58-32-2

Usage

Originator

Persantine,Boehringer Ingelheim,US,1961

Manufacturing Process

Urea may be reacted with acetoacetic ester and that product nitrated to give 5-nitro-orotec acid. That is hydrogenated, then reacted with urea and potassium cyanate to give tetrahydroxypyrimidopyrimidine. The tetrahydroxy compound is converted to the tetrachloro compound POCl3. Reaction with diethanolamine and then with piperidine gives dipyridamole.

Therapeutic Function

Coronary vasodilator

Biological Activity

Coronary vasodilator; adenosine transport inhibitor. Phosphodiesterase inhibitor (IC 50 values are 0.37, 0.38, 0.45, 0.9 and 4.5 μ M? for PDE11, 6, 10, 5 and 8 respectively).

Biochem/physiol Actions

Selective inhibitor of phosphodiesterase V (PDE 5); potent coronary vasodilator drug; adenosine transport inhibitor; inhibitor of platelet aggregation.

Mechanism of action

Dipyridamole exerts its antiplatelet function by increasing cellular concentrations of cAMP via its inhibition of the degradating enzyme, cyclic nucleotide PDE3. It also blocks adenosine uptake, which acts at A2 adenosine receptors to stimulate platelet adenyl cyclase. Less common uses for this drug include inhibition of embolization from prosthetic heart valves when used in combination with warfarin (the only currently recommended use) and reduction of thrombosis in patients with thrombotic disease when used in combination with aspirin. Alone, dipyridamole has little, if any, benefit in the treatment of thrombotic conditions.

Clinical Use

Dipyridamole is a pyrimidopyrimidine derivative with vasodilatory and antiplatelet properties.

Safety Profile

Poison by intraperitoneal and intravenous routes. Moderately toxic by ingestion and subcutaneous routes. Human systemic effects cardiomyopathy including infarction. Mutation data reported. Used as a coronary vasodilator. When heated to decomposition it e

Synthesis

Dipyridamole, 2,2',2'',2'''-[(4,8-dipiperidinopirimido[5,4-d]pirimidin-2,6- diyl)-diimino]-tetraethanol (19.4.13), is easily synthesized from 5-nitroorotic acid (19.4.8), easily obtained, in turn, by nitrating of 2,4-dihydroxy-6-methylpyrimidine, which is usually synthesized by the condensation of urea with acetoacetic ether. Reduction of the nitro group in 5-nitroorotic acid by various reducing agents gives 5-aminoorotic acid (19.4.9), which is reacted with urea or with potassium cyanide to give 2,4,6,8- tetrahydroxypyrimido[5,4-d]pyrimidine (19.4.10). This undergoes a reaction with a mixture of phosphorous oxychloride and phosphorous pentachloride, which forms 2,4,6,8- tetrachloropyrimido[ 5,4-d]pyrimidine (19.4.11). Reacting the resulting tetrachloride with piperidine replaces the chlorine atoms at C4 and C8 of the heterocyclic system with piperidine, giving 2,6-dichloropyrimido-4,8-dipiperidino[5,4-d]pyrimidine (19.4.12). Reacting the resulting product with diethanolamine gives dipyridamole (19.4.13).

Drug interactions

Potentially hazardous interactions with other drugsAnti-arrhythmics: effects of adenosine enhanced and extended.Anticoagulants: anticoagulant effect of coumarins, phenindione and heparin enhanced.

Metabolism

Dipyridamole is metabolised in the liver. Renal excretion of the parent compound is negligible (< 0.5%). Urinary excretion of the glucuronide metabolite is low (5%), the metabolites are mostly (about 95%) excreted via the bile into the faeces, with some evidence of entero-hepatic recirculation.

