Substituted amidino compounds, their manufacture and methods of treatment

Description

The invention relates to substituted amidinophenoxyalkoxyphenyl derivatives and thio analogs as defined herein which are particularly useful as selective Leukototriene B.sub.4 (LTB.sub.4) receptor antagonists, methods for preparation thereof, pharmaceutical compositions comprising said compounds, and a method of antagonizing LTB-4 and of treating conditions or syndromes in mammals which are responsive to LTB-4 antagonism using said compounds or pharmaceutical compositions comprising said compounds of the invention.
Leukotriene B.sub.4 (LTB.sub.4) is an important inflammatory mediator being a potent chemotactic agent and activator of polymorphonuclear leucocytes (PMN's) and monocytes. It modulates the production and effects of other important inflammatory mediators e.g. Interleukin-1 and gamma interferon. LTB.sub.4 has been implicated in the pathogenesis of a number of inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, non-steroidal-antiinflammatory-drug-induced gastropathy, adult respiratory distress syndrome (ARDS), myocardial infarction, allergic rhinitis, hemodialysis-induced neutropenia, and late phase asthma.
The compounds of the invention are useful for the treatment of the conditions mediated by LTB.sub.4 which are cited above. In addition, the compounds are also useful for the treatment of pain and osteoarthritis, for the treatment of ocular conditions, such as ocular allergy and inflammation, and also for the treatment of dermatitis, such as atopic and contact dermatitis.
There is a strong need in the art in finding potent antagonism of LTB.sub.4 on human PMN's, especially those which are orally active. It has been found that the compounds according to the present invention exhibit significant LTB.sub.4 antagonistic activity on human PMN's and are orally active.
The invention relates to substituted amidinophenoxyalkoxyphenyl derivatives and thio analogs of the formula ##STR2## wherein the C(.dbd.NH)--NHR.sub.3 group may be in tautomeric or isomeric form; and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is amino which is mono- or disubstituted by a substituent selected from an aliphatic hydrocarbon radical, an araliphatic hydrocarbon radical, an aromatic radical, and a cycloaliphatic hydrocarbon radical, or is amino which is disubstituted by a divalent aliphatic hydrocarbon radical or a said radical interrupted by oxygen;
R.sub.2 is hydroxy which is etherified by an aliphatic alcohol which is substituted by carboxy, by esterified carboxy or by amidated carboxy;
R.sub.3 is hydrogen or an acyl radical which is derived from an organic carbonic acid, an organic carboxylic acid, a sulfonic acid, or a carbamic acid;
X.sub.1 and X.sub.3, independently of one another, are oxygen (--O--) or sulphur (--S--); and
X.sub.2 is a divalent aliphatic hydrocarbon radical which may be interrupted by an aromatic radical;
wherein the phenyl rings of formula I may be, independently of one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; wherein aryl in the above definitions may be, independently of one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid;
wherein a cycloaliphatic hydrocarbon radical may be substituted by an aliphatic radical; which are particularly useful as selective LTB-4 antagonists, methods for preparation thereof, pharmaceutical compositions comprising said compounds, and a method of antagonizing LTB-4 and of treating diseases in mammals which are responsive to LTB-4 antagonism using said compounds or pharmaceutical compositions comprising said compounds of the invention.
The compounds of the invention wherein the C(.dbd.NH)--NHR.sub.3 group is in tautomeric or isomeric form are represented by formula I' ##STR3## wherein R.sub.1, R.sub.2, R.sub.3, X.sub.1, X.sub.2 and X.sub.3 have the meanings as defined for formula I.
As compounds according to the invention have a basic centre, they can thus form acid addition salts, especially pharmaceutically acceptable salts. These are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (C.sub.1 -C.sub.4 --)alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, benzoic acid or with organic sulfonic acids, such as (C.sub.1 -C.sub.4 --)alkane- or arylsulfonic acids which are unsubstituted or substituted, for example, by halogen, for example methane- or toluenesulfonic acid. Preferred are salts formed with hydrochloric acid, methanesulfonic acid and maleic acid.
The general definitions used below have, if not defined differently, the following meanings:
An aliphatic hydrocarbon radical is, for example, lower alkyl, lower alkenyl and secondarily lower alkynyl.
An araliphatic hydrocarbon radical is, for example, optionally substituted phenyl-lower alkyl and secondarily phenyl-lower alkenyl and phenyl-lower alkynyl.
A cycloaliphatic hydrocarbon radical is, for example, cycloalkyl and secondarily cycloalkenyl, which is unsubstituted or mono- or polysubstituted, for example, disubstituted, by lower alkyl.
A divalent aliphatic hydrocarbon radical is, for example, lower alkylene.
A divalent aliphatic radical interrupted by oxygen is, for example, lower alkylene interrupted by oxygen, e.g. ethylene-O-ethylene.
A divalent aliphatic hydrocarbon radical which is interrupted by an aromatic radical is, for example, lower alkylene-phenylene-lower alkylene or lower alkylene-naphthylene-lower alkylene.
An aliphatic alcohol is, for example, a lower alkanol or lower alkenol, and an araliphatic alcohol is, for example, a phenyl-lower alkanol, for example, benzylalcohol.
Hydroxy which is etherified by an aliphatic or araliphatic alcohol is, for example, lower alkoxy or lower alkenyloxy and phenyl-lower alkoxy.
An aliphatic carboxylic acid is, for example, a lower alkanoic or lower alkenoic acid, and an araliphatic carboxylic acid is, for example, a phenyl-lower alkanoic acid.
An acyl radical which is derived from an an organic carboxylic acid is, for example, lower alkanoyl, phenyl-lower alkanoyl or unsubstituted or substituted aroyl, such as benzoyl, naphthoyl, indanoyl or fluorenoyl, or heteroaroyl such as pyridylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, furanylcarbonyl, and imidazolylcarbonyl.
An acyl radical which is derived from an organic carbonic acid is, for example, alkoxycarbonyl or alkenyloxycarbonyl which in each case are unsubstituted or substituted by an aromatic radical or is cycloalkoxycarbonyl which unsubstituted or substituted by lower alkyl.
An acyl radical which is derived from a sulfonic acid is, for example, alkanesulfonyl, arylalkanesulfonyl, cycloalkanesulfonyl or arylsulfonyl.
An acyl radical which is derived from a carbamic acid is, for example, amino-carbonyl which is substituted by alkyl, arylalkyl or aryl.
An aromatic radical is, for example, unsubstituted or substituted such as monosubstituted or polysubstituted, for example, disubstituted or secondarily trisubstituted carbocyclic aryl, such as phenyl, naphthyl, indanyl or fluorenyl, or heterocyclic aryl, such as pyridyl, thienyl, pyrrolyl, furanyl, and imidazolyl.
Aryl represents preferably monocarbocyclic aryl, advantageously optionally substituted phenyl, such being phenyl or phenyl substituted by e.g. lower alkyl, lower alkoxy, halogen or trifluoromethyl.
The phenyl rings of formulae I and IA as well as aromatic radicals referred to before and hereafter are generally unsubstituted or further substituted such as monosubstituted or polysubstituted, for example disubstituted or secondarily trisubstituted, in particular, for example, by a substituent selected from the group consisting of halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy, lower alkenoyloxy, and phenyl-lower alkanoyloxy. Preferably, the phenyl rings of formula I and IA do not exhibit any additional substituent.
Preferred positions of the following structural elements in the corresponding phenyl ring in formula I are: positions 4 (para) or 5 (meta) for --CO--R.sub.1, position 2 (ortho) or 3 (meta) for R.sub.2, and position 4 (para) for --C(.dbd.NH)--NHR.sub.3. The substituent R.sub.3 may be located on either nitrogen of the --C(.dbd.NH)NH.sub.2 grouping and both tautomeric or isomeric forms are encompassed by the instant invention.
The term "substituted by one or more substituents" refers preferably to one, two or three such substituents, advantageously one or two.
The expression "lower" means that corresponding groups and compounds in each case contain in particular not more than 7, preferably not more than 4, carbon atoms.
Halogen is, in particular, fluorine, chlorine or bromine, and furthermore includes iodine.
Lower alkyl is, in particular, C.sub.1 -C.sub.7 -alkyl and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and furthermore includes corresponding pentyl, hexyl and heptyl radicals. C.sub.1 -C.sub.4 -Alkyl is preferred.
Lower alkenyl is, in particular, C.sub.3 -C.sub.7 -alkenyl and is, for example, 2-propenyl or 1-, 2- or 3-butenyl. C.sub.3 -C.sub.5 -Alkenyl is preferred.
Lower alkynyl is, in particular, C.sub.3 -C.sub.7 -alkynyl and is preferably propargyl.
Phenyl-lower alkyl is, in particular, phenyl-C.sub.1 -C.sub.4 -alkyl and is preferably benzyl, 1- and 2-phenethyl, while phenyl-lower alkenyl and phenyl-lower alkynyl are, in particular, phenyl-C.sub.2 -C.sub.5 alkenyl and -alkynyl, in particular 2-phenyl-vinyl, 3-phenylallyl and 3-phenylpropargyl.
Cycloalkyl is, in particular, C.sub.3 -C.sub.7 -cycloalkyl and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.
Cycloalkenyl is, in particular, C.sub.3 -C.sub.7 -cycloalkenyl and is preferably cyclopent-2- or 3-enyl, or cyclohex-2- and -3-en-yl.
Lower alkylene e.g. in amino which is disubstituted by lower alkylene is, in particular, C.sub.2 -C.sub.6 -alkylene and is, for example, butylene, pentylene, or 2,6-butylene. Preferred is C.sub.4 -C.sub.5 -alkylene, especially pentylene.
Lower alkylene X.sub.2 is, in particular, C.sub.2 -C.sub.8 -alkylene, preferably straight-chain, and is, for example, ethylene, propylene, butylene, pentylene, hexylene, heptylene and also octylene. C.sub.4 -C.sub.7 -Alkylene is preferred, especially pentylene and also butylene, hexylene or heptylene.
Lower alkylene which is interrupted by a phenyl radical (X.sub.2) is, in particular, lower alkylene-phenylene-lower alkylene or lower alkylene-naphthylene-lower alkylene such as C.sub.2 -C.sub.4 -alkylene-phenylene-C.sub.2 -C.sub.4 -alkylene or C.sub.2 -C.sub.4 -alkylene-naphthylene-C.sub.2 C.sub.4 -alkylene, preferably straight-chain, and is, for example, methylene-phenylene-methylene, 1,2-ethylene-phenylene- 1,2-ethylene, such as 1,2-ethylene-1,4-phenylene-1,2-ethylene, 1,3-propylene-phenylene- 1,3-propylene, such as 1,3-propylene-1,4-phenylene-1,3-propylene, or butylene-phenylene-butylene radicals, also a corresponding 1,2-ethylene-naphthylene-1,2-ethylene radical. C.sub.2 -C.sub.4 -alkylene-phenylene-C.sub.2 -C.sub.4 -alkylene or C.sub.2 -C.sub.3 -alkylene-naphthylene-C.sub.2 -C.sub.3 -alkylene is preferred, especially 1,2-ethylene- 1,4-phenylene- 1,2-ethylene.
Lower alkoxy is, in particular, C.sub.1 -C.sub.7 -alkoxy and is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and furthermore includes corresponding pentyloxy, hexyloxy and heptyloxy radicals. C.sub.1 -C.sub.4 -Alkoxy is preferred.
