US3641128A - Antifibrinolytic compounds - Google Patents
Antifibrinolytic compounds Download PDFInfo
- Publication number
- US3641128A US3641128A US834138A US3641128DA US3641128A US 3641128 A US3641128 A US 3641128A US 834138 A US834138 A US 834138A US 3641128D A US3641128D A US 3641128DA US 3641128 A US3641128 A US 3641128A
- Authority
- US
- United States
- Prior art keywords
- compound
- antifibrinolytic
- carboxylic acid
- acid
- bicyclo
- 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
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
Definitions
- This invention relates to a new antifibrinolytic compound and to a method of counteracting certain hemorrhagic conditions and other disorders resulting from a pathological fibrinolytic state in patients. More specifically, this invention relates to a new compound of the structure i u uca-@ coon wherein R is lower alkyl and the pharmaceutically acceptable salts thereof. More specifically, it relates to the prevention or treatment of a pathological fibrinolytic state in patients by the oral administration of from 1 to 20 and preferably 2 to 8 mg./kg. of body weight per day of the above compounds for varying periods of treatment.
- fibrin deposits in mammals is due to their lysis by the enzyme plasmin (fibrinolysin) which is formed in the blood from plasminogen, also present in the blood.
- plasmin fibrinogen
- This conversion from plasminogen to plasmin is promoted by activators in the blood and it would appear that excessive fibrinolytic activity results from an overabundance of such activators.
- activators in the blood and it would appear that excessive fibrinolytic activity results from an overabundance of such activators.
- the clotting system of the blood becomes unbalanced, viable clots cannot be maintained, and hemor rhage may result. This situation is known as a fibinolytic state.
- Other enzyme systems i.e., the kallikreins, complement
- antifibrinolytic agents i.e. drugs which will inhibit the activation of plasminogen to form plasmin.
- antifibrinolytic agents are believed to interfere with the function of the activators of converting plasminogen to plasmin.
- the clinical uses of such drugs include their administration to persons undergoing various kinds of surgery (such as heart-lung and prostate surgery), obstetrical hemorrhage problems, menorrhagia, and many other uses which have been suggested in the literature (e.g. see Nilssen, Acta Medica Scand. Suppl. 448, volume 180, 1966).
- EACA epsilon aminocaproic acid
- AMCHA trans-4-aminomethylcyclohexane carboxylic acid
- PAMBA 4-aminomethylbenzoic acid
- the new compound of my invention has the general wherein R is lower alkyl.
- the compound can be used as the racernate or either the d or 1 isomer.
- the pharmaceutically acceptable salts of the compound also show antifibrinolytic activity.
- the present invention also provides a process of preparing a compound of the structure which comprises the catalytic hydrogenation of a compound of the structure wherein R is lower alkyl.
- the hydrogenation is carried out under conventional conditions'generally in the presence of a catalyst such as platinum.
- the lower alkyl group R of 1 to 5 carbon atoms. is either methyl or ethyl.
- the compound is used in the method of this invention by either oral or intravenous administration, although the oral route is preferred.
- the esters and amides of this class compound are not themselves very active in vitro but the action of enzymes in vivo cause the slow liberation of the highly active amino acids, thus providing a prolonged availability of the drug in the body. This is important because of the tendency of these drugs to be swiftly eliminated in the urine.
- Such amides and esters are to be considered as being within the scope of the present invention since it is actually the present compound which produces the result within the body.
- the compound of this invention can be used in a composition comprising any pharmaceutically acceptable carrier, in the form of pills, tablets or capsules.
- pharmaceutically acceptable salts both of the amino group such as the hydrochloride, hydrobromide, sulfate, citrate, tartrate, etc.and of the carboxy group-such as the alkali metal, alkaline earth metal, etc., salts
- the pharmaceutically acceptable salts are readily usable, especially in injectable compositions.
- the invention can be illustrated by the cfollowing examples.
- the triester is hydrolyzed directly without purification by refluxing for 16 hours with a mixture of 25 ml. glacial acetic acid and 25 ml. concentrated hydrochloric acid. Evaporation leaves 1.83 g. (63% crude) of a white solid, which is chromatographed on silica gel (CHCl eluant) to remove a minor slower moving impurity. The chromatographed material is recrystallized from benzene-hexane, giving a white crystalline solid, M.P. 1655-168 C.
