e.g. the benzyl ester, the t-butyl ester, and the like as commonly used.
In a resulting protected compound of formula I or intermediate, in which one or more of the functional groups are protected, the protected functional groups, e.g. amino or carboxy groups can be liberated, in a manner, known per se, e.g. by means of solvolysis, especially hydrolysis with acid, or by means of reduction, especially hydrogenolysis.
The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert ot the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperature, preferably at the boiling point of the solvents used, at atmospheric or superatmospheric pressure.
The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions or in which the reaction components are used in the form of their
? ° 55 0
salts or optically pure antipodes. Whenever desirable, the above processes are carried out after first suitably protecting any potentially interfering reactive functional groups, as illustrated above and in the examples herein.
Advantageously, those starting materials should be used in said reactions, that lead to the formation of those compounds indicated above as being especially preferred.
The invention also relates to novel starting materials and processes for their manufacture.
Depending on the choice of starting materials and methods, the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as pure geometric isomers (cis or trans), as pure optical isomers (as antipodes), or as mixtures of optical isomers such as racemates, or as mixtures of geometric isomers.
In case geometric or diastereomeric mixtures of the above compounds or intermediates are obtained, these can be separated into the single racemic or optically active isomers by methods in themselves known, e.g. by fractional distillation crystallization and/or chromatography. The racemic products of formula I or basic intermediates can be resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, such as according to J. Org. Chem. 43, 3803 (1978), e.g., by the fractional crystallization of d- or l-(tartrate, mandelate or camphorsulfonate) salts. Any acidic intermediates can be resolved by separation of e.g. the d- and l-(a-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychnine)-salts of any compounds having an acidic salt-forming group.
20550
Advantageously, the more active of the antipodes of the compounds of this invention is isolated.
Finally, the compounds of the invention are either obtained in the free form, or as a salt thereof. Any resulting base can be converted into a corresponding acid addition salt, preferably with the use of a pharmaceutically acceptable acid or anion exchange preparation, or resulting salts can be converted into the corresponding free bases, for example, with the use of a stronger base, such as a metal or ammonium hydroxide, or any basic salt, e.g., an alkali metal hydroxide or carbonate, or a cation exchange preparation. These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for the crystallization.
The present invention additionally relates to the compounds of the formula I and their pharmaceutically acceptable, non-toxic acid addition salts for use as medicaments, especially for their use for the preparation of pharmaceutical compositions, especially compositions having serotonin-uptake inhibiting activity, particularly antidepressant activity.
The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, and parenteral
20550
administration to mammals, including man, comprising an effective amount of a pharmacologically active compound of formula I, or pharmaceutically acceptable salts thereof, alone or in combination with one or more pharmaceutically acceptable carriers.
The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or poly-ethyleneglycol; for tablets also binders, e.g. magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose,
sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired, disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or absorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, the compositions may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively and contain about 0.1 to 75 %, preferably about 1 to 50 %, of the active ingredient.
More specifically, the invention relates advantageously to the method of treatment of psychotropic disorders, especially depression. The dosage of active compound administered is dependent on the. species of warm-blooded animal,the body weight, age and individual
2055
condition, and on the form of administration. A unit dosage for a mammal of about 50 to 70 kg may contain between about 10 and 100 mg of the active ingredient.
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and 100 mm Hg.
Example 1: A mixture of 2-benzyl-3-dimethylaminopropanol (4.2 g), dicyclohexylcarbodiimide (4.6 g) and cuprous chloride (0.2 g) is maintained at 80° for 40 hours. 4-Trifluoromethylphenol (5.0 g) is added, and the mixture maintained at 130° for 12 hours. The reaction mixture is cooled and ether (100 ml) is added. The insoluble material is filtered off and the filtrate extracted with 2 N hydrochloric acid (3 x 100 ml). The acidic solutions are combined and made basic by the addition of concentrated aqueous ammonia. The aqueous solution is extracted with ether (3 x 150 ml), and the combined extracts dried over magnesium sulfate and evaporated under reduced pressure to give the ether as a yellow oil. This material is converted to the oxalate salt by dissolving in ether and adding the calculated quantity of oxalic acid dihydrate in ether. Filtration gives N,N-dimethyl-2-benzyl-3-(4-trifluoromethylphenoxy)-propylamine oxalate, m.p. 147 - 149°.
The starting material is prepared as follows:
A solution of 30.0 g of methyl a-benzylacrylate, prepared by the method of R.B. Miller and B.F. Smith, Synth. Commun. 3^ 359 (1973) in methanol (50 ml) is added to a solution of dimethylamine (71.0 g) in methanol (210 ml), and the mixture is stirred at room temperature
20550
for 48 hours. The solvent is removed under reduced pressure to give methyl 2-benzy1-3-dimethylaminopropionate as a yellow oil, used without purification in the next synthetic step; NMR^7.14 (s, 5H), 3.52 (s, 3H), 2.82 (m, 3H), 2.17 (s, 6H), 2.63 - 2.17 (m,
remaining H).