Lower alkenyloxy is, in particular, C.sub.3 -C.sub.7 -alkenyloxy and is, for example, allyloxy or but-2-en- or but-3-enyloxy. C.sub.3 -C.sub.5 -Alkenyloxy is preferred.
Phenyl-lower alkoxy is, in particular, phenyl-C.sub.1 -C.sub.4 -alkoxy, such as benzyloxy, 1- or 2-phenylethoxy, or 1-, 2- or 3-phenylpropyloxy.
Lower alkanoyloxy is, in particular, C.sub.2 -C.sub.8 alkanoyloxy, in particular, C.sub.2 -C.sub.5 -alkanoyloxy, such as acetyloxy, propionyloxy or pivaloyloxy.
Lower alkenoyloxy is, in particular, C.sub.3 -C.sub.8 -alkenoyloxy, in particular, C.sub.3 -C.sub.5 -alkenoyloxy, such as propenoyloxy.
Phenyl-lower alkanoyloxy is, in particular, phenyl-C.sub.2 -C.sub.8 -alkanoyloxy, in particular, phenyl-C.sub.2 -C.sub.5 -alkanoyloxy, such as phenylacetyloxy, phenylpropionyloxy or phenylpivaloyloxy.
Alkoxycarbonyl is, in particular, C.sub.2 -C.sub.12 -alkoxycarbonyl and is, for example, methoxy-, ethoxy-, propyloxy- pivaloyloxy- or octyloxy-carbonyl. C.sub.2 -C.sub.9 -Alkoxycarbonyl is preferred.
Alkenyloxycarbonyl is, in particular, C.sub.3 -C.sub.12 -alkenyloxycarbonyl, for example, allyloxycarbonyl. Preferred is C.sub.3 -C.sub.5 -alkenyloxycarbonyl.
Cycloalkyloxycarbonyl is, in particular, C.sub.3 -C.sub.7 -cycloalkoxycarbonyl, preferred is cyclopentyloxycarbonyl or cyclohexyloxycarbonyl.
Alkanesulfonyl is, in particular, C.sub.1 -C.sub.7 alkanesulfonyl and is, for example, methane-, ethane-, n-propane- or isopropanesulfonyl. C.sub.1 -C.sub.4 -Alkanesulfonyl is preferred.
Arylalkanesulfonyl is, in particular, phenyl-C.sub.1 -C.sub.7 alkanesulfonyl, for example, benzyl- or 1- or 2-phenylethan-sulfonyl. Phenyl-C.sub.1 -C.sub.4 -alkane-sulfonyl is preferred.
Cycloalkanesulfonyl is, in particular, C.sub.3 -C.sub.7 -cyclopentanesulfonyl, preferred is cyclopentanesulfonyl or cyclohexanesulfonyl.
Naphthyl is 1- or 2-naphthyl.
Indanyl is, for example, 1-, 2-, 3- or 4-indanyl.
Fluorenyl is, for example, 1-, 2-, 3-, 4- or 5-fluorenyl.
Lower alkanoyl is, in particular, C.sub.1 -C.sub.7 -alkanoyl and is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl or pivavolyl. C.sub.2 -C.sub.5 -Alkanoyl is preferred.
Phenyl-lower alkanoyl is, in particular, phenyl-C.sub.2 -C.sub.7 -alkanoyl and is, for example, phenylacetyl or 2- or 3-phenylpropionyl. Phenyl-C.sub.2 -C.sub.4 -alkanoyl is preferred.
Substituted aroyl represents aroyl, such as benzoyl, which is substituted e.g. by lower alkoxy, lower alkyl, hydroxy, hydroxymethyl or by acyloxymethyl (such as lower alkanoyloxymethyl or benzoyloxymethyl.
Naphthoyl is 1- or 2-naphthoyl.
Indanoyl is, for example, 1-, 2-, 3- or 4-indanoyl.
Fluorenoyl is, for example, 1-, 2-, 3-, 4- or 5-fluorenoyl.
Esterified carboxyl represents preferably lower alkoxycarbonyl or aryl-lower alkoxycarbonyl.
Amidated carboxyl represents preferably aminocarbonyl, mono- or di-lower alkylaminocarbonyl, (mono-aryl-mono-lower alkyl)aminocarbonyl, mono- or di-(aryl-lower alkyl)aminocarbonyl or (mono-aryl-lower alkyl-mono-lower alkyl)aminocarbonyl.
The compounds of the invention exhibit valuable pharmacological properties in mammals, and are particularly useful as selective Leukotriene B.sub.4 (LTB.sub.4) receptor antagonism, e.g. for the treatment of a condition or syndrome in a mammal responsive to the selective antagonism of LTB.sub.4 receptors, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, non-steroidal-antiinfiammatory-drug-induced gastropathy, adult respiratory distress syndrome (ARDS), myocardial infarction, allergic rhinitis, hemodialysis-induced neutropenia, and late phase asthma. The compounds of the invention are also useful as analgesics for the treatment of pain of any origin, and for the treatment of osteoarthritis, also for the treatment of ocular conditions, such as ocular allergy and inflammation, and also for the treatment of dermatitis, e.g. atopic and contact dermatitis.
The above-cited properties are demonstrable in in vitro and in vivo tests, using advantageously mammals, e.g. rats. Said compounds can be applied in vitro in the form of solutions, e.g. preferably aqueous solutions, and in vivo either enterally or parenterally, advantageously orally, e.g. as a suspension or in aqueous solution. The dosage in vitro may range between about 0.5 ng/ml and about 100 ng/ml. The dosage in vivo may range, depending on the route of administration, between about 1 and about 1000 mg/kg per day.
Beneficial effects are evaluated in pharmacological tests generally known in the art, e.g. as illustrated herein.
Receptor Binding with [.sup.3 H]-LTB.sub.4 to Intact Human Neutrophils:
Neutrophils (PMN's) are prepared from uncoagulated human venous blood. Blood is dispersed into 50 ml polypropylene tubes containing 15 ml of HESPAN (Dupont, Wilmington, Del.), and mixed. Tubes are allowed to stand at room temperature for 40 minutes until most of the red blood cells sediment. The supenatants are removed and centrifuged for 5-10 min at 400.times.g. The remaining pellets are diluted in 70 ml of Phosphate Buffered Saline without calcium and magnesium (PBS without metals; GIBCO, Grand Island, N.Y.) and 35 ml of this suspension are placed in each of two polypropylene tubes containing 15 ml of Ficoll-Paque (Sigma, St. Louis, Mo.). Gradients are then centrifuged for 15 minutes at 420.times.g. The mononuclear cell layer is discarded and the remaining red blood cell pellet is resuspended in 10 ml of PBS without metals. Twenty ml of filtered deionized water are added to the suspension for approximately 20 sec followed by the same volume of buffer at two times the normal concentration. The cell suspension is mixed and centrifuged for 5 min at 200.times.g, followed by one wash with buffer, and final resuspension.
Binding of [.sup.3 H]LTB.sub.4 to LTB.sub.4 receptors is measured in intact human polymorphonuclear leukocytes, as described by Gorman and Lin (Gorman, R. and Lin, A Methods Enzymol. 141: 372-378, 1987). Intact human neutrophils are suspended in Hank's Balanced Salt Solution (HBSS) at a concentration of 3.times.106 cells/assay tube. An aliquot of the cell suspension (300 .mu.l) is added to triplicate tubes containing 50 .mu.l [3H]LTB.sub.4 (specific activity 32 Ci/mmol, DuPont-NEN, Boston, Mass.) at a final concentration of 0.5 nM, 100 .mu.l buffer and 50 .mu.l drug or buffer. Nonspecific binding is determined in the presence of 300 nM LTB,.sub.4. The reaction is initiated by addition of cell suspension and continued at 0.degree. C. for 20 min. Bound radioactivity is isolated by vacuum filtration through Whatman GF/C glass fiber filters using a Brandel cell harvester and unbound radioactivity removed with 2.times.5 ml washes with ice-cold saline. Filters are placed in polyethylene scintillation mini-vials to which is added 3.5 ml of Formula-989 scintillation cocktail (NEN). After equilibration, radioactivity determinations and data calculations are performed using non-linear regression analysis on RS/1.
LTB.sub.4 -Induced PMN Aggregation
Human PMNs are prepared as previously described. Neutrophil aggregation is assessed by monitoring the intensity of light passing through a suspension of cells (Craddock et al., J. Clin. Invest. 60: 260-264, 1977) using a Payton dual channel aggregometer (model 300BD). Cuvettes containing 0.25 ml of cell suspension (25.times.106 cells/ml) in PBS without calcium and magnesium are incubated with 5 .mu.g/ml ml of cytochalasin B for 2 minutes at 37.degree. C. 5 .mu.l of 2 .mu.M LTB.sub.4 in PBS (20 nM final concentration) are added and the aggregation response monitored for 3-5 min, the time required for optimal response, Compounds are solubilized in 0.01M DMSO and then diluted in PBS to 0.001M. 5 .mu.l of compound solution is added along with cytochalasin B and cells as described above. Following the preincubation period 5 .mu.l of 2 .mu.M LTB.sub.4 are added and aggregation is measured. Percent inhibition of aggregation is calculated by comparing peak heights in the presence and absence of compound. Percent inhibition is plotted as a function of the log concentration of compound and the IC.sub.50 determined directly from the graph.
LTB.sub.4 -Induced Neutropenia in the Rat
Male Sprague Dawley rats (crl: CDBR; Charles River, Wilmington, Mass.) (250-300 grams) are fasted overnight prior to the experiment. At least six animals are used per treatment group. Rats are given vehicle or compound either intravenously or orally and at intervals after dosing, neutrophil counts are determined from blood samples obtained just prior to and 20 seconds after intravenous infusion of 200 ng LTB.sub.4. In studies where compound is administered orally, drug is given by gavage. When drug is administered intravenously, rats are first anesthetized with 50 mg/kg i.p. of Sodium Pentabarbital. The jugular vein is exposed and cleaned of the surrounding tissue. At 3,4 or 18 hours following administration of compound or vehicle by either route, blood samples are taken (0.3 ml of blood in 1.5 ml polypropylene microcentrifuge tube containing 0.01 ml 7.5% EDTA). Blood neutrophil counts are determined using a Technicon H-1 hematinstrum instrument. Antagonism of the LTB.sub.4 -induced neutropenia for the compounds tested is calculated.
Analgesic activity can be demonstrated e.g. in the Randall-Selitto test for analgesia, e.g. as described in Arch. Int. Pharmacodyn. Ther. 111, 409 (1957).
Antiinflammatory activity can be demonstrated by measuring the inhibition of the edema and inhibition of the influx of polymorphonuclear (PMN's) and mononuclear leukoeytes (monoeytes and macrophages) after oral administration in the rat model in which pleurisy is first induced by injecting carrageenin into the pleural cavity, e.g. according to A. P. Almeida et al., J. Pharmacol. Exp. Therap. 214, 74 (1980), in particular during the late phase of the carrageenin-induced pleurisy.
Bronchial effects such as anti-asthmatic activity, can be demonstrated in the antigen-induced guinea pig bronchoconstriction test, e.g. as described by Anderson et at, Br. J. Pharmacol. 198.3, 78, 67-74.