- the resulting crystalline solid is collected, washed with water and air-dried. Weight: 0.44 g. M.P. 242-245 C.
- the material is recrystallized from ethanol or ethyl acetate, M.P. 245247 C.
- EXAMPLE 2 The compound is tested in vitro by measuring the effect of the inhibitor at various concentrations on the lysis times of a fibrin clot with a constant concentration of streptokinase in plasminogen-rich plasma. The concentration of the inhibitor which increases the geometric mean lysis time by 50% is estimated. Epsilon amino caproic acid (EACA) is used as a standard and the relative potencies are obtained, with the following results:
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
THE COMPOUND 4 - (A - AMINO LOWER ALKYL) BICYCLO(2.2.2)-OCTANE-1-CARBOXYLIC ACID AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF ARE USEFUL AS ANTIFIBRINOLYTIC COMPOUNDS.
Description
United States Patent Oflice 3,641,128 Patented Feb. 8, 1972 ABSTRACT OF THE DISCLOSURE The compound 4 (a amino lower alkyl)bicyclo- [2.2.2]-octane-1-carboxylic acid and the pharmaceutically acceptable salts thereof are useful as antifibrinolytic compounds.
This invention relates to a new antifibrinolytic compound and to a method of counteracting certain hemorrhagic conditions and other disorders resulting from a pathological fibrinolytic state in patients. More specifically, this invention relates to a new compound of the structure i u uca-@ coon wherein R is lower alkyl and the pharmaceutically acceptable salts thereof. More specifically, it relates to the prevention or treatment of a pathological fibrinolytic state in patients by the oral administration of from 1 to 20 and preferably 2 to 8 mg./kg. of body weight per day of the above compounds for varying periods of treatment.
The dissolution of fibrin deposits in mammals is due to their lysis by the enzyme plasmin (fibrinolysin) which is formed in the blood from plasminogen, also present in the blood. This conversion from plasminogen to plasmin is promoted by activators in the blood and it would appear that excessive fibrinolytic activity results from an overabundance of such activators. When too much plasmin is present, the clotting system of the blood becomes unbalanced, viable clots cannot be maintained, and hemor rhage may result. This situation is known as a fibinolytic state. Other enzyme systems (i.e., the kallikreins, complement) may also be activated in an undesirable manner when such a state exists.
An interest has recently developed in antifibrinolytic agents, i.e. drugs which will inhibit the activation of plasminogen to form plasmin. These antifibrinolytic agents are believed to interfere with the function of the activators of converting plasminogen to plasmin. The clinical uses of such drugs include their administration to persons undergoing various kinds of surgery (such as heart-lung and prostate surgery), obstetrical hemorrhage problems, menorrhagia, and many other uses which have been suggested in the literature (e.g. see Nilssen, Acta Medica Scand. Suppl. 448, volume 180, 1966).
A standard antifibrinolytic agent, against which newer ones are generally tested and compared is epsilon aminocaproic acid, known as EACA. One deficiency of this agent has been the very high dosages needed; in some cases 3-6 grams or more every 4 to 6 hours. Also, side effects such as dizziness, nausea and diarrhea have been observed. More recently, two more potent agents have been described, namely trans-4-aminomethylcyclohexane carboxylic acid (AMCHA) and 4-aminomethylbenzoic acid (PAMBA). Each is reported to be more active than EACA by both in vitro and in vivo tests (e.g. see Anderssen et al. Scand. J. Haemat. (1965) 2, 230 and Melander et al. Acta Pharmacol. et Toxicol 22, 340 (1965 both of which discuss AMCI-IA).
I have found a new class of aminomethyl bicyclic carboxylic acids which show an activity of about 50 times that of EACA in tests essentially the same as those known to correlate with clinical results. I have thus also found an improved antifibrinolytic method of therapeutic treatment requiring much smaller doses of the drug.
The new compound of my invention has the general wherein R is lower alkyl. The compound can be used as the racernate or either the d or 1 isomer. The pharmaceutically acceptable salts of the compound also show antifibrinolytic activity.