A solution of methyl 2-benzyl-3-dimethylaminopropionate (60.0 g) in ether (300 ml) is added dropwise with stirring under a nitrogen atmosphere to a suspension of lithium aluminium hydride (28.0 g)
in ether (700 ml). The reaction mixture is refluxed for 4 hours, then stirred at room temperature for 18 hours. The reaction mixture is cooled to 0°, and water (30 ml) is added cautiously (dropwise initially) followed by 10 Z NaOH (60 ml). The solid inorganic material is filtered off, and the filtrate dried over magnesium sulfate. The solvent is removed under reduced pressure to give 2-benzyl-3-dimethylaminopropanol as an oil which is used without further purification; NMlUCDCl^) / 7.12 (m, 5H), 5.62 (broad s, 1H), 3.57 (m, 2H).
Example 2: A mixture of 2-(3-chlorobenzyl)-3-dimethylaminopropanol (5 g), 4-methylmercaptophenol (3.3 g), and dicyclohexylcarbodiimide (4.5 g) is maintained at 180° for 72 hours. The reaction mixture is cooled to room temperature and ether (100 ml) and 1 N hydrochloric acid (120 ml) are added. The layers are separated and the aqueous solution is extracted with more ether (100 ml), made basic by the addition of concentrated ammonia, and extracted with ether (2 x 100 ml). These latter combined ether solutions are dried over potassium carbonate, and the solvent removed under reduced pressure. Treatment of the resulting oil with oxalic acid in ether yields N,N-dimethyl-2-(3-chlorobenzy1)-3-(4-methylmercaptophenoxy)-propylamine oxalate, m.p. 122 - 124°.
205509
Example 3: The following compounds of formula I, isolated and characterized as the oxalate salt are prepared essentially according to the procedures illustrated in Examples 1 and 2 (Me - methyl: Ph ■ phenyl)
Ex.
R1
R2
R3
Ar
X
m.p. (°C) of
1
J
oxalate salt
3/1
Me
Me
H
3-OMe-Ph
0
85-88 (dec)
3/2
Me
Me
H
4-SMe-Ph
0
128-130
3/3
Me
Me
H
2-Cl-Ph
0
91-93 (dec)
3/4
Me
Me
H
4-Cl-Ph
0
133-136 (dec)
3/5
-
(ch2)5~
H
4-OMe-Ph
0
139-141
3/6
Me
Me
H
3-Cl-Ph
0
112-114
3/7
Me
Me
H
4-Me-Ph
0
115-117
3/8
Me
Me
H
3-Me-Ph
0
94-97
3/9
Me
Me
H
4-OMe-Ph s
124-127
3/10
Me
Me
H
3-CF3~Ph
0
97-99
3/11
Me
Me
H
3-OMe-Ph s
94-97
3/12
Me
Me
H
3,5-di-OMe-Ph
0
106-108
3/13
Me
Me
H
3-(OCH2CH=CH2)-Ph
0
110-112
3/14
Me
Me
4-C1
4-SMe-Ph
0
114-116
3/15
Me
Me
3-C1
4-CF^-Ph
0
138-140
3/16
Me
Me
H
4-OMe-Ph
0
108-111
[ (dec) = decomposition]
The novel starting materials are prepared as follows:
a) Ethyl a-(chlorobenzyl)acrylates are prepared as described below:
A solution of potassium hydroxide (26 g) in absolute eth«JlHil"(,375 ml)
is added during 30 minutes to an ice-cold solution of diethyl
E N
chlorobenzylmalonate (112 g) in absolute ethanol (375 ml),
a
2 4 MAR 1987
J
55
solution is stirred at room temperature for 18 hours, and the solvent removed under reduced pressure. The residue is dissolved in water (1200 ml) and the solution cooled in an ice-baeh. Concentrated hydrochloric acid (29 ml) is added, and the solution extracted with ether (2 x 350 ml). The combined ether solutions are washed with water (250 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give as an oil, 3-chlorobenzylmalonic acid monoethyl ester; NMR (CDCl^^: 10.13 (s, 1H), 7.2 (m, 4H), 4.15 q, 2H), 3.5 (m, 3H), 1.21 (t, 3H).