The trinitrobenzenesulfonic acid-induced chronic colitis test in the rat, e.g. as described by Wallace et at, Gastroenterology 1989, 96, 29-36, can be used to evaluate compounds for effects indicative of utility in inflammatory bowel diseases.
The arachidonic acid-induced mouse ear edema test, e.g. as described by Young et al, J. Invest, Dermatol. 1984, 82, 367-371 can be used to evaluate compounds for effects indicative of utility in dermatological disorders such as psoriasis.
The invention especially relates to compounds of formula I and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is amino which is mono- or disubstituted by a substituent selected from lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl, phenyl, naphthyl, indanyl, fluorenyl, cycloalkyl, and cycloalkenyl, cycloalkyl and cycloalkenyl each being unsubstituted or mono- or polysubstituted by lower alkyl, or is amino which is disubstituted by lower alkylene;
R.sub.2 is lower alkoxy substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or mono- or di-lower alkylaminocarbonyl;
R.sub.3 is hydrogen, alkoxycarbonyl or alkenyloxycarbonyl, each of which is unsubstituted or substituted by phenyl, naphthyl, indanyl or fluorenyl, or is cycloalkoxycarbonyl being unsubstituted or mono- or polysubstituted by lower alkyl, or is lower alkanoyl or phenyl-lower alkanoyl, or is benzoyl, naphthtoyl, indanoyl or fluorenoyl, or is C.sub.1 -C.sub.7 alkanesulfonyl, phenyl-C.sub.1 -C.sub.7 alkanesulfonyl, C.sub.3 -C.sub.7 -cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which is substituted by lower alkyl, phenyl-lower alkyl or phenyl;
X.sub.1 and X.sub.3, independently of one another, are O or S;
X.sub.2 is lower alkylene, lower alkylene-phenylene-lower alkylene or lower alkylene-naphthylene-lower alkylene;
wherein the phenyl rings of formula I may be, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy, lower alkenoyloxy and phenyl-lower alkanoyloxy;
wherein the aromatic radicals in the above definitions may be, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy, lower alkenoyloxy and phenyl-lower alkanoyloxy.
The invention especially relates to compounds of formula I and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is amino which is mono- or disubstituted by a substituent selected from C.sub.1 -C.sub.7 -alkyl, phenyl-C.sub.1 -C.sub.7 -alkyl, phenyl and C.sub.3 -C.sub.6 -cycloalkyl, C.sub.3 -C.sub.6 -cycloalkyl being unsubstituted or mono- or polysubstituted by C.sub.1 -C.sub.7 -alkyl, or is amino which is disubstituted by C.sub.3 -C.sub.6 -alkylene;
R.sub.2 is C.sub.1 -C.sub.7 -alkoxy substituted by carboxy or lower alkoxycarbonyl;
R.sub.3 is hydrogen, C.sub.1 -C.sub.12 -alkoxy-carbonyl, C.sub.2 -C.sub.5 -alkanoyl, phenyl-C.sub.2 -C.sub.5 -alkanoyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C.sub.1 -C.sub.7 -alkyl, or C.sub.1 -C.sub.7 -alkoxy, C.sub.3 -C.sub.6 -cycloalkylcarbonyl which is unsubstituted or substituted by C.sub.1 -C.sub.7 -alkyl, or is benzoyl, naphthtoyl, indanoyl or fluorenoyl, or is C.sub.1 -C.sub.7 alkanesulfonyl, phenyl-C.sub.1 -C.sub.7 alkanesulfonyl, C.sub.3 -C.sub.7 -cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which is substituted by C.sub.1 -C.sub.7 -alkyl, phenyl-C.sub.1 -C.sub.7 -alkyl or phenyl;
X.sub.1 and X.sub.3 each are --O--, or furthermore are, independently of one another, --O-- or --S--;
X.sub.2 is C.sub.2 -C.sub.7 -alkylene or C.sub.2 -C.sub.4 -alkylene-phenylene-C.sub.2 -C.sub.4 -alkylene;
wherein the phenyl rings of formula I may be unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, C.sub.1 -C.sub.7 -alkyl, and C.sub.1 -C.sub.7 -alkoxy;
wherein phenyl in the above definitions is unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, C.sub.1 -C.sub.7 -alkyl, and C.sub.1 -C.sub.7 -alkoxy.
The invention especially relates to compounds of formula I and pharmaceutically acceptable salts thereof, in which --CO--R.sub.1 is located in position 4 (para) or 3 or 5 (meta) of the corresponding phenyl ring with respect to --X.sub.1 --; R.sub.2 -- is located in position 2 (ortho) or 3 (meta) of the corresponding phenyl ring with respect to --X.sub.1 --; and --C(.dbd.NH)--NHR.sub.3 is located in position 4 (para) of the corresponding phenyl ring with respect to --X.sub.3 --.
The invention especially relates to compounds of formula IA ##STR4## wherein the C(.dbd.NH)--NHR.sub.3 group may be in tautomeric or isomeric form, and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino, such as di-ethylamino or di-isopropylamino, C.sub.1 -C.sub.4 alkyl-(phenyl)amino, such as phenyl-isopropyl-amino, C.sub.1 -C.sub.4 alkyl-(phenyl-C.sub.1 -C.sub.4 -alkyl)-amino, such as methyl-benzyl-amino, di-C.sub.3 -C.sub.6 -cycloalkylamino, such as di-cyclohexylamino, which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, or 1-piperidino substituted by C.sub.1 -C.sub.4 -alkyl, such as 2-methyl-1-piperidino;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxy which is substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or by mono- or di-lower alkylaminocarbonyl;
R.sub.3 is hydrogen, C.sub.1 -C.sub.12 -alkoxycarbonyl, such as methoxycarbonyl or octyloxycarbonyl, phenyl-C.sub.1 -C.sub.4 -alkoxycarbony, such as benzyloxycarbonyl, C.sub.2 -C.sub.5 -alkanoyl, such as acetyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C.sub.1 -C.sub.4 -alkyl or by C.sub.1 -C.sub.4 -alkoxy, such as 3,4-dimethoxybenzoyl, C.sub.3 -C.sub.6 -cycloalkylcarbonyl which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, such as 2-isopropyl-5-methyl-cyclohexylcarbonyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene, such as pentylene;
wherein the phenyl rings of formula IA may be unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifiuoromethyl, C.sub.1 -C.sub.4 -alkyl, and C.sub.1 -C.sub.4 -alkoxy.
The invention especially relates to compounds of formula IA and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino, such as di-ethylamino or di-isopropylamino, C.sub.1 -C.sub.4 -alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino, C.sub.1 -C.sub.4 -alkyl-(phenyl-C.sub.1 -C.sub.4 -alkyl)-amino, such as methyl-benzyl-amino, di-C.sub.3 -C.sub.6 -cycloalkylamino, such as di-cyclohexylamino which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, or 1-piperidino substituted by C.sub.1 -C.sub.4 -alkyl, such as 2-methyl-1-piperidino;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxy which is substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or mono- or di-lower alkylaminocarbonyl;
R.sub.3 is C.sub.1 -C.sub.4 alkanesulfonyl, such as methane-, ethane- or isopropanesulfonyl, phenyl-C.sub.1 -C.sub.4 -alkanesulfonyl, such as benzylsulfonyl, C.sub.3 -C.sub.7 -cycloalkane-sulfonyl, such as cyclohexanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which is substituted by C.sub.1 -C.sub.4 -alkyl, phenyl-C.sub.1 -C.sub.4 -alkyl or phenyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene, such as pentylene.
The invention especially relates to compounds of formula IA and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino, such as di-ethylamino or di-isopropylamino, C.sub.1 -C.sub.4 -alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino, C.sub.1 -C.sub.4 -alkyl-(phenyl-C.sub.1 -C.sub.4 -alkyl)-amino, such as methyl-benzyl-amino, di-C.sub.3 -C.sub.6 -cycloalkylamino, such as di-cyclohexylamino which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, or 1-piperidino substituted by C.sub.1 -C.sub.4 -alkyl, such as 2-methyl-1-piperidino;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxy substituted by C.sub.1 -C.sub.4 -alkoxycarbonyl, such as ethoxycarbonylmethyl, or by aminocarbonyl;
R.sub.3 is hydrogen; or R.sub.3 is lower alkanoyl, such as acetyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene, such as pentylene.
The invention further especially relates to compounds of formula IA and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino, such as di-isopropylamino;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxy substituted by C.sub.1 -C.sub.4 -alkoxycarbonyl, such as ethoxycarbonyl or by aminocarbonyl
R.sub.3 is C.sub.1 -C.sub.12 -alkoxycarbonyl, such as methoxycarbonyl or octyloxycarbonyl, phenyl-C.sub.1 -C.sub.4 -alkoxycarbonyl, such as benzyloxycarbonyl, C.sub.2 -C.sub.5 -alkanoyl, such as acetyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C.sub.1 -C.sub.4 -alkyl, or C.sub.1 -C.sub.4 -alkoxy, such as 3,4-dimethoxybenzoyl, C.sub.3 -C.sub.6 -cycloalkylcarbonyl which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, such as 2-isopropyl-5-methyl-cyclohexylcarbonyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene, especially pentylene.
The invention further especially relates to compounds of formula IA and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino, such as di-ethylamino or di-isopropylamino;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxy substituted by C.sub.1 -C.sub.4 -alkoxycarbonyl such as ethoxycarbonyl or by aminocarbonyl,
R.sub.3 is hydrogen or C.sub.1 -C.sub.4 -alkanoyl, such as acetyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene, especially pentylene.
The invention also particularly relates to the compounds of formula IB ##STR5## wherein the C(.dbd.NH)--NHR.sub.3 group may be in tautomeric or isomeric form, and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino, such as di-ethylamino or di-isopropylamino, C.sub.1 -C.sub.4 alkyl-(phenyl)amino, such as phenyl-isopropyl-amino, C.sub.1 -C.sub.4 -alkyl-(phenyl-C.sub.1 -C.sub.4 -alkyl)-amino, such as methyl-benzyl-amino, di-C.sub.3 -C.sub.6 -cycloalkylamino, such as di-cyclohexylamino, which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, or 1-piperidino substituted by C.sub.1 -C.sub.4 -alkyl, such as 2-methyl-1-piperidino;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxy which is substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or by mono- or di-lower alkylaminocarbonyl;
R.sub.3 is hydrogen, C.sub.1 -C.sub.12 -alkoxycarbonyl, such as methoxycarbonyl or octyloxycarbonyl, phenyl-C.sub.1 -C.sub.4 -alkoxycarbonyl, such as benzyloxycarbonyl, C.sub.2 -C.sub.5 -alkanoyl, such as acetyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C.sub.1 -C.sub.4 -alkyl, or C.sub.1 -C.sub.4 -alkoxy, such as 3,4-dimethoxybenzoyl, C.sub.3 -C.sub.6 -cycloalkylcarbonyl which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, such as 2-isopropyl-5-methyl-cyclohexylcarbonyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene, such as pentylene;
wherein the phenyl rings of formula IB may be unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, C.sub.1 -C.sub.4 -alkyl, and C.sub.1 -C.sub.4 -alkoxy.