References

1) Fujishige et al. (1999), Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A); J. Biol. Chem., 274 18438 2) Soderling et al. (1998), Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase; Proc. Natl. Acad. Sci. USA, 95 8991 3) Lin and Buolamwini (2007), Synthesis, flow cytometric evaluation, and identification of highly potent dipyridamole analogues as equilibrative nucleoside transporter 1 inhibitors.; J. Med. Chem., 50 3906 4) Coccheri (2010), Antiplatelet drugs – do we need new options? With a reappraisal of direct thromboxane inhibitors; Drugs, 70 887

InChI:InChI=1/C24H40N8O4/c1-15(33)31(16(2)34)23-25-19-20(21(27-23)29-11-7-5-8-12-29)26-24(32(17(3)35)18(4)36)28-22(19)30-13-9-6-10-14-30/h15-18,33-36H,5-14H2,1-4H3

Synthetic route

2,6-dichloro-4,8-bis(piperidin-1-yl)pyrimido[5,4-d]pyrimidine (7139-02-8) + 2,2'-iminobis[ethanol] (111-42-2) → dipyridamole (58-32-2)

Conditions	Yield
Stage #1: 2,6-dichloro-4,8-bis(piperidin-1-yl)pyrimido[5,4-d]pyrimidine; 2,2'-iminobis[ethanol] In toluene at 0 - 155℃; for 9.5h; Stage #2: With benzenesulfonic acid In water; toluene at 0 - 95℃; for 2h; Stage #3: With ammonia; pyrographite In ethanol for 0.333333h; pH=8; Temperature;	95%
With 001x7 strong acid cation exchange resin In 1,3-dioxane at 78℃; for 4.5h; Temperature;	75%
Stage #1: 2,6-dichloro-4,8-bis(piperidin-1-yl)pyrimido[5,4-d]pyrimidine; 2,2'-iminobis[ethanol] at 180℃; for 3h; Stage #2: With sodium hydroxide In water; acetone at 25℃; for 4h;	70%

C16H24N6O2 + 2,2'-iminobis[ethanol] (111-42-2) → dipyridamole (58-32-2)

Conditions	Yield
With hydrogen at 240℃; under 11251.1 Torr; for 3h;	50.31%

piperidine (110-89-4) + 2-<2,6-dihydroxy-3,5-dimethyl-phenoxy>-3,5-dinitro-benzophenone → dipyridamole (58-32-2)

Conditions	Yield
1: Substitution / 2: Substitution;

2,4,6,8-Tetrachloro-pyrimido[5,4-d]pyrimidine (32980-71-5) → dipyridamole (58-32-2)

Conditions	Yield
1: Substitution / 2: Substitution;
Multi-step reaction with 2 steps 1: acetone; tetrachloromethane / 1 h / 30 °C 2: 0.25 h / 200 °C View Scheme

2,2'-(6-chloro-4,8-di-piperidin-1-yl-pyrimido[5,4-d]pyrimidin-2-ylazanediyl)-bis-ethanol (54093-92-4) + 2,2'-iminobis[ethanol] (111-42-2) → dipyridamole (58-32-2)

Conditions	Yield
at 25 - 115℃;

2,4,6,8-tetrahydroxypyrimidine-[5,4-d]pyrimidine (6713-54-8) → dipyridamole (58-32-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride / 1,4-dioxane / 1 h 1.2: 1.5 h / Darkness 2.1: caesium carbonate; copper(l) iodide / nitrobenzene / 16 h / 180 °C / Inert atmosphere 3.1: 3 h / 180 °C 3.2: 4 h / 25 °C View Scheme
Multi-step reaction with 3 steps 1: trichlorophosphate; phosphorus trichloride; chlorine / 24 h / 110 °C 2: acetone; tetrachloromethane / 1 h / 30 °C 3: 0.25 h / 200 °C View Scheme

6-Methyluracil (626-48-2) → dipyridamole (58-32-2)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: 2,2'-azobis(isobutyronitrile); cobalt(II) acetate; acetic acid; oxygen / 15 h / 80 °C 2.1: sodium hydroxide / water / 3 h 2.2: 25 - 45 °C / Inert atmosphere 3.1: copper; hydrogenchloride / water / 13 h / 40 °C / Inert atmosphere 4.1: sodium hydroxide / water / 4 h / 100 °C 5.1: thionyl chloride / 1,4-dioxane / 1 h 5.2: 1.5 h / Darkness 6.1: caesium carbonate; copper(l) iodide / nitrobenzene / 16 h / 180 °C / Inert atmosphere 7.1: 3 h / 180 °C 7.2: 4 h / 25 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide; water; oxygen / 95 °C 2.1: nitric acid; sulfuric acid / 1 h / 10 - 30 °C 3.1: sodium dithionite / water / 0.5 h / 35 °C 4.1: 0.33 h / 100 °C 4.2: 1 h / 90 - 100 °C 4.3: 0.5 h / 60 °C / pH 4 5.1: trichlorophosphate; phosphorus trichloride; chlorine / 24 h / 110 °C 6.1: acetone; tetrachloromethane / 1 h / 30 °C 7.1: 0.25 h / 200 °C View Scheme

