IL33072A - Compositions containing dopa and alpha-hydrazino-3,4-dihydroxyphenylpropionic acid for increasing the dopamine content in the brain tissue of animals - Google Patents
Compositions containing dopa and alpha-hydrazino-3,4-dihydroxyphenylpropionic acid for increasing the dopamine content in the brain tissue of animalsInfo
- Publication number
- IL33072A IL33072A IL33072A IL3307269A IL33072A IL 33072 A IL33072 A IL 33072A IL 33072 A IL33072 A IL 33072A IL 3307269 A IL3307269 A IL 3307269A IL 33072 A IL33072 A IL 33072A
- Authority
- IL
- Israel
- Prior art keywords
- compound
- composition according
- dopa
- hydrazino
- brain tissue
- Prior art date
Links
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 title claims description 40
- 229960003638 dopamine Drugs 0.000 title claims description 20
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 title claims description 15
- 210000005013 brain tissue Anatomy 0.000 title claims description 10
- 239000000203 mixture Substances 0.000 title claims 11
- 241001465754 Metazoa Species 0.000 title description 7
- IPHPUCLNGNPXOU-UHFFFAOYSA-N 2-(3,4-dihydroxyphenyl)-2-hydrazinylpropanoic acid Chemical compound NNC(C)(C(O)=O)C1=CC=C(O)C(O)=C1 IPHPUCLNGNPXOU-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 8
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 11
- 210000004556 brain Anatomy 0.000 description 7
- -1 hydrazine compound Chemical class 0.000 description 7
- 239000002253 acid Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000003387 muscular Effects 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 206010001541 Akinesia Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- AKWHTKRUNUYXDS-UHFFFAOYSA-N Dihydroxyphenylpropionic acid Chemical compound OC(=O)CC(O)C1=CC=C(O)C=C1 AKWHTKRUNUYXDS-UHFFFAOYSA-N 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 208000027089 Parkinsonian disease Diseases 0.000 description 2
- 206010034010 Parkinsonism Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 210000001653 corpus striatum Anatomy 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 208000002740 Muscle Rigidity Diseases 0.000 description 1
- 102100026459 POU domain, class 3, transcription factor 2 Human genes 0.000 description 1
- 101710133394 POU domain, class 3, transcription factor 2 Proteins 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002021 butanolic extract Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000013114 circling movement Diseases 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000012956 testing procedure Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (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)
- Medicinal Preparation (AREA)
Description
nan containing and acid for the the brain tissue of Abstract of the Disclosure The dopamine content in brain tissue of animals is increased by administering to the animal dopa or its salts in combination with or D or acid the substituent is H or lower or its The increased dopamine content in brain tissue tends to alleviate some of the symptoms caused by Parkinsonism and similar The present invention relates to a novel and useful method of increasing the dopamine content in the brain tissue of More it relates to such a method wherein dopa or its salts is administered in combination with phenylpropionic acid or its wherein the substituent is H or lower A dopamine deficiency has been demonstrated to occur in certain nuclei of brain tissue in patients with Parkinsons Dopamine is 3 phenylethylamine of the structure A dopamine deficiency in the corpus striatum results in increased muscular tension and akinesia which is defined as the absence or disturbance of motion in a This 1 is characterized by the rigidity of limbs and difficulty 2 in noted in Parkinson 3 syndrome It was first suggested that perhaps dopamine could be administered directly to the animal to compensate 6 for the a natural 7 barrier in the body prevented the absorption in brain It then proposed that a metabolic precursor 9 of dopamine be utilized viith the body changing the 0 precursor into dopamine after it has traversed the 1 brain racemic dopa was employed for 2 this purpose as it was a known precursor of 3 Dopa is 3 of the formula i and is known to be racemic due to its asymmetric carbon In employing dopa to increase the dopamine content of brain numerous side effects were encountered 7 such as nausea and as well as hypertension in 8 some instances and hypotension in Also noted were 9 certain changes in blood chemistry which have not been 0 fully the overall results ranged from 1 poor to excellent in alleviating muscular tension 2 3 An effort to minimize side effects led to a separation of the which is into its D and L forms with subsequent testing of It was found that 6 was far more effective and resulted in less side 1 effects than the use of has 2 now been experimentally accepted as a treatment for the 3 muscular tension and akinesia but it too produces side effects as nausea and in certain patients due to the fact that it must be administered in quite high 6 dosage if a 7 bination of drugs could be found which would reduce the 8 amount of which was required to 9 obtain remission of symptoms thereby lessening or 10 ing side it would receive widespread acceptance in 11 the 12 It is an object of the present invention to 13 vide a combination of drugs which increases the dopamine content in brain tissue with a lessening or omission of side It is a further object to produce a tion of drugs which requires less or in increasing the dopamine content in the brain tissue of Other objects will become apparent as the 19 description of the invention 20 These objects are accomplished by the present 21 invention which provides a method of increasing the 22 