IE46382B1 - Benzopyrans - Google Patents
BenzopyransInfo
- Publication number
- IE46382B1 IE46382B1 IE164/78A IE16478A IE46382B1 IE 46382 B1 IE46382 B1 IE 46382B1 IE 164/78 A IE164/78 A IE 164/78A IE 16478 A IE16478 A IE 16478A IE 46382 B1 IE46382 B1 IE 46382B1
- Authority
- IE
- Ireland
- Prior art keywords
- hydroxy
- oxo
- salt according
- pyrogen
- acetyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrane Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Salt formed with a basic amino sugar or basic amino acid by a compound of formula: the symbols having the meanings shown in Claim 1. They have an antagonist activity towards the slow-reacting substance of anaphylaxis.
Description
This invention concerns new compounds, processes for their preparation, and compositions containing them.
The new compounds of the present invention arc the salts with basic aminosugars or basic amino acids (i.e. those having more than one amino group) o£ the 5 compounds of formula I:
wherein r\ R7, R^, R4, R$ and R7 indy be the same or different^____·.
and. are hydrogen,, hydroxy, alkoxy,*aikojy'substituted by phenyl, carboxylic acyl, amino, 'acylamino,”alkenyl, halogen or alley 1, provided that at least
2 3 7 V10 one of R , R , R and R are other thaii. hydrogen and hydroxy,
3 7 or an adjacent pair of R , R , R and R either represent hydroxyl and a 3-(Ν,Ν-dialkylamino)acryloyl radical or together
I represent a chain
I
I
-COCH=CH- 0— j
X is a hydrocarbon chain containing from 2 to 10 carbon atoms and optionally substituted by a hydroxy group, and
B is a carboxy group or a tetrazole group.
The compounds of the present invention possess pharmacological properties. In particular, the compounds are antagonists of the 20 slow-reacting substance of anaphylaxis (SRS-A), or its pathological
- 2 4 6 3 8 2 effects, as is indicated by their activity in the test set out in Example A. The compounds also antagonise the effects of SRS-A obtained during antigen challenge of sensitized human chopped lung on isolated guinea pig ileum as described in Example A. Tne compounds also have the same utility at the same dosages as the compounds of Dutch Patent Specification Ko 68,11740.
The compounds are thus indicated for use in the treatment of disorders in which SRS-A is a factor, for example skin afflictions, hay fever and obstructive airway diseases, e.g. asthma.
For the above-mentioned uses, the dosage administered will, cf course, vary depending upon the compound employed mode of administration and treatment desired. However, in general satisfactory results are obtained ivlien administered at a daily dosage of from about 1 milligram to about 10 milligrams per kilogram of animal hotly weight, preferably given in divided doses 2 to 4 times a day or in sustained release form. For the larger mammals, the total daily dosage is in the range of from about 50 milligrams to about 700 milligrams, and dosage forms suitable for administration comprise from about 12 milligrams to about 350 milligrams of the compound admixed with a solid or liquid pharmaceutical carrier or diluent. The compounds may be administered during or before the attack of tho
2? disorder to be treated.
-3-\ ' ί
--4The compounds may be administered in association with, a pharmaceutically acceptable adjuvant, diluent or carrier, the composition used depending on many factors including the disorder to be treated. The compounds may be administered . ,, preferably by inhalation.
parenterally by inhalation. or topically,
For inhalation they are desirably presented either as aqueous solutions or as powders. The powders may conveniently contain lactose as the carrier material.
~ It is preferred that no more than 3 of R1, R2, R3 and
17
R are other tJian hydregen. Preferred values of R , R , · ι*-.... 3 4 5 7
i. R , R , R and Ri are hydrogen, hydroxy, lower alkoxy, t« lower alkoxy substituted by phenyl, lower acyl (e.g. lower alkanoyl or lower alkenoyi), or .lower alkanoyl substituted by an amino or a mono- or di-loweralkyl amino grbup^am^io^ lower acyl amino (e.g. lower alkanoylamina), lower alkenyl,
--- ··,/' ' ι halogen (i.e. chlorine, bromine or iodine) or lower /,alkyl. · /
Specific examples of values of R1, R2, R3, R4, R5 and R7 are hydrogen, hydroxy, methoxy, benzyloxy, acetyl, dirnethylaminoacryloyl, go amino, acetylamino, allyl, methyl, ethyl, n-propyl and n-butyl.
