US3245877A - Method of treating inflammation - Google Patents

Method of treating inflammation Download PDF

Info

Publication number
US3245877A
US3245877A US3245877DA US3245877A US 3245877 A US3245877 A US 3245877A US 3245877D A US3245877D A US 3245877DA US 3245877 A US3245877 A US 3245877A
Authority
US
United States
Prior art keywords
compound
quinuclidine
edema
compounds
treating inflammation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
Publication date
Application granted granted Critical
Publication of US3245877A publication Critical patent/US3245877A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms

Definitions

  • a d'renocorticoids such as cortisone, hydrocortisone, prednisone and prednisolone.
  • these adrenocorticoids generally exhibit undesirable side actions, when continuously administered for a long time.
  • some non-adrenocortical anti-infiamatory agents such as acetylsalicylic acid, gentisic acid, 2 (,6 chloroethyl) 2,3 dihydro- '4 oxo 1,3 ben'zoxazine, salicylamide, aminopyrine,
  • a primary object of the present invention is to provide a preparation for anti-infiamatory administration which includes the said quinuclidine compound I or II or their salt with a non-toxic acid as an active ingredient.
  • Another object of the present invention is to provide a process for anti inflamatory activity in living body.
  • a further object of the present invention is to provide a utilization method of the naturally-existing cinchona alkaloid, quinine.
  • the quinuclidine compounds I possess a high anti-inflammatory activity.
  • the animal test data of the quinuclidine compound corresponding to the following formula:
  • the average edema inhibition shows that from one to three hours after the administration of the edema producing agent.
  • the edema inhibition activity of the compound Ia is at least 10 times that of chloroquine diphosphate, when orally administered to rats.
  • Compound Ia N0Tn The rats were subcutaneously pretreated with the test compound and then subcutaneously administered the edema producing agnt. The produced edema was measured and compared with that produced without pretreatment.
  • ⁇ it can be said that the compound In is at least 100 times as effective as aminopyrine in the edema inhibiting action, when subcutaneously administered to rats. Adding to this, it can be also said that they exhibit a total activity, when administered together.
  • Chloroquine diphosphate Norm- The test compound was subcutaneously administered to mice. For the comparison of the eflect, there was employed Trypan Blue test.
  • the anti-inflammatory efiect of the compound la is approximately 100 times that of chloroquine diphosphate, when subcutaneously administered to mice.
  • the compound Ia is more toxic than the commercially available anti-inflammatory agent, e.g. chloroquine diphosphate, but the former is remarkably more effective than the latter.
  • the quinuclidine compounds I are the non-adrenocortical anti-inflammatory agents which can be used safely, compared with the heretofore known non-adrenocortical anti-inflammatory agents.
  • the quinuclidine compounds I have a relatively high toxicity, but, the toxicity can be decreased by their conversion into the corresponding N- oxides.
  • the quinuclidine N- oxide compounds II are less toxic than the quinuclidine compounds I, the former being parallelly less potent than the latter in anti-inflammatory activity.
  • the animal test data of the quinuclidine-N-oxide compound corresponding to the following formula:
  • the quinuclidine-N-oxide compounds II are less toxic and less potent than the quinuclidine compounds I. But, they are still remarkably active, comparedwith the heretofore known anti-inflammatory agents. Therefore, they are useful as non-adrenocortical anti-inflammatory agents can be employed safely, too.