mine content in the brain tissue of animals which comprises 23 administering to the animal a compound selected from the group consisting of dopa and the pharmaceutically acceptable salts thereof in combination a compound 26 selected from the group consisting of 27 wherein the 28 substituent is H or lower and the pharmaceutically 29 acceptable salts The hydrazine like the 30 contains an asymmetric carbon atom and and can be used as the L the D or the 1 The compounds employed in the present invention 2 have the structural formula 3 wherein R is H or lower In a preferred embodiment of the present tion both the dopa and hydrazine compound are employed in 6 the L form and the drugs are administered 7 the drugs are administered sequentially with the 8 acid being given a few minutes to about hours prior to 0 the administration of a practical 1 the drugs are generally given simultaneously in a 2 single pill or The combination is usually given in amounts of from about to about 200 of body weight with the ratio of to the hydrazine compound being from about to about 8 preferably about to about 6 with about 2 being the optimum ratio In a preferred embodiment of the present the hydrazine compound is dihydroxyphenylpropionic acid or phenylpropionic acid and the compounds are used in their The pharmaceutically acceptable salts of the drugs which may be used without the alkali metal and ammonium salts of the carboxy function and the sulfate and the like salts of the amino The term 1 means an alk l group containing from 1 to about carbon 2 In one of the preferred embodiments of the present 3 the free base compounds are used and not the The invention will now be described by reference 6 to the following examples in which all parts are expressed 7 in parts by weight unless otherwise 8 EXAMPLES 1 to l8 9 Female albino mice weighing between l8 and 22 10 each are the 11 dihydroxyphenylpropionic acid and combinations of the two 12 are administered in solution or suspension in 13 and the animals are decapitated 90 minutes Brains are removed and pooled in groups of three separate pools per drug 16 The brains are homogenized with per The butanol extract is back extracted 18 with 1 hydrochloric an aliquot of which is 19 subjected to iodine oxidation for the fluorimetric 20 determination of dopa plus dopamine 21 and 17 22 23 Control groups of mice are and results are expressed as the ratio of total dopa plus dopamine in 2 the brains of mice to the total dopa plus 26 dopamine in the brains of untreated The average 27 value for the three trials at each dosage level is given 8 in Table In the Example 9 is a repeat run as a 29 control for Example 1 I e Ratio Normal Dopa Dopamine 7 1 None None 8 2 None 77 9 3 None 0 960 None 32 1 5 20 10 racemate 79 2 6 20 racemate 73 3 7 80 racemate 8 20 only 7 5 9 20 racemate 6 As shown by the 30 of the combination 7 drug as effective as of by 8 itself 2 60 of the combinatio 9 drug 6 is as effective as of by 0 itself 3 Also as shown by the 120 of 1 the combination drug 7 is much more effective 2 than 960 of by itself The table also shows the of the hydrazine compound 8 to be more active than the racemate 9 In order to determine the optimum ratio of 6 to the hydrazine compound to be utilized in the 7 the testing procedure given above is carried out 8 using a constant dosage of 60 of body Only 9 the ratio of the two drugs is The results are 0 given in Table The hydrazine compound is used in the 1 TABLE II 2 Ratio Ratio 3 Hydr Compound Normal k 10 8 11 6 racemate 6 12 k racemate 7 13 2 racemate 8 1 racemate 9 racemate 10 16 racemate 11 17 racemate 12 18 racemate 13 As shown by the the most effective dosage is obtained when the ratio of the to the racemic hydrazine compound is from about to about 8 with a 16 preferred ratio being from about to about In actuality the optimum ratio of about 2 be 18 EXAMPLES 19 and 20 19 The procedures of Examples 13 and above are 20 repeated employing 21 acid in place of the hydrazino The 22 results show the desmethyl compound to be from 2 3 times as active as the 2k EXAMPLE 21 2 In order to again test the effectiveness of 26 in combination the hydrazine compound 27 compared to the method of Anden and 28 workers is employed 29 and et 30 administered 1 peritoneally to rats with appropriate unilateral brain 2 lesions causes the rats to circle in the direction of the 3 lesion showing effectiveness of the This effect is believed to result from the being converted by the body into dopamine which acts upon the corpus striatum of 6 the intact side of the The beneficial effect of 7 in Parkinsonian patients is also believed to result 8 from the action of dopamine upon the corpus 9 Lower doses of is 10 after one hour pretreatment with 11 racemic 12 acid a dose of of 13 is now sufficient to again cause circling movements in lesioned While in the above examples only the combination 16 of the two compounds is it should be noted that the compounds would generally be utilized with other drugs 18 such as c agents muscle 19 nes and the like to alleviate other 0 symptoms of Parkinsonism and like 21 Many other equivalent modifications of the 2 invention would be apparent to those skilled in the art 3 from a reading of the foregoing without a departure from the inventive 9 insufficientOCRQuality
Claims (11)
1. A pharmaceutical composition for increasing the dopamine content of the brain tissue, comprising as active ingredients a compound (A) selected from the group consisting of dopa and the pharmaceutically acceptable salts thereo , in combination with a compound (B) selected from the group consisting of a-hydrazino-a-substituted-3»4-dihydroxyphenyl-propionic acid, wherein the substituent is H or lower alkyl, and the pharmaceutically acceptable salts thereof.