The invention especially relates to compounds of formula IB and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino, such as di-ethylamino or di-isopropylamino, C.sub.1 -C.sub.4 -alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino, C.sub.1 -C.sub.4 alkyl-(phenyl-C.sub.1 -C.sub.4 -alkyl)-amino, such as methyl-benzyl-amino, di-C.sub.3 -C.sub.6 -cycloalkylamino, such as di-cyclohexylamino, which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, or 1-piperidino substituted by C.sub.1 -C.sub.4 -alkyl, such as 2-methyl- 1-piperidino;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxy which is substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or mono- or di-lower alkylaminocarbonyl;
R.sub.3 is C.sub.1 -C.sub.4 -alkanesulfonyl, such as methane-, ethane- or isopropanesulfonyl, phenyl-C.sub.1 -C.sub.4 -alkanesulfonyl, such as benzylsulfonyl, C.sub.3 -C.sub.7 -cycloalkane-sulfonyl, such as cyclohexanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which is substituted by C.sub.1 -C.sub.4 -alkyl, phenyl-C.sub.1 -C.sub.4 -alkyl or phenyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene, such as pentylene.
The invention especially relates to compounds of formula IB and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino, such as di-ethylamino or di-isopropylamino, C.sub.1 -C.sub.4 -alkyl-(phenyl)-amino, such as phenyl-isopropyl-amino, C.sub.1 -C.sub.4 alkyl-(phenyl-C.sub.1 -C.sub.4 -alkyl)-amino, such as methyl-benzyl-amino, di-C.sub.3 -C.sub.6 -cycloalkylamino, such as di-cyclohexylamino, which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, or 1-piperidino substituted by C.sub.1 -C.sub.4 -alkyl, such as 2-methyl-1-piperidino;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxy substituted by C.sub.1 -C.sub.4 -alkoxycarbonyl, such as ethoxycarbonylmethoxy or by aminocarbonyl, such as carbamoylmethoxy;
R.sub.3 is hydrogen; or R.sub.3 is C.sub.2 -C.sub.5 -alkanoyl, such as acetyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene, such as pentylene.
The invention further especially relates to compounds of formula IB and pharmaceutically acceptable salts thereof, in which:
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino, such as di-ethylamino or di-isopropylamino;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxycarbonylmethoxy, such as ethoxycarbonylmethoxy or aminocarbonyimethoxy;
R.sub.3 is hydrogen or C.sub.2 -C.sub.5 -alkanoyl, such as acetyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene, especially pentylene.
The invention relates in particular to the novel compounds itemized in the examples and to the manners of preparation described therein.
The invention further relates to methods for the preparation of the compounds according to the invention. The preparation of compounds of the formula I is, for example, characterized in that,
a) a compound of the formula IIa ##STR6## or a salt thereof in which Z.sub.1 is a radical which can be converted into the variable --CO--R.sub.1, Z.sub.1 is converted into the variable --CO--R.sub.1 or,
b) for the manufacture of compounds of the formula I in which R.sub.3 is hydrogen, in a compound of the formula IIIa ##STR7## or a salt thereof in which Z.sub.2 is a radical which can be converted into the variable --C(.dbd.NH)--NH--R.sub.3, Z.sub.2 is converted into the variable --C(.dbd.NH)--NH--R.sub.3, or
c) a compound of the formula IVa ##STR8## or a salt thereof is reacted with a compound of the formula IVb ##STR9## or a salt thereof in which Z.sub.3 is a group of the formula --X.sub.1 --X.sub.2 --Z.sub.5 and Z.sub.4 is --Z.sub.6, or Z.sub.3 is --Z.sub.6 and Z.sub.4 is a group of the formula --Z.sub.5 --X.sub.2 --X.sub.3 --, wherein one of the radicals Z.sub.5 and Z.sub.6 is hydroxy or mercapto and the other is hydroxy, mercapto or reactive esterfied hydroxy,
and, if desired, a compound of the formula I or a salt thereof obtainable according to the process or in another manner is converted into another compound or a salt thereof according to the invention, a free compound of the formula I obtainable according to the process is converted into a salt, a salt obtainable according to the process is converted into the free compound of the formula I or into another salt, or a mixture of isomers obtainable according to the process is resolved and the desired compound is isolated.
Salts of starring materials which contain at least one basic centre, for example of the formula IIa, are appropriate acid addition salts, while salts of starring materials which contain an acid group are present as salts with bases.
A radical Z.sub.1 which can be converted into the variable --CO--R.sub.1 is, for example, cyano, carboxy or a salt or activated carboxy.
A radical Z.sub.2 which can be converted into the variable --C(.dbd.NH)--NHR.sub.3 is, for example, (lower) alkoxy-iminocarbonyl or halogeno-iminocarbonyl [Halogeno-C(.dbd.NH)--].
Reactive esterified hydroxy (e.g. Z.sub.5 or Z.sub.6) is, inparticular, hydroxy esterified with a strong inorganic acid or organic sulfonic acid, and is, for example, halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, such as, fluorosulfonyloxy, (C.sub.1 -C.sub.7 -)alkanesulfonyloxy which, if desired, is substituted, for example, by halogen, such as, methane- or trifluoromethanesulfonyloxy, (C.sub.5 -C.sub.7 -)cycloalkanesulfonyloxy, such as, cyclohexanesulfonyloxy, or benzenesulfonyloxy which, if desired, is substituted, for example by (C.sub.1 -C.sub.7 -)alkyl or halogen, such as, p-bromobenzene- or p-toluenesulfonyloxy.
The reactions described in the variants above and below are carried out in a manner known per se, for example in the absence or in the customary manner in the presence of a suitable solvent or diluent or a mixture thereof, the reaction being carried out, according to need, with cooling, at room temperature or with warming, for example in a temperature range. from about -80.degree. C. up to the boiling point of the reaction medium, preferably from about -10.degree. C. to about +180.degree. C., and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.
Process a):
A compound of the formula IIa in which Z.sub.1 is activated carboxy (Z.sub.1) is, for example, an anhydride thereof, including a mixed anhydride, such as an acid halide, for example chloride, or an anhydride with a formic ester, an activated carboxylic ester such as cyanomethyl, (4-)nitrophenyl, polyhalogenophenyl, for example pentachlorophenyl, esters.
The reaction is, for example, carried out with an agent suitable to introduce R.sub.3, for example, an amine of the formula H--R.sub.1. The reaction with compounds of the formula IIa in which Z.sub.1 carboxy or a salt thereof, for example, takes place under water-eliminating conditions, for example, with azeotropic removal of the water of reaction, or by treatment with a suitable condensing agent, for example, N,N'-dicyclohexyl-carbodiimide. The reaction with an activated carboxy derivative may advantageously be carried out in the presence of a base.
Suitable bases are, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, di(lower alkyl)amides, aminoalkylamides or lower alkyl silylamides, or naphthaleneamines, lower alkylamines, basic heterocycles, ammonium hydroxides, and also carbocyclic amines. Examples which may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium (m)ethoxide, potassium tert-butoxide, potassium carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium 3-(aminopropyl)amide, potassiumbis(trimethylsilyl)amide, dimethylaminonaphthalene, di- or triethylamine, or ethyldiisopropylamine, N-methylpiperidine, pyridine, benzyltrimethylammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
Preferably, those compounds of the formula IIa are employed in which Z.sub.1 is activated carboxy. The corresponding reaction is carried out using an amine of the formula H--R.sub.1. Preferred compounds of the formula IIa are corresponding acid halides such as acid chlorides or bromides derivatives thereof.
Process b):
Alkoxy-iminocarbonyl is, for example C.sub.1 -C.sub.4 alkoxy-iminocarbonyl such as methoxy- or ethoxy-iminocarbonyl, whereas halogeno-iminocarbonyl is, for example chloro-iminocarbonyl.
Preferably, those compounds of the formula IIIa are employed in which Z.sub.2 is C.sub.1 -C.sub.4 alkoxy-iminocarbonyl such as methoxy- or ethoxy-iminocarbonyl. The reaction is preferably carried out by reacting with ammonia and using an acid resulting in the corresponding acid addition salt of the product. As acids are used, for example, inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (C.sub.1 -C.sub.4)alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, benzoic acid or with organic sulfonic acids, such as (C.sub.1 -C.sub.4)alkane- or arylsulfonic acids which are unsubstituted or substituted, for example, by halogen, for example methane- or toluenesulfonic acid. Preferred acids are hydrohalic acids, especially hydrochloric acid, organic sulfonic acids, especially methanesulfonic acid, or dicarboxylic acids, especially maleic acid.
Process c):
Preferably, those compounds of the formulae IVa and IVb are employed in which Z.sub.3 is a group of the formula --X.sub.1 --X.sub.2 --Z.sub.5, wherein Z.sub.5 is halogen, especially bromine, and Z.sub.4 is hydroxy.
The reaction is carried out preferably in the presence of a base e.g. as mentioned above, such as cesium carbonate.
The starting material can be prepared following methods known per se.
In order to prepare the starting material of the formula IIa, for example, a compound of the formula (IIb) ##STR10## in which Z.sub.3 preferably is a group of the formula --X.sub.1 --X.sub.2 --Z.sub.5, wherein Z.sub.5 preferably is reactive esterified hydroxy, is reacted with a compound of the formula ##STR11## in which Z.sub.4 is hydroxy or mercapto, following the method as described in process c).
If one of variables Z.sub.3 and Z.sub.5 represents reactive esterified hydroxy, the other preferably represents hydroxy or mercapto. A compound of the formula IVb can be obtained, for example, by convening Z.sub.2 of a compound of the formula ##STR12## in which Z.sub.2 is a radical which can be converted into the variable --C(.dbd.NH)--NH--R.sub.3 following the method as described in process b). Compounds of formulae (IIb) and (IIc) are known or can be prepared according to methods known per se.
Preferably, Z.sub.3 is a group of the formula X.sub.1 --X.sub.2 --Z.sub.5, wherein Z.sub.5 preferably is reactive esterfied hydroxy, such as chlorine or bromine, and Z.sub.4 is hydroxy or furthermore mercapto. A corresponding compound of the formula IIb can be obtained, for example, by reacting a compound of the formula Z.sub.5 --X.sub.2 --Z.sub.5 (IId) with a compound of the formula ##STR13## preferably in the presence of a base.
In order to prepare the starting material of the formula IIIa, Z.sub.1 of a compound of the formula (IIb) is converted into radical --CO--R.sub.1 following the method as described in process a) resulting in compound of the formula ##STR14## which, in the next step, is reacted with a compound of the formula (IIc) following the method as described in process c).
Relating to compounds wherein R.sub.2 represents lower alkoxy substituted by carboxy, by esterified carboxy or by amidated carboxy, such compounds can be prepared from intermediates obtained by alkylation of starting materials or intermediates wherein R.sub.2 is hydroxy with the appropriate reactive esterified hydroxy-substituted carboxylic acids or amides, e.g. the bromo-substituted lower alkyl carboxylic acid esters or amides. The esters can in turn be convened to the carboxylic acids or amides by methods well-known in the art. The starting materials and intermediates wherein R.sub.2 is hydroxy are prepared from compounds wherein R.sub.2 is e.g. methoxy by solvolysis thereof, e.g. with boron tribromide.
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 salts or optically pure antipodes.
A compound according to the invention which is obtainable by the process can be convened into another compound according to the invention in a manner known per se.