  • the quinuclidine compounds I or the quinuclidine-N-oxide compounds II or their salts with non-toxic acids those with hydrochloric, hydrobromic, sulfuric, acetic, latic, succinic, tartaric, citric, ascorbic, cinnamic, salicyclic or 4-aminosalicyclic acid. (3f these salts, the salicyclic acid addition salt is particularly preferred in easy crystallizability.
  • the active medicaments e.g. the quinuclidine compounds I or their salts with non-toxic acids
  • the preparation is orally administered, although they are just as effective when As the salts, there may be exampled otherwise administered.
  • They may be administered in various dosages such as 3, 5, 10, 15, 20, 25 or 30 milligrams, athough the unit dosage range may vary more broadly from about 1 to about milligrams and preferably from about 5 to about 30 milligrams. They may be added to or otherwise used with various pharmaceutical carriers.
  • various solid carriers may be employed such as lactose, mannitol, cornstarch, talc and magnesium stearate as well as other tableting aids and fillers.
  • some other ingredients such as hydrocortisone, prednisolone, aminopyrine, chloroquine and the like may be mixed with the said active medicaments.
  • the medicinal mixture may then be tableted or encapsulated in a hard gelatine capsule, depending on the commercial unit form desired. Ordinarily tableting is preferred.
  • the amount of carrier or diluent may vary, according to tablet size desired or whether the dosage is made up in encapsulated form, from .Zero amount to the maximum amount consistent with the practical limits of bulk for a dosageunit. Normally the carrier with which the medicament is mixed does not exceed about 300 to about 500 milligrams.
  • the quinuclidine-N-oxide compounds II or their salts with non-toxic acids can be administered in dosage unit form to living bodies.
  • This mixture is tableted in the usual way to give 100,- 000 tablets. Each tablet weighing 37.5 milligrams contains 12.73 milligrams of the active ingredient (equal to 10 milligrams of the free base).
  • Example 3 To a solution of 4-(3-ethylquinuclidin-8-yl)-4-hydroxy- 3- 2-toluenesulfonamido-5-methoxyphenyl -butanol (300 mg.) in glacial acetic acid (2.5 rnl.), there is added 30% hydrogen peroxide (0.3 ml.), and the resultant solution is allowed to stand for 24 hours atroom temperature. Then, 30% hydrogen peroxide (0.3 ml.) is further added to the solution and allowed to stand for 48 hours at room temperature. The reaction mixture is adjusted with 10% aqueous sodium hydroxide to alkalinity and shaken with chloroform. The chloroform layer is Washed with water and dried over anhydrous sodium sulfate.
  • Example 4 I To a solution of 4-(3-ethylquinuclidin-8-yl)-4-hydroxy- 3-(2-toluenesulfonamido-S-methoxyphenyl) butanol (0.2 g.) in ethyl acetate, there is added a solution of salicylic acid (0.026 g.) in ethyl acetate, and the resultant mixture is allowed to stand for 5 hours.
  • Method of treating inflammation in the living animal body which comprises administering to said 'body an effective dose of the member selected from the group consisting of the compound of the formula:
  • R is a member selected from the group consisting of lower alkyl, phenyl and lower alkylphenyl, the compound of the formula:
  • R is a member selected from the group consisting of lower alkyl, phenyl and lower alkylphenyl, the compound of the formula:
  • CHzOHzOH 7 Method of treating inflammation in the living animal body which comprises subcutaneously administering to said body an effective dose of the member selected from the group consisting of the compound of the formula:
  • R is a member selected from the group consisting of lower 'alkyl, phenyl and lower alkylphenyl, the compound of the formula:

Description

United States Patent 3,245,877 METHOD OF TREATING INFLAMMATION Eiji Ochiai, 72 Myogadani-cho, Bunkyo-lnr, Tokyo, Japan, and Ryonosuke Kido, 1679 Kamiikeda-cho, Ikeda-shi, Osaka Prefecture, Japan No Drawing. Filed Sept. 21, 1962, Ser. No. 225,386 9 Claims. (Cl. 167-65) This invention relates to producing anti-inflammatory activity in living bodies.
As anti-inflammatory agents, there have been mostly used a d'renocorticoids such as cortisone, hydrocortisone, prednisone and prednisolone. However, these adrenocorticoids generally exhibit undesirable side actions, when continuously administered for a long time. Because of the drawback present in -adrenocorticoids, there have been proposed and made available some non-adrenocortical anti-infiamatory agents such as acetylsalicylic acid, gentisic acid, 2 (,6 chloroethyl) 2,3 dihydro- '4 oxo 1,3 ben'zoxazine, salicylamide, aminopyrine,
phenylbutazone, sulfinpyrazone, quinacrine, chloroquine, hydroxychloroquine, amodiaquin, gold sodium thiosulfate and e-aminocaproic acid. However, these nonadrenocortical compounds are generally inferior to the said adrenocorticoids in anti-inflamatory activity. Therefore, it has been desired to realize any other non-adrenacortical compounds possessing a high anti-infiamator activity as well as the adrenocorticoids.
As the results of the pharmacological investigation on a variety of heretofore known or novel quinuclidine compounds derived from a naturally existing cinchona alkaloid, quinine, it has been now discovered that the quinuclidine compounds, corresponding to the following for- I mula:
compounds I can be remarkably decreased without a large depression of the desirable activity by their conversion into the N-oxides, corresponding to the following formula:
CH O CHCH(OH) wherein R has the same significance as designated above.
Accordingly, a primary object of the present invention is to provide a preparation for anti-infiamatory administration which includes the said quinuclidine compound I or II or their salt with a non-toxic acid as an active ingredient. Another object of the present invention is to provide a process for anti inflamatory activity in living body. A further object of the present invention is to provide a utilization method of the naturally-existing cinchona alkaloid, quinine. These and other objects will It has been Patented Apr. 12, 1966 be apparent to those skilled in the art to which the present invention pertains from the subsequent description.
The production of the quinuclidine compounds I from quinine can be illustratively shown by the following scheme Quinine N (iJH(OH) S C2116 H202 CH3C OOH (IJH(OH) S CQHE H2808 )l J, v O
N (|3H(OH) HK GzHt P0013 v I N L wherein R has the same significance as designated above. All the compounds in the above scheme are known and can be prepared in a conventional manner [Heidelberger et al.: J. Am. Chem. Soc., 41, 819 (1919); Ochiai et al.: J. Pharm. Soc. Japan, 67, 101 (1947); Ochiai et al.: J. Pharm. Soc. Japan, 71, 260 (1951); Ochiai et al.: Pharm. Bull., 6, 212 (1958); Ochiai et al.: Pharm. Bull., 1, 156 (1953); Ochiai et al.: Pharm. Bull., 2, 128 (1954); Ishikawa: Pharm. Bull., 6, 71 (1958)].
The quinuclidine compounds I possess a high anti-inflammatory activity. For instance, the animal test data of the quinuclidine compound, corresponding to the following formula:
are shown in Tables I, II, III, IV, V and VI in contrast with some commercially available anti-inflammatory agents.
TABLE I.-EDEMA INHIBITION ACTIVITY TEST N orno- NOTE-The rats were subcutaneously pretreated with the test compound and then subcutaneously administered the edema producing agent. The produced edema was measured and compared with that produced without pretreatment.
The average edema inhibition shows that from one to three hours after the administration of the edema producing agent.
In the above table, it is shown that the edema inhibition activity of the compound Ia is more than 100 times that of chloroquine diphosphate, when subcutaneously administered to rats.
TABLE II.EDEMA INHIBITION ACTIVITY TEST Average edema inhibition (percent) Dose (mgJkg. Time after administration of Test compound of body formalin (hour) weight) 40 39 20 18 Compound Ia 20 32 29 18 10 17 8 Chloroquine di- 500 20 12 6 phosphate. 250 16 12 5 100 18 12 13 No'rE.The rats were orally pretreated with the test compound and then subcutaneously administered formalin. The produced edema was measured and compared with that produced without pretreatment.
4 Thus, the edema inhibition activity of the compound Ia is at least 10 times that of chloroquine diphosphate, when orally administered to rats.
TABLE III.EDEMA INHIBITION ACTIVITY TEST Average edema inhibition (percent) Edema producing agent Dose (mg./ kg. of body weight) Test compound Amiu'opyrine plus Compound Ia Aminbpyrine- Compound Ia Aminopyrine Formalin.
Compound Ia N0Tn.The rats were subcutaneously pretreated with the test compound and then subcutaneously administered the edema producing agnt. The produced edema was measured and compared with that produced without pretreatment.