Preferred conpounds of formula I are those in whidi RS is hydrogen, R is hydrogen, n-propyl or allyl, R is hydrogen, R is hydrogen, propyl or allyl, R2 is hydroxy and R3 is acetyl.
The group X is preferably a straight chain alkylene group 2s containing, for example, from 3 to 7 carbon atoms and optionally substituted by a hydroxy group.
The aminosugar and amino acid salts of the following compounds are specifically preferred:
- 4 I
6 3 8 3
1-H 5- (4-acetyl-3-hydroxyphenoxy)pentyloxyJ7-4-oxo-4H-lbenzopyran-2-carboxylic acid,
8-Allyl-7-Z?5-(4-acetyl-2-allyl-3-hydroxyphenoxy)pentyloxy_7-4oxo-411-1 -bcnzopyran-2-carboxylic acid,
8-Allyl-7-Z75-(4~acetylphenoxy)pentyloxy_7-4-oxo-41I-l~bcnzopyran-2-carboxylic acid,
8-Allyl-7-/75“ (2-acetyl-3-hydroxyphcnoxy)pentyloxy.Z7-'1-oxo-411l-benzopyrnn-2-carboxylic acid,
8-Allyl-7-0-(4-acetyla]ninophenoxy)pentyloxyL74-oxo-4H-l~ benzopyran-2-carboxylic acid,
7-ZZ5-(4-Acctylphenoxy)pentyloxyZ7-4“Oxo-4H-l-benzopyran-2carboxylic acid,
7-Z?5-(3-M0thoxyphenoxy)pentyloxyJ7-4-oxo-4H-l-benzopyran-2carboxylic acid,
7-/Ξ5-(3-Bcnzyloxyphenoxy)pentyloxy27-4~oxo-4H-l-benzopyran-2carboxylic acid,
7-ZZ5-(2-Acetyl-4-allyl-3-hydroxyphenoxy)pentyloxyZ7~4“OXo-4H~ l-benzopyran-2-carboxylic acid,
4-Oxo-7-ZZ5-(2-propylpIicnoxy)pentyloxyZ7-4H-l-benzopyran-2carboxylic acid,
7- /Z5-(2-t-Butylphenoxy)pcntyloxy_7-4-oxo-4H-l-benzopyran-2carboxylic acid,
8- Allyl-7-/73-(4-acetyl-2-allyl-3-hydroxyphenoxy)-2-hydroxypropoxy27“4-oxo-4H-l-beuzopyran-2-carboxylic acid,
7~D>- (4-Acotyl-3-hydroxyphenoxy) -2~liydroxypropoxy_Z7“4-oxo4H-l-benzopyran-2-carboxylic acid,
- 5 -* 6 ~
8-Ally1-7-/73-(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropoxy/74-oxo-4H-l-benzopyran-2-carboxylic acid, l-ft 3- (4 -Ace tyl-3-hydroxy-2~ally lphenoxy) -2-hydroxypropoxyJ7~ 4-oxo-4H-l-benzopyran-2-carboxylic acid,
8-Propyi-7-/73-(4-acetyl-3-hydroxy-2ai-propylphenoxy)-2-hydroxy“ propoxyZ7-4-oxo-4H-l-benzopyran-2-caboxylic acid,
4-Oxo-8-propy 1-7-/73- (2-propy lphenoxy) -2 -hydroxypropoxyT?4H-l-bcnzopyran-2-carboxylic acid,
4-Oxo-7-/73-(2-propylphenoxy)-2-hydroxypropoxy77-4H-l-benzopyran 10 2-carboxylic acid,
7-/73-(2-Allylphenoxy)-2-hydroxypropoxyZ7-4-oxo-l-4H-1-benzopyran-2-carboxylic acid,
7-/73-C4-Acetyl-3-hydroxy-2-propylphenoxy)~2-hydroxypropoxy774-oxo-4H-l-benzopyran-2-carboxylic acid,
7-/73- (4-Acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropoxy774-oxo~6-propyl-4H-l-benzopyran-2-carboxylic acid,
4-Oxo-6-propyl-7-/73- (2-propylphenoxy) -2-hydroxypropoxyT/4H-l-benzopyran-2-carboxylic acid,