Diethylamine (27.6 g, 39 ml) is added dropwise with shaking to 3-chlorobenzylmaIonic acid monoethyl ester (90.0 g) [Chem. Ber. 92, 203 (1959)], in a flask cooled in a water bath. Aqueous formaldehyde (37 Z, 38 ml) is added dropwise with shaking and cooling as before. Gas is evolved, and the reaction mixture becomes lighter in color. The mixture is stirred at room temperature for 65 hours, then water (500 ml) is added, and the solution extracted with ether (2 x 350 ml). The combined ether solutions are washed with water (300 ml), 3 N HC1 (2 x 200 ml) and water (300 ml). The ether solution is dried over magnesium sulfate, and the solvent removed under reduced pressure to give ethyl a-(3-chlorobenzyl)acrylate as a yellow oil, NMR (CDC13)</: 7.15 (m, 4H), 6.22 (s, 1H), 5.45 (m, 1H), 4.13 (q, 2H), 3.58 (s, 2H), 1.23 (t, 3H).
Ethyl a-(4-chlorobenzyl)acrylate is prepared by a similar procedure starting with diethyl 4-chlorobenzylmalonate (J.Med. Chem. _17, 732 (1974): NMR (CDC13) : 7.15 (m, 4H), 6.17 (s, 1H), 5.38 (m, 1H), 4.11 (q, 2H), 3.55 (s, 2H), 1,20 (t, 3H).
b) The following esters are prepared essentially according to the method illustrated in Example 1 under the reaction conditions indicated.
2 0 55
0
3V~%
\ >"cv
RCx/ II
:ch-ch2-n(^1
R1 R2
R3
R
Reaction Conditions
-(CH2)s-
H
Me
Refluxing methanol, 18 hours
■ N,
EC Me
H
Me
Refluxing methanol, 6 days
PhCH2 Me
H
Me
Refluxing methanol, 4 weeks
Me Me
4-C1
EC
Methanol, room temperature, 18 hours
Me Me
3-C1
EC
Methanol, room temperature, 24 hours
H Me
H
Me
Methanol, room temperature, 48 hours
c) The following alcohols are prepared essentially according to the
method illustrated in
Example
1.
"V.
O1
V
\
• :
)-CH2N /l
CH-CH -Nf ho-ch2 r2
r1 R2
R3
NMR ( /, For OH)
-<ch2) -
h
.8
Et Me h
6.1
(,.w.
PhCH2 Me h
.0
Me Me
4-c1
.6
Me Me
3-c1
.6
2 0 : 5
Example 4: A solution of N-carbethoxy-N-methyl-2-benzyl-3-(4-tri-fluoromethylphenoxy)propylamine (25.0 g) and potassium hydroxide (25.0 g) in isopropanol (200 ml) is refluxed for 48 hours. The reaction mixture is cooled to room temperature, and the solvent removed under reduced pressure. Water (250 ml) is added, and the mixture extracted with dichloromethane (2 x 150 ml). The combined dichloromethane solutions are washed with water (150 ml), dried over magnessium sulfate, and the solvent removed under reduced pressure to give an oil. This material is dissolved in ether (500 ml) and dry hydrogen chloride is bubbled in until no further precipitation occurs. The solid is filtered off, washed with ether (250 ml) and dried to give N-methyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine hydrochloride, mp 161-162°, the compound of formula 1 wherein R^ is methyl, R^ and R^ are hydrogen and Ar is 4-trifluoromethylphenyl. The oxalate salt, prepared in the standard way, has m.p. 173 - 175°.
The starting material is prepared as follows:
A solution of N,N-dimethyl-2-benzyl-3-(4-trifluoromethylphenoxy)-propylamine (22.0 g) and ethyl chloroformate (34.1 g, 30.0 ml) in dry toluene (200 ml) is refluxed for 72 hours. The reaction mixture is cooled to room temperature, and the solvent removed under reduced pressure. Water (200 ml) is added, and the mixture extracted with dichloromethane (2 x 150 ml). The combined dichloromethane extracts are washed with 2 N hydrochloric acid (200 ml) and water (200 ml), and dried over magnesium sulfate. The solvent is removed under reduced pressure to give N-carbethoxy-N-methyl-2~benzyl-3-(4-trifluorome thylphenoxy)propylamine as an oil, which is used without purification for the next synthetic step above.
Example 5: A solution of N-benzyl-N-methyl-2-benzyl-3-(3-methoxy-phenoxy)propylamine (0.7 g) in ethanol (100 ml) is hydrogenated at
room temperature and atmospheric pressure until uptake ceases,
using 10 Z palladium on charcoal (2.0 g) as catalyst. The catalyst is filtered off (Hi-flo) and the solvent removed under reduced pressure to give N-methyl-2-benzyl-3-(3-methoxyphenoxy)propylamine as an oil, which is converted with oxalic acid in ether to N-methyl-2-benzyl-3-(3-methoxyphenoxy)propylamine oxalate, m.p. 127-129°.
The starting material as the oxalate salt, prepared by procedure of example 2, has melting point of 79 - 81°.