The present invention also provides a process of preparing a compound of the structure which comprises the catalytic hydrogenation of a compound of the structure wherein R is lower alkyl. The hydrogenation is carried out under conventional conditions'generally in the presence of a catalyst such as platinum. In a preferred embodiment of the present invention, the lower alkyl group R of 1 to 5 carbon atoms. is either methyl or ethyl.
The compound is used in the method of this invention by either oral or intravenous administration, although the oral route is preferred. The esters and amides of this class compound are not themselves very active in vitro but the action of enzymes in vivo cause the slow liberation of the highly active amino acids, thus providing a prolonged availability of the drug in the body. This is important because of the tendency of these drugs to be swiftly eliminated in the urine. Such amides and esters are to be considered as being within the scope of the present invention since it is actually the present compound which produces the result within the body.
The compound of this invention can be used in a composition comprising any pharmaceutically acceptable carrier, in the form of pills, tablets or capsules. The pharmaceutically acceptable salts (both of the amino groupsuch as the hydrochloride, hydrobromide, sulfate, citrate, tartrate, etc.and of the carboxy group-such as the alkali metal, alkaline earth metal, etc., salts) are readily usable, especially in injectable compositions.
The invention can be illustrated by the cfollowing examples.
EXAMPLE 1 Racemic 4-(a-aminoethyl)-bicyclo-[2.2.21-octane-lcarboxylic acid (A) 4-carbomethoxybicyclo [2.2.2] oct-2-ene-1-carboxylic acid chloride.--A solution of 5.0 g. (0.024 mole) methyl hydrogenbicyclo-[2.2.2]-oct 2 ene-1,4-dicarboxylate [F. W. Baker and L. M. Stock, J. Org. Chem. 32 3344 (1967)] in 20 ml. of thionyl chloride is heated to reflux for 3 hours. After removal of the excess thionyl chloride by distillation in vacuo at steam bath temperatures and then reevaporation with 3-20 ml. portions of hexane, the resulting liquid is distilled in vacuo, giving 3 5.3 g. (97%) of a colorless liquid, B.P. 97-98 C./7.0 mmpHg.
(B) 4-acetylbicycl0 [2.2.2] oct-2-ene-l-carboxylic acid.A mixture of 0.42 g. (0.017 mole) magnesium turnings, 2 ml. dry benzene and 0.1 ml. absolute ethanol is heated to reflux until the dissolution of magnesium begins. To this is added, over 30 minutes, a mixture of 2.72 g. (0.017 mole) diethyl malonate, 0.7 ml. absolute ethanol and 3 ml. benzene. After 3 hours of reflux, all of the magnesium has dissolved. The ethanol is then removed by azeotropic distillation with fresh portions of benzene, the volume brought to about ml. with benzene, and a solution of 3.43 g. (0.015 mole) 4-ca.rbomethoxybicyclo- [2.2.2]-oct-2-ene-1-carboxylic acid chloride in 5 ml. benzene is added at reflux over a minute period. After an additional 3 /2 hours at reflux, the viscous mixture is poured into 100 ml. ice water and ml. 6 N hydrochloric acid. The combined benzene extracts, after washing with water and drying over MgSO gives 4.5 g. of a colorless liquid, an infrared spectrum of which exhibited no acid chloride absorption. The triester is hydrolyzed directly without purification by refluxing for 16 hours with a mixture of 25 ml. glacial acetic acid and 25 ml. concentrated hydrochloric acid. Evaporation leaves 1.83 g. (63% crude) of a white solid, which is chromatographed on silica gel (CHCl eluant) to remove a minor slower moving impurity. The chromatographed material is recrystallized from benzene-hexane, giving a white crystalline solid, M.P. 1655-168 C.
(C) 4-(a-oximinoethyl)-bicyclo-[2.2.2]-oct 2 ene-lcarboxylic acid.A mixture of 0.52 g. (7.5 mmoles) hydroxylamine hydrochloride, 3 ml. absolute ethanol and 3 ml. pyridine is refluxed on a steam bath for 5 minutes. To this is added 0.49 g. (2.5 mmoles) 4-acetylbicyclo-[2.2.2]- oct-2-ene-l-carboxylic acid. After 3 hours at reflux, most of the solvent is removed in vacuo, then the residue is stirred with 30 ml. cold 3 N hydrochloric acid. The resulting crystalline solid is collected, washed with water and air-dried. Weight: 0.44 g. M.P. 242-245 C. The material is recrystallized from ethanol or ethyl acetate, M.P. 245247 C.