7-/72-Hydroxy-3-(2,4-dini3thylphcnojy)propoxy7/-4-oxo-4Il-l20 benzopyran-2-carboxylic acid,
7-/73- (2,4-Di-t-butylphenoxy)-2-hydroxypropoxy77-4-oxo-4H-lbenzopyran-2-carboxylic acid,
7-(3-/72-t-Butylphenoxy77-2-hydroxypropoxy)-4-oxo-4H-lbenzopyran-2-carboxylic acid,
7-//5-(4-0x0-411-1-benzapyran-7-yloxy)pentyloxyZ7-4-ΟΧΟ-4Η-1benzopyran-2-carboxylic acid,
- 6 - 7 46382
7-Z73-(4-Oxo-4fI-l-benzopyran-7-ylo^)-2-Iiydro)yi)ropoxyZ7“4oxo-411-1 -bcnzopyran-2-carboxylic acid,
7- /73-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy77“4-oxo-8propyl-4II-l-benzopyran-2-carboxylic acid,
S 4-Oxo-8-propyl~7-Z73- (2-propylphenoxy)propoxy77-4H-l-benzopyran-2-carboxylic acid,
4-Oxo-6-propyl-7-/T3-(2-propylphenoxy)propoxyZ7-4H-l~benzopyran-2-carboxylic acid,
8- (3-/72-£-ftitylphenoxy77-2-b.ydroxypropoxy) -4~oxo-4H-l10 benzopyran-2-carboxylic acid,
8-/ZZ‘iiydroxy-3-(2-iodophcnoxy)propox>'27“4-oxo-4H-l-bcnzopyran· -2-carboxylic acid,
8-/3- (2-n-butylphcnoxy)-2-hydroxypropoxyJ7-4-oxo-4I-I-lbenzopyran-2-carboxylic acid, 15 8-/72-1 iydroxy-3- (2-propy]phenoxy)propox/77-4-oxo-4I!-lbenzopyran-2-carboxylic acid,
8-(3-/72-n-butylphenoxy77propoxy) -4-oxo-4H-l-benzopyran-2carboxylic acid,
4-Gxo-8-/77-(2-n-propylphenoxy)heptyloxy77-4H-l-benzopyran20 2-carboxylic acid,
4- Oxo-7-/77-(2-n-propylphenoxy)heptyloxy77“4H-l-benzopyran2-carboxylic acid,
6-/~~2-tiydroxy-3- (2-propylphenoxy)propoxy77-4-oxo-4H-lbenzopyran-2-carboxylic acid, je
- /72-Uydroxy-3- (2-propylpbenoxy)propoxy77-4-oxo-4Il-l·benzopyran-2-carboxylic acid,
- 7 4 6 382
- 8 4- Oxo-7-(3-/22-propylphenoxyZ7pr°poxy)-4H-l-benzopyran-2carboxylic acid,
- (4-0XO-7-/Z3- (2-propylphenoxy) -propoxyJ7-4 H-l-benzopyran2-yl)tetrazole,
- 8-Ethyl-4-oxo-7-(3-/2-propylphenoxy37propoxy)-411-1benzopyran-2-carboxylic acid,
- (3-/22 -Acetyl-3-hydroxyphenoxy27_2-hydroxypropoxy) -4-oxo4HT-benzopyran-2-carboxylic acid,
- (3-/24-oxo-l-benzopyran-5-yloxy27-2-hydroxypropoxy) -4-oxojq 4iI-l-benzop>Tan-2- carboxylic acid, and
- (3-0” (3-dimethylaininoncryloyl) -3-liydroxyphcnoxy27~2-liydroxypropoxy)-4-oxo-4II”l~benzopyran~2-carboxylic acid,
In this specification and in the claims ’lower' is used to 15 mean a group containing up to 6, i.e. 1 to 6, or, as necessary, from 2 to 6 or 3 to 6 carbon atoms.
The preferred amino acids which form the salts are lysine, ornithine and arginine or-an N-alkyl, especially an N-methyl, derivative thereof. Hie preferred aminosugars are glucamine, N-methylglucamine and glucosamine.The amine
2q sugar or amino acid, employed may be in optically active or racemic form.