Example 6: The following compounds of formula I wherein represents hydrogen and X represents 0, isolated and characterized as the oxalate salt, are prepared similarly to the compounds of example 4 and 5 essentially according to the procedures described therein (Me ■ methyl, Ph ■ phenyl)
Example
Ar m.p. (°C) of oxalate salt
6/1 6/2 6/3
Me Me Me
H H
3-C1
4-OMe-Ph 4-SMe-Ph 4-SMe-Ph
142 - 144 172 - 174 177 - 179
A starting material for example 6/1 is N,2-dibenzyl-n-methyl-3-(4-methoxyphenoxy)propylamine oxalate, m.p. 147 - 149°.
Example 7; Sodium hydride (4.2 g of 50 % mineral oil dispersion) is washed with petroleum ether (3 x 100 ml) and dried under a stream of dry nitrogen. Dimethylformamide (65 ml, dried with 4A molecule sieves) is added. A solution of 2-benzyl-3-dimethylaminopropanol
(14 g) in dry dimethylformamide (30 ml) is added with «-fr*«xing.t
Stirring is maintained for 10 minutes at room temperature,
at 55° for 1 hour. A solution of 4-fluorobenzotrifluoride
2 4 MAR 1987
' "" 0
in dry dimethylformamide (25 ml) is added dropwise, and the reaction mixture is stirred at 60° for 6 hours, and then at room temperature for 18 hours. Water (300 ml) is added, and the solution extracted with ether (2 x 200 ml). The combined ether solutions are extracted with 3 N hydrochloric acid (2 x 150 ml). The combined acidic extracts are washed with ether (200 ml), and made basic by the addition of concentrated aqueous ammonia. The aqueous solution is extracted with ether (2 x 250 ml), and the combined ether solutions washed with water (100 ml), and dried over magnesium sulfate. The solvent is removed under reduced pressure to give N,N-dimethyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine, identical to the compound of Example 1, which may be converted to N,N-dimethyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine oxalate as described in Example 1.
Example 8: A mixture of 10 Z palladium on charcoal (2.0 g) and N,N-dimethyl-2-benzyl-3-(2-methoxyphenoxy)propylamine (2 g from oxalate salt melting at 76 - 79° dec.) in methanol (300 ml) is stirred at room temperature in an open flask for 18 hours. The catalyst is filtered off and the solvent removed under reduced pressure. The residual oil is converted with an equivalent amount of oxalic acid in ether to N-methyl-2-benzyl-3~(2-methoxyphenoxy)-propylamine oxalate, m.p. 135 - 139°.
Example 9:
A solution of N-methyl-N-acetyl-2-benzyl-3-(4-methylthiophenoxy)-propylamine (12.6 g) in dry ether (100 ml) is added dropwise to a stirred suspension of lithium aluminium hydride (4.0 g) in dry ether (250 ml). The reaction mixture is refluxed for 18 hours, and cooled to 0°. Water (3 ml) is added cautiously, followed by 15 %
sodium hydroxide (3 ml), and water (9 ml). The inorganic salts are filtered off, washed with ether (150 ml) and the combined ether solutions are dried over magnesium sulfate. The solvent is removed under reduced pressure to give N-methyl-N-ethyl-2-benzyl-3-(4-
2 0" 0
methylthiophenoxy)propylamine. M.p. 98 - 100°.
The starting material is prepared as follows:
Treatment of N-methyl-2-benzyl-3-(4-methylthiophenoxy)propylamine with acetyl diloride at room temperature in dichloromethane in the presence of triethylamine yields N-methyl-N-acetyl-2-benzyl-3-(4-methyIthiophenoxy)propylamine.
Example 10: A solution of N,N-dimethyl-2-benzyl-3-(4-methylthio-phenoxy)propylamine (3.0 g) in methanol (350 ml) is added dropwise under nitrogen during 30 minutes to a solution of sodium periodate (4.8 g) in water (160 ml). After the addition is complete, the reaction mixture is stirred at room temperature for 4 hours, added to water (500 ml) and extracted with ether (2 x 250 ml). The combined ether solutions are dried over potassium carbonate, and the solvent removed under reduced pressure to give an oil. Treatment with an equivalent amount of oxalic acid in ether followed by recrystallization of the resulting salt from methanol/ether (3 x) gives N,N-dimethyl-2-benzyl-3-(4-raethylsulfinylphenoxy)propylamine oxalate, m.p. 112 -115°.
Example 11: The following compounds of formula I are prepared essentially according to the procedures illustrated in the previous examples
2»5509
Compound NR^R2
X
R3
Ar salt
m.
.p.
ii/i N(CH3)2
0
H
2"CH3OC6H4
oxalate
76
-
79° dec.
11/2 N(CH3)2
0
H
C6H5
oxalate
120
-
122°dec.