orotic acid (65-86-1) → dipyridamole (58-32-2)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium hydroxide / water / 3 h 1.2: 25 - 45 °C / Inert atmosphere 2.1: copper; hydrogenchloride / water / 13 h / 40 °C / Inert atmosphere 3.1: sodium hydroxide / water / 4 h / 100 °C 4.1: thionyl chloride / 1,4-dioxane / 1 h 4.2: 1.5 h / Darkness 5.1: caesium carbonate; copper(l) iodide / nitrobenzene / 16 h / 180 °C / Inert atmosphere 6.1: 3 h / 180 °C 6.2: 4 h / 25 °C View Scheme

5-nitroorotic acid (17687-24-0) → dipyridamole (58-32-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: copper; hydrogenchloride / water / 13 h / 40 °C / Inert atmosphere 2.1: sodium hydroxide / water / 4 h / 100 °C 3.1: thionyl chloride / 1,4-dioxane / 1 h 3.2: 1.5 h / Darkness 4.1: caesium carbonate; copper(l) iodide / nitrobenzene / 16 h / 180 °C / Inert atmosphere 5.1: 3 h / 180 °C 5.2: 4 h / 25 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium dithionite / water / 0.5 h / 35 °C 2.1: 0.33 h / 100 °C 2.2: 1 h / 90 - 100 °C 2.3: 0.5 h / 60 °C / pH 4 3.1: trichlorophosphate; phosphorus trichloride; chlorine / 24 h / 110 °C 4.1: acetone; tetrachloromethane / 1 h / 30 °C 5.1: 0.25 h / 200 °C View Scheme

5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (7164-43-4) → dipyridamole (58-32-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydroxide / water / 4 h / 100 °C 2.1: thionyl chloride / 1,4-dioxane / 1 h 2.2: 1.5 h / Darkness 3.1: caesium carbonate; copper(l) iodide / nitrobenzene / 16 h / 180 °C / Inert atmosphere 4.1: 3 h / 180 °C 4.2: 4 h / 25 °C View Scheme
Multi-step reaction with 4 steps 1.1: 0.33 h / 100 °C 1.2: 1 h / 90 - 100 °C 1.3: 0.5 h / 60 °C / pH 4 2.1: trichlorophosphate; phosphorus trichloride; chlorine / 24 h / 110 °C 3.1: acetone; tetrachloromethane / 1 h / 30 °C 4.1: 0.25 h / 200 °C View Scheme

orotic acid sodium salt (154-85-8) → dipyridamole (58-32-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: nitric acid; sulfuric acid / 1 h / 10 - 30 °C 2.1: sodium dithionite / water / 0.5 h / 35 °C 3.1: 0.33 h / 100 °C 3.2: 1 h / 90 - 100 °C 3.3: 0.5 h / 60 °C / pH 4 4.1: trichlorophosphate; phosphorus trichloride; chlorine / 24 h / 110 °C 5.1: acetone; tetrachloromethane / 1 h / 30 °C 6.1: 0.25 h / 200 °C View Scheme

acetyl chloride (75-36-5) + dipyridamole (58-32-2) → 2,2',2'',2'''-tetrakis-acetoxy-1,1',1'',1'''-(4,8-di-piperidin-1-yl-pyrimido[5,4-d]pyrimidin-2,6-diylbisazanediyl)-tetrakis-ethane (63023-20-1)

Conditions	Yield
dmap In tetrahydrofuran at 0 - 5℃; for 3h;	95%

toluene-4-sulfonic acid (104-15-4) + dipyridamole (58-32-2) → dipyridamole di-p-toluenesulfonate

Conditions	Yield
In tetrahydrofuran	93.7%

formic acid (64-18-6) + dipyridamole (58-32-2) → 2,2',2'',2'''-tetrakis-formyloxy-1,1',1'',1'''-(4,8-di-piperidin-1-yl-pyrimido[5,4-d]pyrimidine-2,6-diylbisazanediyl)-tetrakis-ethane (107628-98-8)