(D) dl-4-(a-aminoethyl)-bicyclo [2.2.2] octane-1- carboxylic acid hydrochloride.To a solution of 270 mg. (1.29 mmoles) 4-(a-oximinoethyl) bicyclo-[2.2.2]-oct 2-ene-l-carboxylic acid in 50 ml. 90% ethanol is added 0.5 ml. 6.0 N hydrochloric acid and 50 mg. platinum oxide. The mixture is shaken in a Parr hydrogenation apparatus at 30 lbS./in. and 25 C. for 3 hours. Filtration and evaporation leaves a white solid, which is recrystal lized from ethanol-ether. Yield: 240 mg. (80%). The
material, which is not noticeably hydroscopic, is purified by recrystallization from ethanol-ether and dried for anallysis at C. in vacuo, M.P. 313.5-315 C. dec.
EXAMPLE 2 The compound is tested in vitro by measuring the effect of the inhibitor at various concentrations on the lysis times of a fibrin clot with a constant concentration of streptokinase in plasminogen-rich plasma. The concentration of the inhibitor which increases the geometric mean lysis time by 50% is estimated. Epsilon amino caproic acid (EACA) is used as a standard and the relative potencies are obtained, with the following results:
Compound: Relative in vitro activity (weight basis) (A) Reference compound: EACA 1.0
(B) New compound: 4-(a-aminoethyl)bicyclo- [2.2.2] octane-l-carboxylic acid 50 Many other equivalent modifications of the invention would be apparent to those skilled in the art from a reading of the foregoing without a departure from the inventive concept.
.I claim:
1. A compound selected from the group consisting of n ncn @coou References Cited UNITED STATES PATENTS 6/1970 Loefpler 2605l4 OTHER REFERENCES House, Modern Synthetic Reactions, p. 15, 1965.
LEWIS GOTTS, Primary Examiner R. GERSTL, Assistant Examiner U.S. Cl. X.R.
260468 B, 501.11, 557 B; 424-3l9
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US83413869A | 1969-06-17 | 1969-06-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
US3641128A true US3641128A (en) | 1972-02-08 |
Family
ID=25266213
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US834138A Expired - Lifetime US3641128A (en) | 1969-06-17 | 1969-06-17 | Antifibrinolytic compounds |
Country Status (10)
Country | Link |
---|---|
US (1) | US3641128A (en) |
BE (1) | BE752042A (en) |
CH (1) | CH537366A (en) |
DE (1) | DE2029756C3 (en) |
ES (1) | ES380714A1 (en) |
FR (1) | FR2052980B1 (en) |
GB (1) | GB1252248A (en) |
IL (1) | IL34651A (en) |
NL (1) | NL7007536A (en) |
ZA (1) | ZA704088B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3888506A (en) * | 1973-10-10 | 1975-06-10 | Gen Motors Corp | Occupant knee restraint |
US3907326A (en) * | 1972-07-28 | 1975-09-23 | Gen Motors Corp | Occupant knee restraint |
US4663474A (en) * | 1983-02-22 | 1987-05-05 | Pfizer Inc. | Synthetic intermediates for a chiral 3-(substituted-phenyl)-4-(3-hydroxypropyl) cyclohexanol |
US10202331B2 (en) | 2014-11-03 | 2019-02-12 | Thrombolytics, Llc | Antifibrinolytic compounds |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL31192A (en) * | 1967-12-14 | 1972-03-28 | Merck & Co Inc | Anti-fibrinolytic bicycloheptane,bicyclooctane and bicyclononane compounds |
-
1969
- 1969-06-17 US US834138A patent/US3641128A/en not_active Expired - Lifetime
-
1970
- 1970-05-25 NL NL7007536A patent/NL7007536A/xx not_active Application Discontinuation
- 1970-06-02 IL IL34651A patent/IL34651A/en unknown
- 1970-06-12 ES ES380714A patent/ES380714A1/en not_active Expired
- 1970-06-12 CH CH890670A patent/CH537366A/en not_active IP Right Cessation