11/3 N(CH3)2
0
H 3
,4-CH2°2C6H3
oxalate
118
-
120°
11/4 N<CH3)2
0
H
3"CH3SC6H4
oxalate
125
-
129®
11/5 N(CH3)C2H5
0
H
3-CH30C6H4
oxalate
56
-
©
GO
11/6 N(CH3>2
0
3-C1
4-CH3S-C6h,
oxalate
106
-
108°
11/7 11/8 11/9
nhch3 n(ch3>2
n(g2ii5)2
0
N-CH,
—e—
H H
-H-
C6H5
4-CH_0C,H. 3 6 4
~er#
HC1 oxalate H€i
136 - 138° 118 - 120° -KH!
6 5
The starting materials are prepared as described in the previous examples.
Methyl 2-benzyl-3-dimethylaminopropionate (see example 1) is also advantageously prepared as follows:
Liquid dimethylamine (500 g) is added to 1800 ml of methanol cooled to -35°. A solution of 500 g of methylacrylate in 850 ml of methanol is then added keeping the temperature between -50° and -60°. The reaction mixture is kept at -50° to -60° for 2 1/2 hours and then at room temperature overnight. The solvent is removed in vacuo and the residue is distilled under reduced pressure to give methyl 3-dimethylaminopropionate b.p. 60 - 70°/16 mm Hg.
A solution of 101 g of diisopropylamine in 200 ml of tetrahydrofuran is cooled to -78° under nitrogen. 2.1 M n-butyllithium in tetrahydrofuran (470 ml) is added dropwise keeping the temperature at -78°.
f
I |
\ i i
t
I
i
I
2 o r : 9
The reaction mixture is stirred for 1/2 hour at the same temperature, a solution of 179 g of hexamethylphosphoramide in 200 ml of tetrahydrofuran is added and stirring is continued for 1/2 hour at -78°.
At the same temperature a solution of 125 g of methyl N,N-dimethylamino-propionate in 200 ml of tetrahydrofuran is then added dropwise and stirring is continued for 20 minutes. A solution of 171 g of benzyl-bromide in 300 ml of tetrahydrofuran is then added, again at -78°.
The solution is stirred at this temperature for 2 hours and then quenched, first with 250 ml of saturated aqueous ammoniumchloride and then 250 ml of saturated aqueous sodium chloride solution. To this is added 1500 ml of ether. The layers are separated and the aqueous layer is extracted with 4 x 200 ml of ether. The ether extract is dried over magnesium sulfate and evaporated to dryness. The resulting oil is redissolved in 300 ml of ether, the ether solution is washed with 100 ml of water and the aqueous layer is reextracted with 3 x 100 ml ether. The combined ether solutions are dried over magnesium sulfate and evaporated to dryness to yield an oil which is purified by fractional distillation to yield pure methyl 2-benzyl-3-dimethylaminopropionate, b.p. 104°/0.2 - 0.4 mm Hg.
Example 12: Compounds of the previous examples are tested for their ability to block the uptake of tritiated serotonin into synaptosomal nerve endings from rat whole brain in vitro essentially by the method of Thornburg and Moore as described in Res. Comm. Chem.
Pathol. Pharmacol. .5, 81 (1973). The preincubation period of the test compound (added in ethanol solution) with the whole brain synaptosome suspension in Krebs buffer is 5 minutes. The incubation
.3
period, following the addition of tritiated serotonin ( H-5—HT) to a final concentration of about I x 10 ''m, is 4 minutes. The concentration of test agent required to inhibit serotonin uptake by 50 % of control value,i.e. the is determined graphically and expressed in micromolar concentration.
r
The concentration of test agent required to inhibit norepinephrine
(NE) uptake by 50 7. of the control value, i.e., the lC-n is similarly
3
determined using tritiated norepinephrine ( H-NE) and is also expressed in micromolar concentration.
Compound 5—HT Uptake Inhibition NE Uptake Inhibition of Example *^50 ^50
1
0.49
.25
2
0.03
.0
3/1
0.43
4.3
3/2
0.27
.8
3/3
1.3
.3
3/4
1.49
12.0
3/5
6.1
39.5
3/6
2.7
16.1
3/7
1.22
12.5
3/8
1.25
3.25
3/9
1.53
8.1
3/10
2.25
6.9
3/11
1.95
7.6
3/12
1.52
4.3
3/13
1.59
1.44
3/14
0.67
7.1
3/15
6.0
32.0
3/16
0.56
0.57
4
0.39
12.6
0.94
1.39
6/1
0.44
1.25
6/2
0.14
2.5
6/3
2.7
11.0
8
.4
8.9
Example 13: Preparation oE 10,000 tablets each containing 10 mg of the active ingredient of Example 4:
Formula:
N-Methyl-2-benzyl-3-(4-trifluoromethylphenoxy)-propylamine hydrochloride
Lactose Corn Starch
Polyethylene glycol 6,000 Talcum powder Magnesium stearate Purified water
Procedure:
All the powders are passed through a screen with openings of 0.6 mm Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 150 ml of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35, broken on a screen with 1.2 mm openings and compressed into tablets using concave punches with 6.4 mm diameter, uppers bisected.