Conditions	Yield
for 6h; Heating;	92%

maleic acid (110-16-7) + dipyridamole (58-32-2) → C24H40N8O4*C4H4O4

Conditions	Yield
In isopropyl alcohol	91.3%

propyl bromide (106-94-5) + dipyridamole (58-32-2) → C36H64N8O4

Conditions	Yield
Stage #1: dipyridamole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: propyl bromide In N,N-dimethyl-formamide Further stages.;	85%

dipyridamole (58-32-2) + methyl iodide (74-88-4) → N2,N2,N6,N6-tetrakis(2-methoxyethyl)-4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine-2,6-diamine

Conditions	Yield
Stage #1: dipyridamole With sodium hydride In N,N-dimethyl-formamide for 1h; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere;	84%
Stage #1: dipyridamole With sodium hydride In N,N-dimethyl-formamide at 25℃; for 1h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 25℃; for 4h;	69%
Stage #1: dipyridamole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: methyl iodide In N,N-dimethyl-formamide Further stages.;	64%

ethyl bromide (74-96-4) + dipyridamole (58-32-2) → C32H56N8O4

Conditions	Yield
Stage #1: dipyridamole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: ethyl bromide In N,N-dimethyl-formamide Further stages.;	84%

dipyridamole (58-32-2) → 2-[{6-[Bis-(2-hydroxy-ethyl)-amino]-4,8-di-piperidin-1-yl-pyrimido[5,4-d]pyrimidin-2-yl}-(2-hydroxy-ethyl)-amino]-ethanol; hydrochloride (59681-39-9)

Conditions	Yield
With hydrogenchloride In isopropyl alcohol	62.7%

dipyridamole (58-32-2) → C24H40N8O4*2H2O4S

Conditions	Yield
With sulfuric acid In isopropyl alcohol	58.6%

dipyridamole (58-32-2) + isopropyl bromide (75-26-3) → C30H52N8O4

Conditions	Yield
Stage #1: dipyridamole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: isopropyl bromide In N,N-dimethyl-formamide Further stages.;	55%

dipyridamole (58-32-2) + benzenesulfonic acid (98-11-3) → C24H40N8O4*2C6H6O3S

Conditions	Yield
In isopropyl alcohol	48.6%

dipyridamole (58-32-2) → C24H40N8O4*2H3O4P

Conditions	Yield
With phosphoric acid In isopropyl alcohol	47%

dipyridamole (58-32-2) + 3-Methyl-3-[(2,4,6-trimethoxyphenyl)methylthio]butanoic acid (194596-99-1) → 2,6-bis(diethyl-3-methyl-3(2,4,6-trimethoxyphenylmethylthio)butyric acid ester amino)-4,8-dipiperidinopyrimido-[5,4-d]-pyrimidine

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 50℃; for 44h;	23%

acetic anhydride (108-24-7) + dipyridamole (58-32-2) → 2,2',2'',2'''-tetrakis-acetoxy-1,1',1'',1'''-(4,8-di-piperidin-1-yl-pyrimido[5,4-d]pyrimidin-2,6-diylbisazanediyl)-tetrakis-ethane (63023-20-1)

Conditions	Yield
With pyridine Ambient temperature;	0.067 g

dipyridamole (58-32-2) → 1-{2,6-bis-[bis-(2-hydroxy-ethyl)-amino]-8-piperidin-1-yl-pyrimido[5,4-d]pyrimidin-4-yl}-piperidin-2-one

Conditions	Yield
With dihydrogen peroxide; 5-amino-2,3-dihydrophthalazine-1,4-dione; sodium chloride In phosphate buffer at 37℃; pH=7.4; Product distribution; Kinetics; Further Variations:; Reagents;

tartaric acid (87-69-4) + dipyridamole (58-32-2) → dipyridamole tartaric acid monoester + C32H48N8O14

Conditions	Yield
With water In neat (no solvent, solid phase) at 40℃; for 240h;

Upstream product

• 7139-02-8 2,6-dichloro-4,8-bis(piperidin-1-yl)pyrimido[5,4-d]pyrimidine 
• 111-42-2 2,2'-iminobis[ethanol] 
• 110-89-4 piperidine 
• 32980-71-5 2,4,6,8-Tetrachloro-pyrimido[5,4-d]pyrimidine 
• 54093-92-4 2,2'-(6-chloro-4,8-di-piperidin-1-yl-pyrimido[5,4-d]pyrimidin-2-ylazanediyl)-bis-ethanol 
• 6713-54-8 2,4,6,8-tetrahydroxypyrimidine-[5,4-d]pyrimidine 
• 626-48-2 6-Methyluracil 
• 65-86-1 orotic acid 
• 17687-24-0 5-nitroorotic acid 
• 7164-43-4 5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid 
• 154-85-8 orotic acid sodium salt 