If one of the variables contains mono-substituted amino (for example R.sub.1), corresponding compounds of the formula I or salts thereof can be N-alkylated in a manner known per se; likewise, N-mono-substituted carbamoyl (for example R.sub.1) can further be N-alkylated. The (aryl-)alkylation is carried out, for example, using a reactive ester of an (aryl-)C.sub.1 -C.sub.7 -alkyl halide, for example a bromide or iodide, an (aryl-)C.sub.1 -C.sub.7 -alkylsulfonate, for example a methanesulfonate or p-toluenesulfonate, or a di-C.sub.1 -C.sub.7 -alkyl sulfate, for example dimethyl sulfate, preferably under basic conditions, such as in the presence of sodium hydroxide solution or potassium hydroxide solution, and advantageously in the presence of a phase-transfer catalyst, such as tetrabutylammonium bromide or benzyltrimethylammonium chloride, where, however, stronger basic condensing agents, such as alkali metal amides, hydrides or alkoxides, for example sodium amide, sodium hydride or sodium ethoxide, may be necessary.
If R.sub.3 is hydrogen, the corresponding amidino group can be N-acylated accordingly. The acylation is carried out in a manner known per se using a suitable acylating agent. An example of a suitable acylating agent is a compound of the formula Ac-Z.sub.7, where Ac denotes an acyl radical corresponding to the variable R.sub.3, and Z.sub.7 denotes in particular reactive activated hydroxyl. Appropriate hydroxyl can be activated, for example, by strong acids such as hydrohalic or carboxylic acid, for example by hydrochloric, hydrobromic acid, an optionally substituted, for example by halogen, alkanecarboxylic acid or by an acid of the formula Ac-OH, or by suitable activating or coupling reagents of the type detailed hereinafter, in particular in situ. Ac-Z.sub.7 can furthermore represent an activated ester, where Z.sub.7 denotes, in particular, cyanomethoxy, phenoxy, (4-)nitrophenoxy or polyhalogeno-, such as pentachlorophenoxy. Activating and coupling reagents which can be employed are, in particular, carbodiimides, for example N,N'-di-C.sub.1 -C.sub.4 -alkyl- or N,N'-di-C.sub.5 -C.sub.7 -cycloalkyl-carbodiimide, such as diisopropylcarbodiimide or N,N'-dicyclohexylcarbodiimide, advantageously with the addition of an activating catalyst such as N-hydroxysuccinimide or optionally substituted, for example by halogen, C.sub.1 -C.sub.7 -alkyl or C.sub.1 -C.sub.7 -alkoxy, N-hydroxy-benzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxamide, furthermore C.sub.1 -C.sub.4 -alkyl halogenoformate, for example isobutyl chloroformate, suitable carbonyl compounds, for example N,N-carbonyldiimidazole, suitable 1,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1,2-oxazolium 3'-sulfonate or 2-tert-butyl-5-methy-isoxazolium perchlorate, suitable acylamino compounds, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or suitable phosphoryl cyanamides or azides, for example diethylphosphoryl cyanamide or diphenylphosphoryl azide, furthermore triphenylphosphine disulfide or 1-C.sub.1 -C.sub.4 -alkyl-2-halogeno-pyridinium halides, for example 1-methyl-2-chloropyridinium iodide. Z.sub.7 preferably denotes halogen such as chlorine or bromine, Ac-O--, and advantageously phenoxy.
If the compounds of the formula (I), (IA) or (IB) contain unsaturated radicals, such as (lower)alkenyl groups, these can be converted into saturated radicals in a manner known per se. Thus, for example, multiple bonds are hydrogenated by catalytic hydrogenation in the presence of hydrogenation catalysts, suitable for this purpose being, for example, nickel, such as Raney nickel, and noble metals or their derivatives, for example oxides, such as palladium or platinum oxide, which may be applied, if desired, to support materials, for example to carbon or calcium carbonate. The hydrogenation may preferably carried out at pressures between 1 and about 100 at and at room temperature between about -80.degree. to about 200.degree. C., in particular between room temperature and about 100.degree. C. The reaction is advantageously carried out in a solvent, such as water, a lower alkanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a lower alkanecarboxylic acid, for example acetic acid.
The invention also relates to any novel starting materials and processes for their manufacture and their use.
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 substantially pure geometric (cis or trans) isomers, optical isomers (antipodes), racemates, or mixtures thereof. The aforesaid possible isomers or mixtures thereof are within the purview of this invention.
Any resulting mixtures of isomers can be separated on the basis of the physico-chemical differences of the constituents, into the pure geometric or optical isomers, diastereoisomers, racemates, for example by chromatography and/or fractional crystallization.
Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g. by separation of the diastereoisomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. Racemic amidines (wherein R.sub.3 represents hydrogen) can thus be resolved into their optical antipodes e.g. by fractional crystallization of a salt formed with an optically active acid.
Finally, the compounds of the invention are either obtained in the free form, or as a salt thereof.
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 their crystallization.
The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, to antagonize LTB.sub.4 receptors, and for the treatment of a condition or syndrome responsive to the selective antagonism of LTB.sub.4 receptors, comprising an effective amount of a pharmacologically active compound of the invention, alone or in combination, with one or more pharmaceutically acceptable carriers.
The novel pharmaceutical products contain, for example, from about 10% to about 80%, preferably from about 20% to about 60%, of the active compound. Examples of pharmaceutical products according to the invention for enteral or parenteral administration are those in dose-unit forms such as coated tablets, tablets, capsules or suppositories, as well as ampoules. These are prepared in a manner known per se, for example using conventional mixing, granulating, coating, dissolving or freeze-drying processes. Thus, pharmaceutical products for oral use can be obtained by combining the active compound with solid excipients, where appropiate granulating a mixture which is obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable auxiliaries to tablets or cores of coated tablets.
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 a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbants, 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. Cores of coated tablets are provided with suitable, optionally enteric, coatings, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose products such as acetyl cellulose phthalate or hydroxypropylmethylcellulose phthalate. Colorants or pigments can be added to the tablets or coatings of coated tablets, for example, to identify or to indicate various doses of active compound. In addition, they 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.
Suitable formulations for topical application, e.g. to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art.
Suitable formulations for transdermal application include an effective mount of a compound of the invention with carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and. predetermined rate over a prolonged period of time, and means to secure the device to the skin.
In conjunction with another active ingredient, a compound of the invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
The invention further particularly relates to a method for the treatment of a condition or syndrome responsive to the selective antagonism of LTB.sub.4 receptors, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, non-steroidal-an antiinflammatory-drug-induced gastropathy, adult respiratory distress syndrome (ARDS), myocardial infarction, allergic rhinitis, hemodialysis-induced neutropenia, and late phase asthma; also for the treatment of osteoarthritis, of pain and of ocular allergies and inflammations; and also for the treatment of atopic and contact dermatitis.
The dosage of active compound administered is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, and on the form of administration. A unit dosage for oral administration to a mammal of about 70 kg may contain e.g. between about 1 and about 1000 mg/kg per day 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 Centrigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and 100 mm Hg. The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g. microanalysis and spectroscopic characteristics (e.g. MS, IR, NMR). Abbreviations used are those conventional in the art.
The compounds wherein R.sub.3 is not hydrogen have been assigned the isomeric structure in which R.sub.3 is located on the imino (C.dbd.N) nitrogen of the amidine group; however, such may also exist in the isomeric form in which R.sub.3 is on the amino nitrogen of the amidine group.

EXAMPLE 1
A stirred, 0.degree. C. solution of ethyl 5-[5-(4-cyanophenoxy)pentyloxy]-2-[N-(1-methyl ethyl)-N-phenylaminocarbonyl]phenoxyacetate (200 mg, 0.44 mmol) in 2.0 mL of anhydrous dichloromethane and 150 mL of anhydrous ethanol at 0.degree. C. is treated with anhydrous hydrogen chloride gas over 30 minutes. This solution is stirred at room temperature for 20 hours and the resulting solution is concentrated in vacuo. The resulting ethyl 4-[5-[3-ethoxycarbonylmethoxy-4-[N-(1-methylethyl)-N-phenyl-aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride is then dissolved in 50 mL of anhydrous ethanol in a pressure tube, and treated with anhydrous ammonia for 5 minutes at 0.degree. C. The pressure tube is sealed and heated to 100.degree. C. for 1 hour. Upon cooling and concentrating in vacuo, the resulting material is purified by chromatography on silica gel (15 g) with 5-20% methanol/diehloromethane as the eluent to afford 4-[5-[4-(amino-iminomethyl)phenoxy]pentyloxy]-2-carbamoylmethoxy-N-(1-methylethyl)-N-phenylbenzamide monohydrochloride as colorless foam; CHN calculated for C.sub.30 H.sub.37 CIN.sub.4 O.sub.5 -0.5 H.sub.2 O:
Theory: % C: 62.33; % H: 6.63; % N: 9.69;
Found: % C: 62.05; % H: 6.68; % N: 9.54.
IR(cm.sup.-1): 1673, 1653, 1609; MS 527 (M+1).
The starting material, ethyl 5-[5-(4-cyanophenoxy)pentyloxy]-2-[N-(1-methylethyl)-N-phenylaminocarbonyl]phenoxyacetate, can be prepared, for example, as follows:
A stirred solution of 2,4-dimethoxybenzoic acid (4.31 g, 23.7 mmol) in 35 mL of dichloromethane is treated with N-isopropylaniline (3.07 mL, 21.33 mmol), hydroxybenzotriazole (3.2 g, 23.7 mmol), and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (4.54 g, 23.7 mmol). This solution is stirred at room temperature for 18 hours and the resulting solution is partitioned between ethyl acetate and 1N hydrochloride solution. The organic layer is washed with water, dried over sodium sulfate and concentrated. The resulting material is purified by chromatography on silica gel (150 g) with 40-60% ethyl acetate/hexane as the eluent to afford 2,4-dimethoxy-N-(1-methylethyl)-N-phenylbenzamide as a colorless foam.
A stirred solution of 2,4-dimethoxy-N-(1-methylethyl)-N-phenylbenzamide (2.4 g, 8.03 mmol) in 10 ml of dichloromethane at 0.degree. C. was treated with 1N boron tribromide (33.2 mL, 33.2 mmol) and stirred at room temperature for 1 hour. The reaction is poured in to the ice water. After stirring for 15 minutes, the reaction was partitioned between ethyl acetate and brine, dried over magnesium sulfate and concentrated in vacuo to afford yellow foam. This material is purified by chromatography on silica gel (70 g) with 3-5% methanol/dichloromethane as the eluent to afford 2,4-dihydroxy-N-(1-methylethyl)-N-phenylbenzamide as colorless foam.
A stirred solution of 2,4-dihydroxy-N-(1-methylethyl)-N-phenylbenzamide (358 mg, 1.32 mmol) in 6 mL of N,N-dimethylformamide is treated with cesium carbonate (520 mg, 1.58 mmol), and 5-(4-cyanophenoxy)pentyl bromide (U.S. Pat. No. 4,451,476, 354 mg, 1.32 mmol) and stirred at 40.degree. C. for 24 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 30-70% ethyl acetate/hexane as the eluent to afford 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N-(1-methylethyl)-N-phenylbenzamide as colorless foam.