Example 14: Preparation of 10,000 capsules each containing 25 rag of the active ingredient of Example 4:
100.00 g
1,157.00 g 75.00 g 75.00 g 75.00 g 18.00 g q.s.
Claims (24)
1. A compound of the general formula I "3 A — CH-CH2-N^ (I) Ar-X-CH2 K2 wherein and independently of the other represent hydrogen or lower alkyl; or and R2 together with the adjacent nitrogen atom represent piperidino or pyrrolidino or a five- or six-membered saturated heterocyclic ring containing NH, N-lower alkyl, 0 or S; R^ represents hydrogen, lower alkyl, lower alkoxy, halogen or tri-fluoromethyl; Ar represents phenyl or phenyl substituted by one to three substituents selected from the group consisting of lover alkyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl, or by one lower alkylenedioxy; and X represents 0, S or N-lower alkyl*, and n roprcccnto ail integer 87—1-7—2 ui 3t" N-oxides thereof; acid addition salts thereof; and N-lower alkyl or N-benzyl quaternary salts thereof; except the compound of formula I wherein Rj and R2 represents ethyl, R3 represents hydrogen, Ar represents phenyl, and X represents 0, and acid addition salts thereof.
2. A compound of the general formula I shown in claim 1, in which formula all the symbols have the meanings given in claim 1, and pharmaceutically acceptable acid addition salts thereof, except the compound of formula I wherein R^ and R^ represent ethyl, R3 represents hydrogen, Ar represents phenyl, and X stands for O, and pharmaceutically acceptable acid addition salts thereof.
3. A compound of the formula I shown in claim 1 wherein R^ and R2 * 305509 - 49 - independently of the other represent hydrogen or lower alkyl; or R^ and together with the adjacent nitrogen atom represent pyrrolidino or piperidino or a five- or six-tnerabered saturated heterocyclic ring containing NH, N-lower alkyl, 0 or S1 represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl**-gg-pfcJOJrtJ infceegj* 0/1 oi* ■&> X represents 0, S or N-lower alkyl; and Ar represents phenyl substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl, or by one lower alkylenedioxy; and phanaaceutically acceptable acid addition salts thereof.
4. A compound of the general formula IA 3Y" ^CH-CH_" * Ar-X-CH2 "R2 (IA) wherein R^ and Rj independently of the other represent hydrogen or lower alkyl; or R^ and Rj togecher with the adjacent nitrogen atom represent pyrrolidino or piperidino or a five- or six-membered saturated heterocyclic ring containing NH, N-lower alkyl, 0 or S; R^ represents hydrogen, lower alkyl, lower alkoxy, halogen or tri-fluoromethyl; Ar represents phenyl substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl, or by one lower alkylenedioxy; and X represents 0 or S; and phanaa-^, . ceutically acceptable acid addition salts thereof.
5- A compound of the formula IA shown in claim 4, wherein R^ and independently represent hydrogen or lower alkyl; or R^ and R - 50 - 205509 together with the adjacent nitrogen atom represent pyrrolidino or piperidino; and R3, Ar and X have the meanings given in claim 4; and pharmaceutically acceptable acid addition salts thereof.
6. A compound of the general formula IB wherein R^ and R^ independently represent hydrogen or lower alkyl; represents hydrogen, halogen or trifluoromethyl; and Ar represents phenyl monosubstituted or disubstituted by identical or different substituents selected from lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, halogen and trifluoromethyl; and pharmaceutically acceptable acid addition salts thereof.
7. A compound of the formula I shown in claim 1, wherein represents hydrogen or methyl; R2 is methyl; R^ represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; n is the integer 1 or 2; X represents 0; and Ar is unsubstituted phenyl; and pharmaceutically acceptable acid addition salts thereof.
8. A compound of the formula I shown in claim 1, and enumerated in the example 3, and pharmaceutically acceptable acid addition salts thereof.
9. A compound of the formula I shown in claim 1, and enumerated in example 11, and pharmaceutically acceptable acid addition salts ^ 2 2 (IB) thereof. - 51 -
10. A compound of the formula I shown in claim 1, and enumerated in example 6, and pharmaceutically acceptable acid addition salts thereof.
11. N,N-Dimethy1-2-benzy1-3-(4-trifluoromethylphenoxy)propylamine and pharmaceutically acceptable acid addition salts thereof.
12. N,N-Dimethyl-2-(3-chlorobenzyl)-3-(4-methylmercaptophenoxy)-propylamine and pharmaceutically acceptable acid addition salts thereof.
13. N-Methy1-2-benzy1-3-(4-trifluoromethylphenoxy)propylamine and pharmaceutically acceptable acid addition salts thereof.