From the above table, \it can be said that the compound In is at least 100 times as effective as aminopyrine in the edema inhibiting action, when subcutaneously administered to rats. Adding to this, it can be also said that they exhibit a total activity, when administered together.
TABLE IV.ANTI-INFLAMMATORY EFFECT Croton, ED (mg./kg. of body weight) Formalin, ED (mg/kg. of body weight) Edema producing agent Test compound:
Chloroquine diphosphate Norm-The test compound was subcutaneously administered to mice. For the comparison of the eflect, there was employed Trypan Blue test.
Thus, the anti-inflammatory efiect of the compound la is approximately 100 times that of chloroquine diphosphate, when subcutaneously administered to mice.
TABLE V.GRANULATION INHIBITION ACTIVITY TEST Total dose (mg. lrat) Weight of granu- Test compound lation (mg) Control Hydrocortisone acetate Compound Ia LD (mgJkg. of bodyweight) Test compound subcutaneously Orally Chlo'ro uine di hos hate q p p 34.8
Compound Ia From the above table, it can be said that the compound la is much more toxic than chloroquine diphosphate, i.e. 5.5 times at the subcutaneous administration and 8 times at the oral administration.
Summarizing the above animal test data, it is concluded that the compound Ia is more toxic than the commercially available anti-inflammatory agent, e.g. chloroquine diphosphate, but the former is remarkably more effective than the latter. Thus, the quinuclidine compounds I are the non-adrenocortical anti-inflammatory agents which can be used safely, compared with the heretofore known non-adrenocortical anti-inflammatory agents.
As disclosed above, the quinuclidine compounds I have a relatively high toxicity, but, the toxicity can be decreased by their conversion into the corresponding N- oxides. The quinuclidine-N-oxide compounds Hare novel and can be produced by subjecting the quinuclidine compounds I to oxidation according to a per se conventional manner. For instance, the quinuclidine compound I is treated with hydrogen peroxide in acetic acid at room temperature to C.) whereby the quinuclidine-N- oxide compound II is prepared. The quinuclidine N- oxide compounds II are less toxic than the quinuclidine compounds I, the former being parallelly less potent than the latter in anti-inflammatory activity. For instance, the animal test data of the quinuclidine-N-oxide compound, corresponding to the following formula:
are compared with that of the quinuclidine compound Ia in Tables VII and VIII.
TABLE VII.EDEMA INHIBITION ACTIVITY TEST N GTE-The rats were subcutaneously pretreated with the test compound and then subcutaneously administered the edema producing agent. The produced edema was measured and compared with that produced without pretreatment.
TABLE VIIL-TOXICITY IN MICE LDsl! (mg/kg. of Test compound bodywerght) intravenously Compound 1a.-.. 2. 0 Compound IIa 42. 3
Thus, the quinuclidine-N-oxide compounds II are less toxic and less potent than the quinuclidine compounds I. But, they are still remarkably active, comparedwith the heretofore known anti-inflammatory agents. Therefore, they are useful as non-adrenocortical anti-inflammatory agents can be employed safely, too.
For the preparations of the present invention, there are equally employed the quinuclidine compounds I or the quinuclidine-N-oxide compounds II or their salts with non-toxic acids. those with hydrochloric, hydrobromic, sulfuric, acetic, latic, succinic, tartaric, citric, ascorbic, cinnamic, salicyclic or 4-aminosalicyclic acid. (3f these salts, the salicyclic acid addition salt is particularly preferred in easy crystallizability.
The active medicaments, e.g. the quinuclidine compounds I or their salts with non-toxic acids, are admintered in dosage unit form, as carried by a suitable pharmaceutical carrier, to living bodies particularly for the relief of rheumatism. Normally, the preparation is orally administered, although they are just as effective when As the salts, there may be exampled otherwise administered. They may be administered in various dosages such as 3, 5, 10, 15, 20, 25 or 30 milligrams, athough the unit dosage range may vary more broadly from about 1 to about milligrams and preferably from about 5 to about 30 milligrams. They may be added to or otherwise used with various pharmaceutical carriers. By way of exemplification, various solid carriers may be employed such as lactose, mannitol, cornstarch, talc and magnesium stearate as well as other tableting aids and fillers. If desired, some other ingredients such as hydrocortisone, prednisolone, aminopyrine, chloroquine and the like may be mixed with the said active medicaments. The medicinal mixture may then be tableted or encapsulated in a hard gelatine capsule, depending on the commercial unit form desired. Ordinarily tableting is preferred. The amount of carrier or diluent may vary, according to tablet size desired or whether the dosage is made up in encapsulated form, from .Zero amount to the maximum amount consistent with the practical limits of bulk for a dosageunit. Normally the carrier with which the medicament is mixed does not exceed about 300 to about 500 milligrams.