A stirred solution of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N-(1-methylethyl)-N-phenylbenzamide (250 mg, 0.55 mmol) in 2.5 mL of N,N-dimethylformamide is treated with 60% sodium hydride (22 mg, 0.55 mmol), and ethyl bromoacetate (67 .mu.L, 0.60 mmol) and heated at 70.degree. C. for 2.5 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 50-70% ethyl acetate/hexane as the eluent to afford ethyl 5-[5-(4-cyanophenoxy)pentyloxy]-2-[N-(1-methylethyl)-N-phenylaminocarbonyl]phenoxyacetate as colorless foam.
EXAMPLE 2
A stirred, 0.degree. C. solution of ethyl 4-[5-[3-ethoxycarbonylmethoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride (400 mg, 0.68 mmol) in 25 mL of anhydrous ethanol is treated with 1.36 mL of 1.0N aqueous sodium hydroxide. After stirring 1.5 hours, the reaction is concentrated in vacuo. The resulting 5-[5-[4-(ethoxyiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxyacetic acid is then dissolved in 50 mL of anhydrous ethanol in a pressure tube, and treated with ammonium chloride (500 mg, 9.4 mmol). This mixture is treated with anhydrous ammonia for 2 minutes at 0.degree. C. The pressure tube is sealed and heated to 50.degree. C. for 1 hour. Upon cooling and concentrating in vacuo, the resulting material is purified by chromatography on silica gel (15 g) with 20-30% methanol/dichloromethane as the eluent to afford a colorless foam. The resulting 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxyacetic acid monohydrochloride is then dissolved in 150 mL of anhydrous ethanol at 0.degree. C. and treated with anhydrous hydrogen chloride gas over 30 minutes. This solution is stirred at room temperature for 20 hours and the resulting solution is concentrated in vacuo. The resulting material is purified by chromatography on silica gel (15 g) with 5-20% methanol/dichloromethane as the eluent to afford ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxyacetate monohydrochloride as colorless foam; CHN calculated for
C.sub.29 H.sub.42 CIN.sub.3 O.sub.6 -1.0 H.sub.2 O:
Theory: % C: 59.83; % H: 7.62; % N: 7.22;
Found: % C: 59.92; % H: 7.22; % N: 7.37.
IR(cm.sup.-1): 1758, 1667, 1609.
The starting material, ethyl 4-[5-[3-ethoxycarbonylmethoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride, can be prepared, for example, as follows:
A stirred solution of 2,4-dimethoxybenzoyl chloride (10.0 g, 50 mmol) in 10 mL of dichloromethane at 0.degree. C. is treated with 30 mL of diisopropylamine. This solution is stirred at room temperature for 1 hour and the resulting solution is partitioned between ethyl acetate and water. The organic layer is washed with 1N hydrochloride solution, 1N sodium hydroxide solution, water and brine, dried over sodium sulfate and concentrated in vacuo to give 2,4-dimethoxy-N,N-bis(1-methylethyl)benzamide.
A solution of 2,4-dimethoxy-N,N-bis(1-methylethyl)benzamide (3.0 g, 11.0 mmol) in 10 ml of dichloromethane at 0.degree. C. is treated with 1N boron tribromide (33.0 mL, 33.0 mmol) and stirred at room temperature for 2 hours. The reaction is concentrated in vacuo, dissolved in 1N sodium hydroxide solution, and acidified with 1N hydrochloric acid to generate solid which is filtered to afford 2,4-dihydroxy-N,N-bis(1-methylethyl)benzamide as white solid.
A solution of 2,4-dihydroxy-N,N-bis(1-methylethyl)benzamide (3 g, 12.7 mmol) in 30 mL of N,N-dimethylformamide is treated with cesium carbonate (4.97 g, 15.2 mmol), and 5-(4-cyanophenoxy)pentyl bromide (3.4 g, 1.27 mmol) and stirred at 40.degree. C. for 24 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 30-70% ethyl acetate/hexane as the eluent to afford 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide as colorless foam.
A stirred solution of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide (0.5 g, 1.18 mmol) in 10.0 mL of N,N-dimethylformamide is treated with 60% sodium hydride (47 mg, 1.18 mmol) and ethyl bromoacetate (144 .mu.L, 1.3 mmol), and heated at 70.degree. C. for 2.5 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford yellow foam. The resulting ethyl 5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxyacetate in 50 mL of anhydrous ethanol at 0.degree. C. is treated with anhydrous hydrogen chloride gas over 30 minutes. This solution is stirred at room temperature for 20 hours and concentrated in vacuo. This material is purified by chromatography on silica gel with 60% ethyl acetate/hexane as the eluent to afford ethyl 4-[5-[3-ethoxycarbonylmethoxy-4-[N,N-bis(1- methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride as colorless foam.
EXAMPLE 3
A stirred, refluxing mixture of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide (0.5 g, 1.18 mmol), sodium hydroxide (480 mg, 1.2 mmol), and 50 mL of acetone is treated with chloroform (125 .mu.L, 1.6 mmol) in 20 mL of acetone. The reaction is refluxed for 4 hours and concentrated in vacuo. The resulting material is partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The resulting material is purified by chromatography on silica gel (20 g) with 40-100% ethyl acetate/hexane followed by 10% MeOH/ethyl acetate as the eluent to afford 5-[5-[4-cyanophenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetic acid as colorless foam. A stirred, 0.degree. C. solution of 5-[5-[4-cyanophenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetic acid (210 mg, 0.411 mmol) in 2.0 mL of anhydrous dichloromethane and 150 mL of anhydrous ethanol at 0.degree. C. is treated with anhydrous hydrogen chloride gas over 30 minutes. This solution is stirred at room temperature for 20 hours and the resulting solution is concentrated in vacuo. The resulting ethyl 4-[5-[3-ethoxycarbonyldimethylmethoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride is then dissolved in 50 mL of anhydrous ethanol in a pressure tube, and treated with anhydrous ammonia for 5 minutes at 0.degree. C. The pressure tube is sealed and heated to 100.degree. C. for 1 hour. Upon cooling and concentrating in vacuo, the resulting material is purified by chromatography on silica gel (15 g) with 5-20% methanol/dichloromethane as the eluent to afford ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate monohydrochloride as colorless foam; CHN calculated for C.sub.31 H.sub.46 CIN.sub.3 O.sub.6 -1.25 H.sub.2 O:
Theory: % C: 60.57; % H: 7.95; % N: 6.84:
Found: % C: 60.57; % H: 7.92; % N: 6.92.
MS: 6.12 (M+1).
EXAMPLE 4
In a way analogously as described in the previous examples, the following compounds can be prepared:
(a) 4-[5-[4-(Aminoiminomethyl)phenoxy]pentyloxy]-2-(dimethylcarbamoylmethoxy)-N,N-bis(1-methylethyl)benzamide monohydrochloride is obtained from ethyl 4-[5-[3-(dimethylcarbamoylmethoxy)-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride as colorless foam;
CHN calculated for C.sub.29 H.sub.43 CIN.sub.4 O.sub.5 -2.5 H.sub.2 O:
Theory: % C : 57.27; % H: 7.96; % N: 9.21;
Found: % C: 57.65; % H: 7.73; % N: 8.88.
IR(cm.sup.-1): 1673, 1653, 1609.
The starting alkylating material is .alpha.-bromo-N,N-dimethylacetamide.
(b) 4-[5-[4-(Aminoiminomethyl)phenoxy]pentyloxy]-2-(diethylcarbamoylmethoxy)-N,N-bis(1-methylethyl)benzamide monohydrochloride is obtained from ethyl 4-[5-[3-(diethylcarbamoylmethoxy)-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride as colorless foam; CHN calculated for C.sub.31 H.sub.47 CIN.sub.4 O.sub.5 -0.5 H.sub.2 O:
Theory: % C: 62.04; % H: 8.06; % N: 9.33;
Found: % C: 61.90; % H: 8.07; % N: 9.25.
IR(cm.sup.-1): 1667, 1644, 1610.
The starting alkylating material is .alpha.-bromo-N,N-diethylacetamide.
(c) 4-[5-[4-(Aminoiminomethyl)phenoxy]pentyloxy]-N,N-bis(1-methylethyl)-2-[bis(1-methylethyl)carbamoylmethoxy]benzamide monohyclrochloride is obtained from ethyl 4-[5-[3-[bis(1-methylethyl)carbamoylmethoxy]-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride as colorless foam; CHN calculated for C.sub.33 H.sub.51 CIN.sub.4 O.sub.5 -1.0 H.sub.2 O:
Theory: % C: 62.20; % H: 8.38; % N: 8.79;
Found: % C: 62.36; % H: 8.05; % N: 8.72.
IR(cm.sup.-1): 1666, 1640, 1609.
The starting alkylating material is .alpha.-bromo-N,N-diisopropylacetamide.
(d) Ethyl 5-[5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[bis(1-methylethyl)carbamoyl]phenoxy]pentanoate monohydrochloride is obtained from ethyl 4-[5-[3-ethoxycarbonylbutoxy-4-[N,N-bis(1- methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride as colorless foam; CHN calculated for C.sub.32 H.sub.48 CIN.sub.3 O.sub.6 :
Theory: % C: 63.40; % H: 7.78; % N: 6.93;
Found: % C: 63.02; % H: 7.87; % N: 7.15.
IR(cm.sup.-1): 1728, 1674, 1609.
The starting alkylating material is ethyl 5-bromopentanoate.
(e) 4-[5-[4-(Aminoiminomethyl)phenoxy]pentyloxy]-2-carbamoylmethoxy-N,N-bis(1-methylethyl)benzamide monohydrochloride is obtained from ethyl 4-[5-[3-ethoxycarbonylmethoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride as colorless foam; CHN calculated for C.sub.27 H.sub.39 CIN.sub.4 O.sub.5 -1.5 H.sub.2 O:
Theory: % C: 57.69; % H: 7.53; % N: 9.97;
Found: % C: 57.64; % H: 7.34; % N: 9.88.
IR(cm.sup.-1): 1676, 1608.
The starting alkylating material is ethyl .alpha.-bromoacetate.
EXAMPLE 5
To a mixture of 0.47 g (1.0 mmol) of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-carbamoylmethoxy-N,N-bis(1-methylethyl)benzamide in 10 ml of methylene chloride is added 0.14 g (1.0 mmol) of phenyl acetate. The mixture is stirred at room temperature for 4 hours and then poured onto a silica gel column and eluted with ethyl acetate, and then 10% methanol/ethyl acetate to give 4-[5-[4[(acetylimino)aminomethyl]-phenoxy]-pentyloxy]-2-carbamoylmethoxy-N,N-bis(1-methylethyl)benzamide as a foam; CHN calculated for C.sub.29 H.sub.40 N.sub.4 O.sub.8.0.5H.sub.2 O:
Theory: % C: 63.37; % H; 7.52; % N: 10.19;
Found: % C: 63.41; % H; 7.53; % N: 9.85;
NMR (CDCl.sub.3): 7.80 (d, 2H), 6.95 (d, 1H), 6.85 (d, 2H), 6.45 (dd, 1H), 6.40 (d, 1H), 4.45 (d, 2H), 3.95 (t, 2H), 3.90 (t, 2 h), 3.80 (br, 1H), 3.45 (br, 1H), 2.20 (s, 3H), 1.80 (m, 4H), 1.60 (m, 2H), 1.45 (br, 6H), 1.05 (br, 6H).