14. N-Methyl-2-benzy1-3-(3-methoxyphenoxy)propylamine and pharmaceutically acceptable acid addition salts thereof.
15. N-Methyl-2-benzyl-3-(2-methoxyphenoxy)propylamine and pharmaceutically acceptable acid addition salts thereof.
16. N-Methyl-N-ethyl-2-benzyl-3-(4-methylthiophenoxy)propylanine and pharmaceutically acceptable acid addition salts thereof.
17. N,N-Dimethy1-2-benzy1-3-(4-methylsulfinylphenoxy)propylamine and pharmaceutically acceptable acid addition salts thereof.
18. A pharmaceutical preparation comprising a compound claimed in any one of claims 2, 3, 7 and 9, in admixture or conjunction with a pharmaceutically suitable carrier.
19. A pharmaceutical preparation comprising a compound claimed in any one of claims 4, 5, 6, 8 and 10 - 17, in admixture or conjunction with a pharmaceutically suitable carrier. 205509 - 52 -
20. A process for the manufacture of a compound of formula I claimed in claim 1 and an acid addition salt thereof, which consists in a) condensing a compound of the formula *3 y-\ -CH^ '^CH-CH W-CH v_y 2v.. . / i {II) ' 2 V 2 2 or an acid addition salt thereof, with a compound of the formula III Ar-Y (III) wherein R^, R^, R^ ■» and Ar have the meanings given in claim 1, one of the symbols W and Y represents a group XH or XH in a metal salt form, in which X has the meaning given in claim I, and the other one represents the group XH in a reactive esterified form thereof or as an N,N'-disubstituted isourea or isothiourea derivative ; or b) condensing an amine of the formula IV A (IV) or an acid addition salt thereof, with a compound of the formula V 1 \ • * ^ \ /~CH2N Ar-X-CH, ,CH-CH=Z (V) in which Z is a hydrogen atom together with a reactive esteri hydroxyl .group or the oxo group and Ar, X and Rj have the given in claim 1; or - 53 - 205509 c) reducing a compound structurally analogous to a compound of formula I defined in claim 1, wherein an oxo group is present on at lease one carbon atom adjacent to the amino nitrogen; or d) saturating (a) multiple bond(s) in a compound structurally analogous to the compound of formula I defined in claim 1, wherein one or two double bonds is (are) present in the aliphatic portion of the molecule inclusive of the amino group; or e) removing the radical R from a compound of the formula VI R, Y"\ \ >"CH2\ •=• CH-CH Ar-X-CH2 <; (VI) wherein R2, n an<* ^ave c^e meanings given in claim 1 anrfR0 is an amino protecting group, to obtain a compound of formula I in which Rj is hydrogen; or f) reducing a compound of the formula CH-T Ar-X-CH, (VII) wherein T represents cyano or azidomethyl, and R3, X ;*• and Ar have the meanings given in claim 1, to obtain a compound of formula I wherein. and are hydrogen; or 205503 - 54 - g) condensing a compound of the formula VIIA Q ' A Ar-X-CH2~CH-CH2-N^ (VIIA) with a compound of the formula VIIB (R,) >\ < i ii (viib) 3 nch2m vherein one of the groups Q and M represents a leaving group, and the other represents a metal or halometal radical, and Ar, X and R1 to and n have meaning as defined in claim 1; if necessary while temporarily protecting any interfering reactive group in all these processes, and isolating the resulting compound of formula I; and/or if required, converting a resulting compound of formula I into another compound of the invention, and/or if required, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt, and/or, if required, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and/or, if required, resolving a racemate obtained into the optical antipodes.
21. The process for the preparation of a compound as claimed in Claim 1 descrioed in any one of examples 1 - 10.
22. The process for the preparation of a compound as claimed in Claim 1 described in example 11. -;*v -r. ,t ( - "•' V f- ■ .'1^* "*•- '•I"'' ' ■■■«» 205509 - 55 -