Particularly preferred are the- salts, particularly the ornithine and arginine and, especially, the lysine salt of 8-propyl-7-/5-(4-acetyl-3hydroxy-2-propyl-phenoxy)“2-hydroxypropoxy27-4-oxo-4II-l-bcnzopyran-2-carboxylic acid.
The amino acid and aminosugar salts of the present invention are
- 8 4 6 3 8 2 surprisingly more soluble than the corresponding alkali-inetal salts. Πιο increased solubility permits, inter alia, the administration of higher concentrations of active ingredient to the patient.Moreover, the salts of the present invention overcome a further problem associated with the use of the corresponding alkali-metal salts namely that of cloudiness of solutions thereof which develops when the solutions have been left to stand for some time.Besides leading to an unacceptable appearance the cloudiness which is caused by precipitation, of the less soluble calcium and magnesium salts can lead to blockage in aerosol dispensers and nebulisers.Although the cloudiness can be removed by filtration,it develops only very slowly and thus may reappear even after filtration.With the present salts the precipitation occurs hnmediately and filtration renders the solutions permanently clear.
Tne invention also provides a process for the preparation of an aminosugar or amino acid salt of a compound of formula I which process comprises reacting a compound of formula I with the desired basic aminosugar or basic amino acid,
For parenteral use it is necessary for the formulation of any compound to be sterile and pyrogen-free and this is also desirable where it is to be used by inhalation,Normally, this can be achieved simply by making up,using pyrogen-free components, a solution or suspension of the compound,which is then sterilised, usually by autoclaving.However in the case of the benzopyran salts of this invention, the solutions are unstable even at ambient temperature and decomposition occurs above about 40°C,such a temperature being too low to effect sterilisation.
We have now developed a method by which the above-mentioned benzopyran salts may be prepared in sterile, pyrogen-free form.
Accordingly, in another aspect, this invention provides a process for the preparation of a pharmaceutically-acceptable basic aminosugar or basic amino acid salt of a compound of formula I in sterile, pyrogen-free form, which
6 3 8 2
- 10 comprises washing a sample of the compound of formula I with pyrogen-free distilled water, optionally (and preferably) suspending the washed material in pyrogen-free distilled water, adding to the acid or suspension thereof a solution of the basic aminosugar or-amino acid in pyrogen-free distilled water, removing any insoluble matter, sterile filtering the resulting, solution, optionally (and preferably) allowing the filtrate to stand followed by further sterile filtration, and freeze-drying under sterile conditions.
The base is desirably added to the acid or suspension thereof in a stoichiometric amount or, failing that, in such an amount that a slight excess of the acid remains. If, as preferred, the formed solution of the desired salt is allowed, to stand, insoluble salts of the compound of formula I with metal cations present precipitate out and may. readily be removed.by<-the sterile filtration step.
The freeze-drying step is desirably effected in sterile,pyrogen-free ampoules, which are sealed ascptically and from which the benzopyran salt may be released as required and dissolved in pyrogen-free distilled water immediately prior to use.The freeze-drying step is preferably effected as soon as possible after the last sterile filtration.
At all.stages, the temperature is preferably kept below 40°C, and more preferably below 25°C.
The pyrogen-free distilled water preferably contains less than 2 ppm zinc and less than 0.04 ppm magnesium.
The invention is further described, though only by way of illustration, in the following Examples, Hhich all 'parts' are by weight.
Example A
The procedure set out below is used to assess the effectiveness of a compound in antagonizing SRS-A.The test makes use of the agonist (contractile) effect of SRS-A on isolated guinea-pig ileum.
- 10 4 6 3 8a
A satisfactory preparation of SRS-Λ can be obtained from egg albumen sensitised guinea-pigs. Three weeks after sensitisation, the lungs from sueli guinea-pigs are removed, perfused free of blood, and chopped. Samples of washed, chopped lung are then challenged with egg albumen (antigen) solution. Tlie suocmatants collected 5 . ' minutes after addition-of antigen contain histamine and SRS-A and can be used, in the presence of an antihistamine, to induce effects due to SRS-A.