EXAMPLE 6
To a mixture of 0.85 g (1.4 mmol) of ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate monohydrochloride in 10 ml of methylene chloride is added 0.39 g (2.8 mmol) of phenyl acetate and 1 ml of triethylamine. The mixture is stirred at room temperature for 2 days and then poured onto a silica gel column and eluted with 80% ethyl acetate/hexane, and then pure ethyl acetate to give ethyl 5-[5-[4-[(acetylimino)aminomethyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate as a foam; CHN calculated for C.sub.33 H.sub.47 N.sub.3 O.sub.7.0.5H.sub.2 O:
Theory: % C: 65.32; % H; 7.97; % N: 6.93;
Found: % C: 65.23; % H; 7.67; % N: 6.84;
NMR (CDCl.sub.3): 7.80 (d, 1H), 6.80 (d, 2H), 6.70 (d, 2H), 6.35 (dd, 1H), 6.20 (d, 1H), 4.10 (q, 2H), 3.90 (t, 2H), 3.80 (t, 2H), 3.70 (septet, 1H), 3.45 (septet, 1H), 2.10 (s, 3H), 1.70 (m, 4H), 1.50 (m, 2H), 1.45 (s, 3H), 1.40 (s, 3H), 1.40 (d, 6H), 1.10 (d, 3H), 1.10 (t, 3H), 0.9 (d, 3H).
EXAMPLE 7
To a mixture of 0.2 g (0.34 mmol) of ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate monohydrochloride in 10 ml of methylene chloride is added 0.11 g (0.67 mmol) of isonicotinoyl chloride hydrochloride and 0.5 ml of triethylamine. The mixture is stirred at room temperature for 2 days and then poured onto a silica gel column and eluted with 80% ethyl acetate/hexane to afford ethyl 5-[5-[4-[(isonieotinoylimino)aminomethyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate as a foam; CHN calculated for C.sub.37 H.sub.48 N.sub.4 O.sub.7.0.5H.sub.2 O;
Theory: % C: 66.35; % H; 7.37; % N: 8.36;
Found: % C: 66.71; % H; 7.15; % N: 8.21;
NMR (CDCl.sub.3): 10.60 (br, 1H); 8.60 (br, 2H), 8.50 (br, 1H), 8.05 (br, 2H), 8.00 (d, 2H), 6.90 (d, 1H), 6.80 (d, 2H), 6.40 (dd, 1H), 6.20 (d, 1H), 4.10 (q, 2H), 3.90 (t, 2H), 3.80 (t, 2H), 3.70 (septet, 1H), 3.40 (septet, 1H), 1.70 (m, 4H), 1.60 (m, 2H), 1.50 (s, 3H), 1.45 (d, 6H), 1.40 (s, 3H), 1.10 (t, 3H), 1.10 (d, 3H), 0.90 (d, 3H).
EXAMPLE 8
A mixture of 0.16 g (0.26 mmol) of ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate monohydrochloride and 10 ml of 6N hydrochloric acid is heated to reflux for 16 hours. The mixture is cooled to room temperature and then concentrated under reduced pressure at 50.degree. C. to afford 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetic acid as an oil; CHN calculated for C.sub.29 H.sub.41 N.sub.3 O.sub.6.HCl.0.5H.sub.2 O:
Theory: % C: 60.77; % H; 7.56; % N: 7.33;
Found: % C: 60.47; % H; 7.56; % N: 7.25;
NMR (CH.sub.3 OD): 9.10 (br, 1H), 8.55 (br, 1H), 7.80 (d, 2H), 7.10 (d, 2H), 7.00 (d, 1H), 6.60 (dd, 1H), 6.40 (d, 1H), 4.15 (t, 2H), 4.00 (t, 2H), 3.80 (septet, 1H), 3.60 (septet, 1H), 1.90 (m, 4H), 1.70 (m, 2H), 1.60 (s, 3H), 1.55 (s, 3H), 1.50 (d, 6H), 1.25 (d, 3H), 1.05 (d, 3H).
EXAMPLE 9
Similarly to procedures described in the previous examples, the following compounds can be prepared:
(a) Ethyl 5-[5-[4-[amino(propanoylimino)methyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate as a colorless foam; CHN calculated for C.sub.34 H.sub.49 N.sub.3 O.sub.7 :
Theory: % C: 65.78; % H: 8.12; % N: 6.77;
Found: % C: 65.87; % H: 7.99; % N: 6.62;
IR(cm.sup.-1): 1732, 1607.
(b) Ethyl 5-[5-[4-[amino(propanoylimino)methyl]phenoxy]-pentyloxy]-2-[N-phenyl-N-(1-methylethyl)aminocarbonyl]phenoxydimethylacetate as an oil; CHN calculated for C.sub.37 H.sub.47 N.sub.3 O.sub.7 :
Theory: % C: 68.81; % H; 7.34; % N: 6.51;
Found: % C: 68.55; % H; 7.10; % N: 6.24;
IR(cm.sup.-1): 1730, 1608.
(c) Ethyl 5-[5-[4-(iminoaminomethyl)-phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy-4-butanoate monohydrochloride as a colorless solid; CHN calculated for C.sub.31 H.sub.46 CIN.sub.3 O.sub.6.0.5H.sub.2 O:
Theory: % C: 61.93; % H; 7.88; % N: 6.99;
Found: % C: 61.99; % H; 8.04; % N: 7.02;
IR(cm.sup.-1): 1729; MS: 556(M+1).
(d) Ethyl 5-[5-[4-[(acetylimino)aminomethyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy-4-butanoate, as an oil; CHN calculated for C.sub.33 H.sub.47 N.sub.3 O.sub.7 :
Theory: % C: 66.31; % H; 7.93; % N: 7.03;
Found: % C: 65.97; % H; 7.67; % N: 6.89;
IR(cm.sup.-1): 1727, 1608; MS: 599(M+1).
(e) 5-[5-[4-(Iminoaminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)-aminocarbonyl]phenoxy-4-butanoic acid monohydrochloride, as a colorless solid; CHN calculated for C.sub.29 H.sub.42 CIN.sub.3 O.sub.6. H.sub.2 O:
Theory: % C: 59.82; % H; 7.62; % N: 7.22;
Found: % C: 60.06; % H; 7.66; % N: 6.64.
(f) Ethyl 5-[5-[4-[(3-pyridylearbonylimino)aminomethyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy-4-butanoate, as an oil; CHN calculated for C.sub.37 H.sub.48 N.sub.4 O.sub.7 :
Theory: % C: 67.26; % H; 7.32; % N: 8.48;
Found: % C: 66.93; % H; 7.40; % N: 8.37;
IR(cm.sup.-1): 1727, 1606.
(g) Ethyl 5-[5-[4-[(3-pyridylcarbonylimino)aminomethyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxydimethylacetate as a colorless foam; CHN calculated for C.sub.37 H.sub.48 N.sub.4 O.sub.7 :
Theory: % C: 67.26; % H; 7.32; % N: 8.48;
Found: % C: 66.93; % H; 7.23; % N: 8.31;
IR(cm.sup.-1): 1728, 1608; MS: 528(M+1).
EXAMPLE 10
a) Preparation of 10,000 tablets each containing 20 mg of the active ingredient, for example, the compound of example 6:
______________________________________active ingredient 200.00 gLactose 2,535.00 gCorn starch 125.00 gPolyethylene glycol 6,000 150.00 gMagnesium stearate 40.00 gPurified water q.s.______________________________________
Procedure:
All the powders are passed through a screen with openings of 0.6 mm. The drug substance, lactose, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 250 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.degree. C. broken on a screen with 1.2 mm openings and compressed into tablets, using concave punches uppers bisected.
Analogously tablets are prepared, containing about 10-100 mg of one of the other compounds disclosed and exemplified herein.
b) Preparation of 1,000 capsules each containing 40 mg of the active ingredient, for example, the compound of example 6:
______________________________________active ingredient 40.00 gLactose 177.00 gModified starch 80.00 gMagnesium stearate 3.00 g______________________________________
Procedure:
All the powders are passed through a screen with openings of 0.6 mm. The drug substance is placed in a suitable mixer and mixed first with the magnesium stearate, then with the lactose and starch until homogenous. No. 2 hard gelatin capsules are filled with 300 mg of said mixture each, using a capsule filling machine.
Analogously capsules are prepared, containing about 10-100 mg of the other compounds disclosed and exemplified herein.
(c) Preparation of 3000 capsules each containing 25 mg of the active ingredient, for example, the compound of example 6:
______________________________________Active ingredient 75.00 gLactose 750.00 gAvicel PH 102 300.00 g(microcrystalline cellulose)Polyplasdone XL 30.00 g(polyvinylpyrrolidone)Purified water q.s.Magnesium stearate 9.0 g______________________________________
The active ingredient is passed through a No. 30 hand screen.
The active ingredient, lactose, Avicel PH 102 and Polyplasdone XL are blended for 15 minutes in a mixer. The blend is granulated with sufficient water (about 500 mL), dried in an oven at 35.degree. C. overnight, and passed through a No. 20 screen.
Magnesium stearate is passed through a No. 20 screen, added to the granulation mixture, and the mixture is blended for 5 minutes in a mixer. The blend is encapsulated in No. 0 hard gelatin capsules each containing an mount of the blend equivalent to 25 mg of the active ingredient.