23. A compound as claimed in Claim 1 when prepared according to Claim 21.
24. A compound as claimed in Claim 1 when prepared according to either of claims 20 and 22. CIBA-GEIGY AG BY THEIR ATTORNEYS 3ALDWJN, SON AXAHEY F0 7.4 ZA/rz* „> ! |2CF£Bf?S7 1 .-Pj: ! ''
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US41500082A | 1982-09-07 | 1982-09-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ205509A true NZ205509A (en) | 1987-07-31 |
Family
ID=23643932
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ205509A NZ205509A (en) | 1982-09-07 | 1983-09-06 | Propylamine derivatives and pharmaceutical compositions |
Country Status (18)
Country | Link |
---|---|
EP (1) | EP0102929B1 (en) |
JP (1) | JPS5973546A (en) |
AT (1) | ATE28069T1 (en) |
AU (1) | AU566564B2 (en) |
CA (1) | CA1242728A (en) |
DD (1) | DD213208A5 (en) |
DE (1) | DE3372283D1 (en) |
DK (1) | DK405183A (en) |
ES (4) | ES525400A0 (en) |
FI (1) | FI83632C (en) |
GR (1) | GR78936B (en) |
HU (1) | HU194157B (en) |
IE (1) | IE55906B1 (en) |
IL (1) | IL69632A (en) |
NO (1) | NO157975C (en) |
NZ (1) | NZ205509A (en) |
PT (1) | PT77291B (en) |
ZA (1) | ZA836597B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003014114A2 (en) * | 2001-08-08 | 2003-02-20 | Neurosearch A/S | Substituted amine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1237352A (en) * | 1969-01-03 | 1971-06-30 | Ct Europ De Rech S Mauvernay | Substituted propylamines |
GB1343527A (en) * | 1971-07-30 | 1974-01-10 | Cerm Cent Europ Rech Mauvernay | Amino-propanol derivatives |
FR2460919A1 (en) * | 1979-07-11 | 1981-01-30 | Prod Synthese Ste Indle | AMINO-ETHERS OXIDES, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC APPLICATION |
-
1983
- 1983-09-01 AT AT83810398T patent/ATE28069T1/en not_active IP Right Cessation
- 1983-09-01 DE DE8383810398T patent/DE3372283D1/en not_active Expired
- 1983-09-01 EP EP83810398A patent/EP0102929B1/en not_active Expired
- 1983-09-02 CA CA000435963A patent/CA1242728A/en not_active Expired
- 1983-09-02 IL IL69632A patent/IL69632A/en unknown
- 1983-09-05 DD DD83254530A patent/DD213208A5/en not_active IP Right Cessation
- 1983-09-05 FI FI833150A patent/FI83632C/en not_active IP Right Cessation
- 1983-09-06 ZA ZA836597A patent/ZA836597B/en unknown
- 1983-09-06 JP JP58162720A patent/JPS5973546A/en active Pending
- 1983-09-06 HU HU833100A patent/HU194157B/en unknown
- 1983-09-06 NO NO833178A patent/NO157975C/en unknown
- 1983-09-06 ES ES525400A patent/ES525400A0/en active Granted
- 1983-09-06 GR GR72391A patent/GR78936B/el unknown
- 1983-09-06 IE IE2093/83A patent/IE55906B1/en not_active IP Right Cessation
- 1983-09-06 DK DK405183A patent/DK405183A/en not_active Application Discontinuation
- 1983-09-06 AU AU18746/83A patent/AU566564B2/en not_active Ceased
- 1983-09-06 PT PT77291A patent/PT77291B/en not_active IP Right Cessation
- 1983-09-06 NZ NZ205509A patent/NZ205509A/en unknown
-
1985
- 1985-03-14 ES ES541258A patent/ES8606244A1/en not_active Expired
- 1985-03-14 ES ES541260A patent/ES8802010A1/en not_active Expired
- 1985-03-14 ES ES541259A patent/ES8702335A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
NO157975C (en) | 1988-06-28 |
NO833178L (en) | 1984-03-08 |
FI83632C (en) | 1991-08-12 |
IL69632A0 (en) | 1983-12-30 |
ES8702335A1 (en) | 1986-12-16 |
FI833150A0 (en) | 1983-09-05 |
IL69632A (en) | 1987-08-31 |
IE55906B1 (en) | 1991-02-14 |
GR78936B (en) | 1984-10-02 |
EP0102929B1 (en) | 1987-07-01 |
FI83632B (en) | 1991-04-30 |
ZA836597B (en) | 1984-04-25 |
AU1874683A (en) | 1984-03-15 |
ATE28069T1 (en) | 1987-07-15 |
DK405183D0 (en) | 1983-09-06 |
IE832093L (en) | 1984-03-07 |
CA1242728A (en) | 1988-10-04 |
ES541259A0 (en) | 1986-12-16 |
PT77291A (en) | 1983-10-01 |
EP0102929A3 (en) | 1984-09-12 |
ES541258A0 (en) | 1986-04-01 |
ES8802010A1 (en) | 1988-03-16 |
ES8606244A1 (en) | 1986-04-01 |
PT77291B (en) | 1986-07-14 |
ES8506582A1 (en) | 1985-08-01 |
DK405183A (en) | 1984-03-08 |
ES525400A0 (en) | 1985-08-01 |
DE3372283D1 (en) | 1987-08-06 |
JPS5973546A (en) | 1984-04-25 |
ES541260A0 (en) | 1988-03-16 |
FI833150A (en) | 1984-03-08 |
AU566564B2 (en) | 1987-10-22 |
HU194157B (en) | 1988-01-28 |
DD213208A5 (en) | 1984-09-05 |
NO157975B (en) | 1988-03-14 |
EP0102929A2 (en) | 1984-03-14 |
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