An isolated section of the terminal portion of a guinea-pig 10 ileum is suspended in Tyrode solution, which contains atropine sulphate 10-¾ (700 g/litre) and mepyramine maleate 10-¾ ( 400 g/litre). Atropine sulphate is included to reduce the spontaneous activity of the ileum preparation and to exclude the effects of possible cholinergic agents. Mepyramine maleate is included to exclude the effects of histamine. The composition of the Tyrode solution in g/1 distilled water is NaCl 8.0, KC1 0.2, CaCl20.2, MgCl2 0.1, NaHCOg 1.0, Nal^PO^iy) 0.05 and dextrose 1.0. A 2 ml organ bath is· preferred for economy of SRS-A, the tension on the tissue should be about 600 mg and the bathing temperature 37°C.
A dose of unpurifiad SRS-Λ is selected which produced similar repetitive submaximal contractions of the ileum. Each contraction is recorded for 90 seconds when the tissue is washed to allow relaxation. Five minutes is allowed between doses of SRS-A.
The compound under test is added to the organ bath 30 seconds before a dose of SRS-A. A range of concentrations of the compound is chosen to give a log concentration/inhibitory response graph.
- 11 4 6 3 B S
- 12 1
From tliis graph, the concentration of compound which would inhibit the ileum contraction to SRS-Λ by 502 (ΐς.θ) is detcimincd.
Example 1
2zz£-.?L.('?~Acc^yl~5-hy(.lrox)r-2-propylphciKixy)-?.-liydrox}'propoxy J.4-oxo-3-propyl-4H-I-bcnzopyran-2-carboxylic acid (-) lysine salt
A solution of 10,5 parts of 7-/ 3-(4-acetyl-3-hydroxy-2propylphenoxy)-2-hydroxypropoxy7~4-oxo-8-propyl-4H-l-bcnzopyran2-carboxylic acid and 2.92 parts of (i)- lysine in 500 parts of distilled water was freeze-dried to give 12.0 parts of colourless 10 salt.
Analysis:
Found: C, 61.0; H, 7.1; N, 4.2¾ C33H44N2°11 re
IS Example 2
7-/3-(4-Acctyl-5-hydroxy-2-propylphcnoxy)-2-hydroxypropoxy74-oxo-8-propyl-4H-l-benzopyran‘-2-carboxylic acid L-lysino salt.
7„f3_(4-Acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxyprcpoxy)4-oxo-8-propyl-4H-l-benzopyran-Z-carboxylic acid (367g) was washed with copious quantities (20 1) of pyrogen-free distilled water, and was then suspended in fiirther pyrogen-free distilled water (9000 ml). A solution of L-lysine (lOOg) in pyrogen-free distilled water (500 ml) was then added with stirring. Stirring was continued until solution of the suspended material was .effected. Any insoluble material remaining was removed by ster .le filtrat jos and the resulting
- 13 46382 solution was then allowed to stand for 16 hours in a sterile environment, and was then stcrile-filtered through a 0.22 m membrane filter directly into sterile pyrogen-free ampoules. The solution was then freeze-dried immediately in a sterile area, and the ampoules were sealed on completion of the freeze-drying precess, using aseptic techniques.
Salts of 8-propy 1-7-/]3-(4-acetyl· -3-hydraxy-2-n-propyl-phenoxy) -2hydroxypropoxy.7-4-0X0-411-l-benzopyran-2-c3rboxylic acid were prepared by reaction of the acid as in Example 1 respectively with ornithine,
Ιθ arginine, glucamine, N-mcthyl-glucamine and glucosamine.
Example 4
By the method of Example 2 are prepared the L-lysine salts of the following compounds which, together with the acid of formula I employed as starting material in that Example, represent a preferred group of compounds
8-allyl-7-(7S-(2-acetyl-3-hydroxyphenoxy)pentyloxy_7~4~oxo-4HTbenzopyran-2-carboxylic acid;
8-ally1-7-/3-(4-acetyl -2-allyl-3-hydroxyphenoxy)-2-hydroxy-propoxy_7~ 4-oxo-4H-l~benzopyran-2~carboxylic acid;
4-oxo~S-propyl-7-/2 3- (2-propylphenoxy) -2Tiydroxypropoxy/7-4H-120 benzopyran-2-carboxylic acid;
7-/7 3- (4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy//~4-oxo4H-l-benzopyran-2-carboxylic acid; and
7-/23-(4-acetyl-3~hydi.Oxy-2-propylphenoxy)propoxy_2”4-oxo“8-propyl“ 4H-l-benzopyran-2-carboxylic acid.