2. A composition according to Claim 1, wherein the compound (A) is L-dopa.
3. A composition according to Claim 2, wherein the compound (A) is racemic dopa.
4. * A composition according to Claim 2 or 3» wherein the compound (B) is L-a-hydrazino-a-methyl-3»4-dihydroxy-phenylpropionic acid.
5. 3· A composition according to Claim 4» wherein the compound (B) is racemic a-hydrazlno-a-meth l-3,4-dihydroxy-phenylpropionic acid.
6. · A composition according to Claim 4, wherein the compound (B) is a-hydragino-3,4-dihydrox phenylpropionic acid.
7. A composition according to Claim 4, wherein the compound (B) is racemic a-hydrazino-3» -dihydrox phenyl-propionic acid. - 10 - 33072/2
8. A composition according to any one of the preceding claims, wherein the ratio of compound (A) to compound (B) is from about 0.2 to about 8.
9. A composition according to any one of the preceding claims wherein the ratio of compound (A) to compound (B) is from about 0.5 to about 6.
10. A composition according to any one of the preceding claims, wherein the ratio of compound (A) to compound (B) is about 2.
11. A composition according to any one of Claims 1 to 10, substantially as hereinbefore described, with reference to the Examples. For the Applicants SR. EEIHHOLD COM AND PARTNERS
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US76432568A | 1968-10-01 | 1968-10-01 | |
| US83573069A | 1969-06-23 | 1969-06-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL33072A0 IL33072A0 (en) | 1969-11-30 |
| IL33072A true IL33072A (en) | 1973-04-30 |
Family
ID=27117439
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL33072A IL33072A (en) | 1968-10-01 | 1969-09-26 | Compositions containing dopa and alpha-hydrazino-3,4-dihydroxyphenylpropionic acid for increasing the dopamine content in the brain tissue of animals |
Country Status (10)
| Country | Link |
|---|---|
| BE (1) | BE739625A (en) |
| CA (1) | CA957945A (en) |
| CY (1) | CY648A (en) |
| DE (1) | DE1949376C3 (en) |
| ES (1) | ES372009A1 (en) |
| FR (1) | FR2019605B1 (en) |
| GB (1) | GB1243474A (en) |
| IE (1) | IE33581B1 (en) |
| IL (1) | IL33072A (en) |
| NL (1) | NL149372B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU464903B2 (en) * | 1970-11-12 | 1975-09-11 | Merck & Co., Inc | Treatment of hypertension |
| DE4101873C2 (en) * | 1991-01-23 | 1993-12-09 | Isis Pharma Gmbh | Orally administrable drug form for the treatment of central dopamine deficiency states |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3462536A (en) * | 1960-07-22 | 1969-08-19 | Merck & Co Inc | Method of inhibiting decarboxylase |
-
1969
- 1969-09-18 NL NL696914185A patent/NL149372B/en not_active IP Right Cessation
- 1969-09-23 IE IE1326/69A patent/IE33581B1/en unknown
- 1969-09-26 CA CA063,304A patent/CA957945A/en not_active Expired
- 1969-09-26 IL IL33072A patent/IL33072A/en unknown
- 1969-09-29 ES ES372009A patent/ES372009A1/en not_active Expired
- 1969-09-29 GB GB47811/69A patent/GB1243474A/en not_active Expired
- 1969-09-30 BE BE739625D patent/BE739625A/xx not_active IP Right Cessation
- 1969-09-30 DE DE1949376A patent/DE1949376C3/en not_active Expired
- 1969-10-01 FR FR696933459A patent/FR2019605B1/fr not_active Expired
-
1972
- 1972-07-04 CY CY64872A patent/CY648A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL33072A0 (en) | 1969-11-30 |
| CY648A (en) | 1972-07-04 |
| FR2019605A1 (en) | 1970-07-03 |
| NL149372B (en) | 1976-05-17 |
| GB1243474A (en) | 1971-08-18 |
| DE1949376B2 (en) | 1977-10-06 |
| CA957945A (en) | 1974-11-19 |
| IE33581B1 (en) | 1974-08-21 |
| NL6914185A (en) | 1970-04-03 |
| DE1949376A1 (en) | 1970-06-18 |
| ES372009A1 (en) | 1972-05-01 |
| DE1949376C3 (en) | 1978-08-31 |
| BE739625A (en) | 1970-03-31 |
| FR2019605B1 (en) | 1973-06-08 |
| IE33581L (en) | 1970-04-01 |
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