In the similar manner, the quinuclidine-N-oxide compounds II or their salts with non-toxic acids can be administered in dosage unit form to living bodies.
The following are typical examples of preparations embodying the present invention.
Example I Kilograms 4-(Z-ethylquinuclidin-S-yl)-4-hydroxy-3-(2 toluenesulfonamido-S-methoxyphenyl)-butanol 1.00 Lactose 8.47
Cornstarch 3.48
Magnesium stearate -I 2.60
Example 2 Kilograms 4-(3-ethylqninuclidin 8-yl) 4 hydroxy-3-(2-toluenesulfonamido-S-methoxyphenyl)-butanol salicylate 12.73 Lactose 20.00
The foregoing are mixed and granulated with a 10% acacia solution and dried. The granule is forced through a 16 mesh screen, and thereafter is mixed with the following:
Kilograms Sodium lauryl sulfate 0.20 Magnesium stearate 1.00
Amylum solani q.v. to 3 7. 50
This mixture is tableted in the usual way to give 100,- 000 tablets. Each tablet weighing 37.5 milligrams contains 12.73 milligrams of the active ingredient (equal to 10 milligrams of the free base).
Example 3 To a solution of 4-(3-ethylquinuclidin-8-yl)-4-hydroxy- 3- 2-toluenesulfonamido-5-methoxyphenyl -butanol (300 mg.) in glacial acetic acid (2.5 rnl.), there is added 30% hydrogen peroxide (0.3 ml.), and the resultant solution is allowed to stand for 24 hours atroom temperature. Then, 30% hydrogen peroxide (0.3 ml.) is further added to the solution and allowed to stand for 48 hours at room temperature. The reaction mixture is adjusted with 10% aqueous sodium hydroxide to alkalinity and shaken with chloroform. The chloroform layer is Washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the chloroform layer, the residue is crystallized from a mixture of acetone and ether to give 4-(3- ethylquinuclidin-8-yl) 4 -'hydroxy 3 (2-toluenesulfonamido-S-methoxyphenyl)-butanol-N-oxide (140 mg.) as white pillars melting at 228 C.
Anzzlysis.-Calcd. for C H O N S: C, 62.55; H, 7.32; N, 5.4-1. Found: C, 63.05; H, 7.64; N, 5.44.
Example 4 I To a solution of 4-(3-ethylquinuclidin-8-yl)-4-hydroxy- 3-(2-toluenesulfonamido-S-methoxyphenyl) butanol (0.2 g.) in ethyl acetate, there is added a solution of salicylic acid (0.026 g.) in ethyl acetate, and the resultant mixture is allowed to stand for 5 hours. Removing the solvent from the mixture, the residue is crystallized from a mixture of acetone and petroleum ether to give 4-(3-ethylquinuclidin-8-yl) 4 hydroxy-3-(2toluenesulfonamido 5-methoxyphenyl)-butanol salicylate (0.16 g.) as crystals melting at -128 C.
Analysis.-Calcd, for C H O N SC H O C, 64.08; H, 7.18; N, 4.90. Found: C, 64.02; H, 7.71; N, 4.32.
What is claimed is:
1. Method of treating inflammation in the living animal body which comprises administering to said 'body an effective dose of the member selected from the group consisting of the compound of the formula:
CHzCHzOH wherein R is a member selected from the group consisting of lower alkyl, phenyl and lower alkylphenyl, the compound of the formula:
CH2CH2OH 3. Method of treating inflammation in the living animal body which comprises administering to said body an effective dose'of the compound of the formula:
CHaO- 4. Method of treating inflammation in the living animal body which comprises orally administering to said body an effective dose of the member selected from the group consisting of the compound of the formula:
CHzCHzOH wherein R is a member selected from the group consisting of lower alkyl, phenyl and lower alkylphenyl, the compound of the formula:
0 C HzC HzOH T wherein R has the same significance as designated above and their salts with non-toxic acids.
5. Method of treating inflammation in the living animal body which comprises orally administering to said body an effective dose of the compound of the formula:
6. Method of treating inflammation in the living animal body which comprises orally administering to said body an effective dose of the compound of the formula:
CHzOHzOH 7. Method of treating inflammation in the living animal body which comprises subcutaneously administering to said body an effective dose of the member selected from the group consisting of the compound of the formula:
-NI-ISO2-R CaH wherein R is a member selected from the group consisting of lower 'alkyl, phenyl and lower alkylphenyl, the compound of the formula:
9. Method of treating inflammation in the living animal body which comprises subcutaneously administering to said body an effective dose of the compound of the formula:
O T jN CH O References Cited by the Examiner UNITED STATES PATENTS Biel et a1 2'60293.4 XR
Grob 260293 Calder 16765 Zellner 167-65 10 OTHER REFERENCES Aralen, brochure published by Winthrop Laboratories, New York 18, New York, August 1957, 8 pp., p. 1 pertinent.
Drug Trade News, Feb, 16, 1953, p.73.
JULIAN s. LEVITT, Primary Examiner.
FRANK CACCIAPAGLIA, Examiner.