Claims (15)
1. A salt with a basic aminosugar or basic amino acid of a compound of the formula: ,.1 2 3 4 5 7 wherein R , R , R , R , R and R , which may be the same or different, each represent hydrogen, hydroxy, alkoxy, alkoxy substituted by phenyl, carboxylic acyl, amino, carboxylic acylamino, alkenyl, halogen or alkyl, provided that at least 12 3 7 ore of R , R , R and R are other than hydrogen or hydroxy, 12 3 7 or an adjacent pair of R , R , R and R either represent hydroxyl and a 3-(Ν,Ν-dialkylamino)acryloyl radical or together represent a chain -C0QI=QI-O-, X represents a hydrocarbon chain of 2 to 10 carbon atoms optionally substituted by a hydroxy group, and E represents a carboxy or tetrazole group.
2. A salt according to claim 1 wherein r\ R 2 , R^, R^, and R each represent hydrogen; hydroxy; C 1 to G alkoxy; C I to 6 alkoxy substituted by phenyl; C 2 to (ί alkanoyl; C 3 to 0 alkenoyl, optionally substituted by amino or mono- or di-(C 1 to 6 alkyl) amino; amino; C 2 to 6 alkanoylamiuo; C 2 to 6 alkenyl; chlorine; bromine; iodine; or C 1 to 6 alkyl. 14 46382 - 15 3. A salt according to claim 2 wherein r\ R 2 , R 3 , R 4 , R J and R 7 each represent hydrogen, hydroxy, methoxy, benzyloxy, acetyl, dincthyl-aminoacryloyl, amino, acetylamino, allyl, methyl, ethyl, n-propyl or n-butyl. 5 7
3. 5 4. A salt according to claim 3 wherein R‘ and R represent hydrogen, R?· and R 4 represent hydrogen, n-propyl or allyl, R 2 represents hydroxy and R represents acetyl. 5. A salt according to any of claims 1 to 4 wherein X represents a C 3 to 7 straight alkylene chain optionally substituted by a hydroxy 10 group.
4. 6. A salt according to any of claims 1 to 5 wherein the compound of formula I is as specifically described herein.
5. 7. A salt according to claim 6 wherein the compound of formula I is 8-propyl-7-/3(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxy15 propoxy.7~4-oxo-4II-I-bcnzopyran-2-carboxylic acid.
6. 8. Λ salt according to any of claims 1 to 7 wlierein the basic aminosugar is N-methylglucaminc, glucamine or glucosamine.
7. 9. A salt according to any of claims 1 to 7 wherein the basic amino acid is lysine, arginine, or ornithine or an N-alkyl 20 derivative thereof.
8. 10. The lysine salt of S-propyl-7-/73-(4-acetyl-3-hydroxy-2~npropylphenoxy)-2-Jiydrox}propoxyJ7-4-oxo-4H-l-bcnzoj)yran-2carboxylic acid.
9. 11. A process for tlie preparation of a salt according to any of 25 claims 1 to 10 wherein a compound of formula I as defined in claim 1 - 15 - 16 is reacted with a basic aminosugar or a basic amino acid.
10. 12. A process according to claim 11 vhich comprises washing a sample of the compound of formula I with pyrogen-free distilled water, optionally suspending the washed material in pyrogen-free 5 distilled water, adding to the acid or suspension thereof a solution of tlie basic aminosugar or amino acid in pyrogen-free distilled water, removing any insoluble matter, sterile filtering tlie resulting solution, optionally allowing the filtrate to stand followed by further sterile filtration, and freeze-drying under 10 sterile conditions.
11. 13. A process according to claim 12 wherein the freeze-drying is effected in pyrogen-free ampoules which are then sealed aseptically.
12. 14. A process according to claim 12 or claim 13 wherein the tenperature at all times is kept below 40°C. IS IS. A process according to any of claims 12 to 14 wherein the pyrogen-free distilled water contains less than 2 ppm zinc and less than 0,04 ppm magnesium.