Claims

1. A compound of the formula ##STR15## wherein the C(.dbd.NH)--NHR.sub.3 group may be in tautomeric or isomeric form,
R.sub.1 is amino which is mono- or disubstituted by a substituent selected from an aliphatic hydrocarbon radical, an araliphatic hydrocarbon radical, an aromatic radical, and a cycloaliphatic hydrocarbon radical, or is amino which is disubstituted by a divalent aliphatic hydrocarbon radical or a said radical interrupted by oxygen;
R.sub.2 is hydroxy which is etherified by an aliphatic alcohol which is substituted by carboxy, by esterfied carboxy or by amidated carboxy;
R.sub.3 is hydrogen or an acyl radical which is derived from an organic carbonic acid, an organic carboxylic acid, a sulfonic acid, or a carbamic acid;
X.sub.1 and X.sub.3, independently of one another, are oxygen (--O--) or sulphur (--S--); and
X.sub.2 is a divalent aliphatic hydrocarbon radical which may be interrupted by an aromatic radical;
wherein the phenyl rings of formula I may be, independently of one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterfied by an aliphatic or araliphatic carboxylic acid;
wherein aryl in the above definitions may be, independently of one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid;
wherein a cycloaliphatic hydrocarbon radical may be substituted by an aliphatic radical; or
a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein
R.sub.1 is amino which is mono- or disubstituted by a substituent selected from lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl, phenyl, naphthyl, indanyl, fluorenyl, cycloalkyl, and cycloalkenyl, cycloalkyl and cycloalkenyl each being unsubstituted or mono- or polysubstituted by lower alkyl, or is amino which is disubstituted by lower alkylene;
R.sub.2 is lower alkoxy substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or mono- or di-lower alkylaminocarbonyl;
R.sub.3 is hydrogen, alkoxycarbonyl or alkenyloxycarbonyl, each of which is unsubstituted or substituted by phenyl, naphthyl, indanyl or fluorenyl, or is cycloalkoxycarbonyl being unsubstituted or mono- or polysubstituted by lower alkyl, or is lower alkanoyl or phenyl-lower alkanoyl, or is benzoyl, naphthoyl, indanoyl or fluorenoyl, or is C.sub.1 -C.sub.7 alkanesulfonyl, phenyl-C.sub.1 -C.sub.7 alkanesulfonyl, C.sub.3 -C.sub.7 -cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which is substituted by lower alkyl, phenyl-lower alkyl or phenyl;
X.sub.1 and X.sub.3, independently of one another, are O or S;
X.sub.2 is lower alkylene, lower alkylene-phenylene-lower alkylene or lower alkylene-naphthylene-lower alkylene;
wherein the phenyl rings of formula I may be, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy, lower alkenoyloxy and phenyl-lower alkanoyloxy;
wherein the aromatic radicals in the above definitions may be, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, lower alkanoyloxy, lower alkenoyloxy and phenyl-lower alkanoyloxy; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 wherein
R.sub.1 is amino which is mono- or disubstituted by a substituent selected from C.sub.1 -C.sub.7 -alkyl, phenyl-C.sub.1 -C.sub.7 -alkyl, phenyl and C.sub.3 -C.sub.6 -cycloalkyl, C.sub.3 -C.sub.6 -cycloalkyl being unsubstituted or mono- or polysubstituted by C.sub.1 -C.sub.7 -alkyl, or is amino which is disubstituted by C.sub.3 -C.sub.6 -alkylene;
R.sub.2 is C.sub.1 -C.sub.7 -alkoxy substituted by carboxy or lower alkoxycarbonyl;
R.sub.3 is hydrogen, C.sub.1 -C.sub.12 -alkoxy-carbonyl, C.sub.2 -C.sub.5 -alkanoyl, phenyl-C.sub.2 -C.sub.5 -alkanoyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C.sub.1 -C.sub.7 -alkyl, or C.sub.1 -C.sub.7 -alkoxy, C.sub.3 -C.sub.6 -cycloalkylcarbonyl which is unsubstituted or substituted by C.sub.1 -C.sub.7 -alkyl, or is benzoyl, naphthoyl, indanoyl or fluorenoyl, or is C.sub.1 -C.sub.7 alkanesulfonyl, phenyl-C.sub.1 -C.sub.7 alkanesulfonyl, C.sub.3 -C.sub.7 -cycloalkanesulfonyl, or phenylsulfonyl, or is aminocarbonyl which is substituted by C.sub.1 -C.sub.7 -alkyl, phenyl-C.sub.1 -C.sub.7 -alkyl or phenyl;
X.sub.1 and X.sub.3 each are --O--;
X.sub.2 is C.sub.2 -C.sub.7 -alkylene or C.sub.2 -C.sub.4 -alkylene-phenylene-C.sub.2 -C.sub.4 -alkylene;
wherein the phenyl rings of formula I may be unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, C.sub.1 -C.sub.7 -alkyl, and C.sub.1 -C.sub.7 -alkoxy;
wherein phenyl in the above definitions is unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, C.sub.1 -C.sub.7 -alkyl, and C.sub.1 -C.sub.7 -alkoxy; or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 wherein --CO--R.sub.1 is located in position 4 (para) of the corresponding phenyl ring with respect to --X.sub.1 --; R.sub.2 -- is located in position 2 (ortho) or 3 (meta) of the corresponding phenyl ring with respect to --X.sub.1 --; and --C(.dbd.NH)--NHR.sub.3 is located in position 4 (para) of the corresponding phenyl ring with respect to --X.sub.3 --.
5. A compound according to claim 1 of the formula IA ##STR16## wherein the C(.dbd.NH)--NHR.sub.3 group may be in tautomeric or isomeric form,
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino, C.sub.1 -C.sub.4 alkyl-(phenyl)amino, C.sub.1 -C.sub.4 alkyl-(phenyl-C.sub.1 -C.sub.4 -alkyl)-amino, di-C.sub.3 -C.sub.6 -cycloalkylamino which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, or 1-piperidino substituted by C.sub.1 -C.sub.4 -alkyl;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxy which is substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or by mono- or di-lower alkylaminocarbonyl;
R.sub.3 is hydrogen, C.sub.1 -C.sub.12 -alkoxycarbonyl, phenyl-C.sub.1 -C.sub.4 -alkoxycarbonyl, C.sub.2 -C.sub.5 -alkanoyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C.sub.1 -C.sub.4 -alkyl or by C.sub.1 -C.sub.4 -alkoxy, or C.sub.3 -C.sub.6 -cycloalkylcarbonyl which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene;
wherein the phenyl rings of formula IA may be unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, C.sub.1 -C.sub.4 -alkyl and C.sub.1 -C.sub.4 -alkoxy; or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 5 wherein
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxy substituted by ethoxycarbonyl or aminocarbonyl; R.sub.3 is hydrogen or C.sub.2 -C.sub.5 -alkanoyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene; or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 6 wherein R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino; R.sub.2 has the meaning as given in claim 6, R.sub.3 is hydrogen or C.sub.2 -C.sub.5 -alkanoyl; X.sub.1 and X.sub.3 are --O--; and X.sub.2 is pentylene; or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 of formula IB ##STR17## wherein the C(.dbd.NH)--NHR.sub.3 group may be in tautomeric or isomeric form,
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino, C.sub.1 -C.sub.4 -alkyl-(phenyl)-amino, C.sub.1 -C.sub.4 -alkyl-(phenyl-C.sub.1 -C.sub.4 -alkyl)-amino, di-C.sub.3 -C.sub.6 -cycloalkylamino which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, or 1-piperidino substituted by C.sub.1 -C.sub.4 -alkyl;
R.sub.2 is C.sub.1 -C.sub.4 -alkoxy which is substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or by mono- or di-lower alkylaminocarbonyl;
R.sub.3 is hydrogen, C.sub.1 -C.sub.12 -alkoxycarbonyl, phenyl-C.sub.1 -C.sub.4 -alkoxycarbonyl, C.sub.2 -C.sub.5 -alkanoyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C.sub.1 -C.sub.4 -alkyl or by C.sub.1 -C.sub.4 -alkoxy, or C.sub.3 -C.sub.6 -cycloalkylcarbonyl which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl;
X.sub.1 and X.sub.3 are --O--;
X.sub.2 is C.sub.4 -C.sub.7 -alkylene;
wherein the phenyl rings of formula IB may be unsubstituted or, furthermore, independently of one another, substituted by one or more substituents selected from halogen, trifluoromethyl, C.sub.1 -C.sub.4 -alkyl, and C.sub.1 -C.sub.4 -alkoxy; or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 8 wherein
R.sub.1 is di-C.sub.1 -C.sub.4 -alkylamino;
R.sub.2 C.sub.1 -C.sub.4 -alkoxycarbonylmethoxy or aminocarbonylmethoxy;
R.sub.3 is hydrogen or C.sub.2 -C.sub.5 -alkanoyl;
X.sub.1 and X.sub.3 are --O--; and
X.sub.2 is C.sub.4 -C.sub.7 -alkylene; or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 8 wherein R.sub.2 is C.sub.1 -C.sub.4 -alkoxycarbonylmethoxy or carbamoylmethoxy, and X.sub.2 is pentylene.
11. 4-[5-[4-(Aminoiminomethyl)phenoxy]pentyloxy]-2-(diethylcarbamoylmethoxy)-N,N-bis(1-methylethyl)benzamide or a pharmaceutically acceptable salt thereof according to claim 1.
12. 4-[5-[4-(Aminoiminomethyl)phenoxy]pentyloxy]-2-N,N-bis(1-methylethyl)-2-[bis((1-methylethyl)carbamoylmethoxy]benzamide or a pharmaceutically acceptable salt thereof according to claim 1.
13. Ethyl 5-[5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[bis(1-methylethyl)carbamoyl]phenoxy]pentanoate or a pharmaceutically acceptable salt thereof according to claim 1.
14. Ethyl 5-[5-[4-[(Acetylimino)aminomethyl]phenoxy]pentyloxy]-2-[N,N-bis-(1- methylethyl)carbamoyl]phenoxydimethylacetate according to claim 1.
15. Ethyl 5-[5-[4-[(-isonicotinoylimino)aminomethyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate according to claim 1.
16. 5-[5-[4-(Aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetic acid or a pharmaceutically acceptable salt thereof according to claim 1.
17. Ethyl 5-[5-[4-[aminopropanoylimino)methyl]phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate according to claim 1.
18. Ethyl 5-[5-[4-[amino(propanoylimino)methyl]phenoxy]pentyloxy]-2-[N-phenyl-N-(1-methylethyl)aminocarbonyl]phenoxydimethylacetate according to claim 1.
19. Ethyl 5-[5-[4-(iminoaminomethyl)-phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy-4-butanoate or a pharmaceutically acceptable salt thereof according to claim 1.
20. A pharmaceutical composition suitable for antagonizing LTB.sub.4 in mammals comprising an effective LTB.sub.4 antagonizing amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
21. Process for the production of compounds of formula I defined in claim 1 and pharmaceutically acceptable salts thereof comprising
a) converting in a compound of the formula IIa ##STR18## or a salt thereof in which Z.sub.1 is a radical which can be converted into the variable --CO--R.sub.1, Z.sub.1 into the variable --CO--R.sub.1, or,
b) for the manufacture of compounds of the formula I in which R.sub.3 is hydrogen, in a compound of the formula IlIa ##STR19## or a salt thereof in which Z.sub.2 is a radical which can be converted into the variable --C(.dbd.NH)--NH--R.sub.3, converting Z.sub.2 into the variable --C(.dbd.NH)--NH--R.sub.3, or
c) reacting a compound of the formula IVa ##STR20## or a salt thereof with a compound of the formula IVb ##STR21## or a salt thereof in which Z.sub.3 is a group of the formula --X.sub.1 --X.sub.2 --Z.sub.5 and Z.sub.4 is --Z.sub.6, or Z.sub.3 is --Z.sub.6 and Z.sub.4 is a group of the formula Z.sub.5 --X.sub.2 --X.sub.3 --, wherein one of the radicals Z.sub.5 and Z.sub.6 is hydroxy or mercapto and the other is hydroxy, mercapto or reactive esterified hydroxy, and, if desired, converting a compound of the formula I or a salt thereof obtainable according to the process or in another manner into another compound or a salt thereof according to the invention, converting a free compound of the formula I obtainable according to the process into a salt, converting a salt obtainable according to the process into the free compound of the formula I or into another salt, or resolving a mixture of isomers obtainable according to the process and isolating the desired compound.
22. A method for the treatment of a condition or syndrome responsive to the selective antagonism of LTB.sub.4 which comprises administering to a mammal in need thereof an effective LTB.sub.4 antagonizing amount of a compound according to claim 1 in a pharmaceutically acceptable carrier.

Parent Case Info

This application is a 371 of PCT/US93/10876 filed Nov. 12, 1993 which is a Continuation-in-Part of 07/978,004 filed Jan. 18, 1992 now U.S. Pat. No. 5,451,700.

PCT Information

Filing Document	Filing Date	Country	Kind	102e Date	371c Date
PCT/US93/10876	11/12/1993			7/25/1995	7/25/1995

Publishing Document	Publishing Date	Country	Kind
WO94/11341

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Continuation in Parts (1)

	Number	Date	Country
Parent	978004	Nov 1992

Substituted amidino compounds, their manufacture and methods of treatment

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Abstract