Claims (1)

1. METHOD OF TREATING INFLAMMATION IN THE LIVING ANIMAL BODY WHICH COMPRISES ADMINISTERING TO SAID BODY AN EFFECTIVE DOSE OF THE MEMBER SELECTED FROM THE GROUP CONSISTING OF THE COMPOUND OF THE FORMULA:
US3245877D Method of treating inflammation Expired - Lifetime US3245877A (en)

Publications (1)

Publication Number Publication Date
US3245877A true US3245877A (en) 1966-04-12

Family

ID=3458116

Family Applications (1)

Application Number Title Priority Date Filing Date
US3245877D Expired - Lifetime US3245877A (en) Method of treating inflammation

Country Status (1)

Country Link
US (1) US3245877A (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2834779A (en) * 1956-12-11 1958-05-13 Lakeside Lab Inc Disubstituted aminoalkyl quinuclidinium derivatives
US2917515A (en) * 1959-12-15 Certificate of correction
US2935448A (en) * 1959-02-25 1960-05-03 Royall M Calder Phosphatide therapeutic composition and method of treatment therewith
US2994640A (en) * 1957-02-22 1961-08-01 Byk Gulden Lomberg Chem Fab Anti-inflammatory therapy with purine molecular compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2917515A (en) * 1959-12-15 Certificate of correction
US2834779A (en) * 1956-12-11 1958-05-13 Lakeside Lab Inc Disubstituted aminoalkyl quinuclidinium derivatives
US2994640A (en) * 1957-02-22 1961-08-01 Byk Gulden Lomberg Chem Fab Anti-inflammatory therapy with purine molecular compounds
US2935448A (en) * 1959-02-25 1960-05-03 Royall M Calder Phosphatide therapeutic composition and method of treatment therewith

Similar Documents

Publication Publication Date Title
US3752888A (en) 2-bromo-alpha-ergocryptine as a lactation inhibitor
US3505337A (en) N - hydrocarbyl-substituted noratropinium,haloalkylates and o-acyl derivatives thereof
EP0236684B1 (en) Galanthamine or analogues thereof for treating alzheimer's disease
EP0908181B1 (en) Remedy for rosacea
DE3318989A1 (en) SS, (GAMMA) -DIHYDROPOLYPRENYL ALCOHOL DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING THEM
AU610469B2 (en) 4-quinoline carboxylic acid derivatives useful for treating skin and muco-epithelial diseases
US6197806B1 (en) Eliminating agent for activated oxygen and free radicals
US3483221A (en) 1 - (isopropylamino)-2-hydroxy-3-(alkenyloxyphenoxy) - propanes and the salts thereof
US2987442A (en) Method of treating hypertension with [2-(2, 6-dimethylphenoxy)-propyl]-trimethyl ammonium salts
US3245877A (en) Method of treating inflammation
US4237165A (en) Treatment of carbohydrate metabolism disorders
US2917432A (en) Leukemia treatment
US3163653A (en) -nhsoz-r
US4851414A (en) Anti-dementia agent
US2918407A (en) Anti-spasmodics specific for upper gastrointestinal pain and spasm
US3781415A (en) Product,process and composition
US3328424A (en) 1-isopropylamino-2-hydroxy-3-(2'-isopropoxy-phenoxy)-propane and salts thereof
US3629467A (en) Pharmaceutical preparations containing a 2 4-diamino-6-substituted-s-triazine and methods of using same
US3231469A (en) beta-benzalbutyramide as an anticholesterolemic agent
EP0132880B1 (en) Pharmaceutical compositions containing epinine or a pharmaceutically acceptable salt thereof
US4298611A (en) Process for reducing blood pressure in animals
US3288679A (en) Steroidal compositions and method of use
US3890441A (en) Pharmaceutical preparations and method of use
US3193458A (en) Method of lowering blood cholesterol level
US4315003A (en) Compositions containing azo compounds and use thereof for therapeutic treatment