13. 16. A process according to any of claims 11 to 15 and substantially as described herein in Examples 1 and 2. 20
14. 17. A salt according to any of claims 1 to 10 whenever prepared by a process according to any of claims 11 to 16.
15. 18. A pharmaceutical composition which comprises one or more compounds according to claims 1-10 and 17 in association with a pharmaceutically acceptable adjwant diluent or carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3061/77A GB1583691A (en) | 1977-01-26 | 1977-01-26 | Benzopyrans |
| GB4133077 | 1977-10-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE780164L IE780164L (en) | 1978-07-26 |
| IE46382B1 true IE46382B1 (en) | 1983-05-18 |
Family
ID=26237992
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE164/78A IE46382B1 (en) | 1977-01-26 | 1978-01-25 | Benzopyrans |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5392775A (en) |
| AU (1) | AU513311B2 (en) |
| CH (1) | CH627463A5 (en) |
| DE (1) | DE2803230A1 (en) |
| DK (1) | DK34378A (en) |
| ES (1) | ES466305A1 (en) |
| FI (1) | FI780195A (en) |
| FR (1) | FR2378795A1 (en) |
| IE (1) | IE46382B1 (en) |
| IL (1) | IL53873A0 (en) |
| LU (1) | LU78943A1 (en) |
| NL (1) | NL7800818A (en) |
| NO (1) | NO780267L (en) |
| NZ (1) | NZ186298A (en) |
| SE (1) | SE7800809L (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5829773A (en) * | 1981-08-06 | 1983-02-22 | ビ−チヤム・グル−プ・ピ−エルシ− | Medicinal compound, manufacture and medicinal composition |
| KR100320588B1 (en) * | 1999-04-28 | 2002-01-12 | 손화섭 | Compositions for freezing dog sperm, freezing methods of the dog sperm utilizing the compositions and artificial insemination method empolying the freezed dog sperm |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1384530A (en) * | 1971-07-29 | 1975-02-19 | Fisons Ltd | Chromone derivatives |
-
1978
- 1978-01-23 FI FI780195A patent/FI780195A/en not_active Application Discontinuation
- 1978-01-23 SE SE7800809A patent/SE7800809L/en unknown
- 1978-01-24 AU AU32694/78A patent/AU513311B2/en not_active Expired
- 1978-01-24 NZ NZ186298A patent/NZ186298A/en unknown
- 1978-01-24 NL NL7800818A patent/NL7800818A/en not_active Application Discontinuation
- 1978-01-24 IL IL53873A patent/IL53873A0/en unknown
- 1978-01-24 DK DK34378A patent/DK34378A/en not_active Application Discontinuation
- 1978-01-25 FR FR7802033A patent/FR2378795A1/en active Granted
- 1978-01-25 DE DE19782803230 patent/DE2803230A1/en not_active Withdrawn
- 1978-01-25 IE IE164/78A patent/IE46382B1/en unknown
- 1978-01-25 ES ES78466305A patent/ES466305A1/en not_active Expired
- 1978-01-25 NO NO780267A patent/NO780267L/en unknown
- 1978-01-25 CH CH80978A patent/CH627463A5/en not_active IP Right Cessation
- 1978-01-25 LU LU78943A patent/LU78943A1/en unknown
- 1978-01-26 JP JP677778A patent/JPS5392775A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ES466305A1 (en) | 1978-10-01 |
| LU78943A1 (en) | 1978-09-28 |
| NO780267L (en) | 1978-07-27 |
| NL7800818A (en) | 1978-07-28 |
| FR2378795B1 (en) | 1980-04-25 |
| NZ186298A (en) | 1979-10-25 |
| FI780195A (en) | 1978-07-27 |
| IE780164L (en) | 1978-07-26 |
| SE7800809L (en) | 1978-07-27 |
| FR2378795A1 (en) | 1978-08-25 |
| AU3269478A (en) | 1979-08-02 |
| CH627463A5 (en) | 1982-01-15 |
| DK34378A (en) | 1978-07-27 |
| JPS5392775A (en) | 1978-08-15 |
| DE2803230A1 (en) | 1978-07-27 |
| IL53873A0 (en) | 1978-04-30 |
| AU513311B2 (en) | 1980-11-27 |
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