- 1970-06-15 GB GB1252248D patent/GB1252248A/en not_active Expired
- 1970-06-16 BE BE752042D patent/BE752042A/en unknown
- 1970-06-16 DE DE2029756A patent/DE2029756C3/en not_active Expired
- 1970-06-16 ZA ZA704088A patent/ZA704088B/en unknown
- 1970-06-16 FR FR7022081A patent/FR2052980B1/fr not_active Expired
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3907326A (en) * | 1972-07-28 | 1975-09-23 | Gen Motors Corp | Occupant knee restraint |
US3888506A (en) * | 1973-10-10 | 1975-06-10 | Gen Motors Corp | Occupant knee restraint |
US4663474A (en) * | 1983-02-22 | 1987-05-05 | Pfizer Inc. | Synthetic intermediates for a chiral 3-(substituted-phenyl)-4-(3-hydroxypropyl) cyclohexanol |
US10202331B2 (en) | 2014-11-03 | 2019-02-12 | Thrombolytics, Llc | Antifibrinolytic compounds |
Also Published As
Publication number | Publication date |
---|---|
ZA704088B (en) | 1972-01-26 |
FR2052980B1 (en) | 1974-05-24 |
CH537366A (en) | 1973-05-31 |
DE2029756A1 (en) | 1971-01-07 |
DE2029756C3 (en) | 1979-01-18 |
DE2029756B2 (en) | 1978-05-11 |
BE752042A (en) | 1970-12-16 |
IL34651A (en) | 1973-07-30 |
FR2052980A1 (en) | 1971-04-16 |
ES380714A1 (en) | 1972-08-16 |
NL7007536A (en) | 1970-12-21 |
IL34651A0 (en) | 1970-08-19 |
GB1252248A (en) | 1971-11-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0931060B1 (en) | Substituted n- (aminoiminomethyl or aminomethyl)phenyl propyl amides | |
PT2101760E (en) | Unit dose formulations and methods of treating thrombosis with an oral factor xa inhibitor | |
JP2736952B2 (en) | Amidinophenol derivative and drug containing the derivative as active ingredient | |
JP2006525328A (en) | How to treat heart disease | |
US4096252A (en) | 4-Trifluoromethylbenzoic acid derivatives as thromboembolic agents | |
US3641128A (en) | Antifibrinolytic compounds | |
US3767814A (en) | Method of treating hemorrhagic conditions | |
US3641129A (en) | Antifibrinolytic compounds | |
US3517055A (en) | Anti-fibrinolytic agent | |
JPH03141221A (en) | Constant imidazole compounds as transglutaminase inhibitor | |
WO2016206576A1 (en) | Deuterated thienopiperidine derivatives, manufacturing method, and application thereof | |
US3526657A (en) | Anti-fibrinolytic agent | |
US5093325A (en) | Combination preparation having antithrombotic action | |
US3743742A (en) | Producing anti-fibrinolytic activity with aminobicycloacetic acid derivatives | |
US3781415A (en) | Product,process and composition | |
JPH08504813A (en) | 17β-N-Mono-substituted-carbamoyl-4-aza-5α-androst-1-en-3-one-Patent application | |
Manley et al. | Thromboxane synthase inhibitors. Synthesis and pharmacological activity of (R)-,(S)-, and (.+-.)-2, 2-dimethyl-6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl) methoxy] methyl] ethoxy] hexanoic acids | |
Ballabeni et al. | Effects of subacute treatment with benzopyranopyrimidines in hemostasis and experimental thrombosis in mice | |
US3720775A (en) | Treatment of a pathological fibrinolytic state in patients | |
US3634499A (en) | Antifibrinolytic compounds | |
US3726969A (en) | Accelerating the lysis of blood clots with urokinase and a benzylamine derivative | |
Tanaka et al. | Antiplatelet effect of Z-335, a new orally active and long-lasting thromboxane receptor antagonist | |
IL31192A (en) | Anti-fibrinolytic bicycloheptane,bicyclooctane and bicyclononane compounds | |
US3594482A (en) | Method of treating a pathological fibrinolytic state in mammals | |
JPH0514708B2 (en) |