Downstream Products

• 49845-74-1 dipyridamole di-p-toluenesulfonate 

Relevant academic research and scientific papers

Efficient synthesis method of dipyridamole

The invention discloses an efficient synthesis method of dipyridamole. The method comprises the following steps: dissolving a dichloro compound and diethanol amine into a solvent 1,3-dioxane to form ahomogeneous reactant; adding a catalyst, namely 001*7 strongly acidic cation exchange resin in the process of a reaction, wherein a reaction temperature is 75-80 DEG C, reaction time is 4-5 hours, and the content of a crude product reaches 95%; carrying out filtering to directly remove diethanol amine hydrochloride; filtering out the cation exchange resin by using a small bag filter, and washingand drying the cation exchange resin so as to recycling the cation exchange resin; drying a filtered crude product in a tray oven at 70-80 DEG C, recycling the solvent for indiscriminate usage, and adding ethanol accounting for 1.5 times of the weight of the dried crude product; carrying out heating to 78-80 DEG C, performing refluxing and dissolving, then conducting cooling to 15-20 DEG C, and performing crystallizing to obtain a finished product. The method is simple in process, beneficial for reducing energy consumption, safe and environment-friendly to operate, low in by-product amount, high in yield and convenient for industrial production.

Production method of dipyridamole bulk drug

The invention provides a production method of a bulk drug of dipyridamole, which relates to the field of the synthesis of chemical bulk drugs. The production method comprises the following steps: protecting carbonyl of urea, performing condensation reaction with 2,3-diaminosuccinic acid, performing chlorination for hydroxyl of a condensation reactant, replacing chlorine with piperidine, hydrolyzing an obtained product, obtaining a compound containing two carbonyls, separating the product, enabling the separated product to have condensation reaction with diethanol amine, obtaining dipyridamole,and refining to obtain a finished product. By adopting the production method, the synthetic procedure of the dipyridamole is simplified, the conversion rate of raw materials can be greatly increased,and the production cost is decreased.

Preparation method for dipyridamole

The invention belongs to the chemical field, and particularly relates to a preparation method for dipyridamole; diethanol amine and 2,6-dichloro-4,8-dipiperidinopyrimidino[5,4-D]pyrimidine are subjected to a reaction at relatively low temperature to generate dipyridamole, the dipyridamole crude product is subjected to secondary refining, and the yield and the chemical purity of the finally obtained dipyridamole are respectively increased to 94% or more and 98% or more; and the preparation method has the advantages of mild reaction, high reaction efficiency, low cost and the like, and is suitable for wide promotion and application.

Novel technology with introduced catalyst to optimize synthesis of dipyridamole

The invention discloses a novel technology with an introduced catalyst to optimize the synthesis of dipyridamole, and belongs to the technical field of medical intermediates. According to the technology, in the step of oxidizing a methyl group of 6-methyl uracil into formic acid, a Co(OAc)2/HOAc/AIBN/O2 catalytic system is introduced, and the reaction yield is increased to 90 to 95%. In the step of reducing a nitro group of nitro-orotic acid into an amino group, activated copper powder is taken as the catalyst, the yield is more than 85%; and moreover, the environmental pollution and danger caused by sodium hydrosulfite are avoided. In the step of converting substituted hydroxyl group into substituted chlorine, SOCl12 and N,N-dimethyl formamide are introduced into the reaction system so as to reduce the environment pollution and the difficulty of post treatment. In the reactions of preparing 2,6-dichloro-4,8-bis(piperidine-1-yl)pyrimido[5,4-d]pyrimidine from perchloro pyrimido[5,4-d]pyrimidine, a CuI/PhNO2 catalytic system is introduced into the reaction system, the reaction yield reaches 95%, moreover, the operation is easy, and the treatment is simple. The provided technology increases the yield, reduces the cost, guarantees the safety, saves the energy, and meets the requirements of green reactions and modern chemical production.

PROCESSES FOR THE PREPARATION OF DIPYRIDAMOLE

The present invention relates to the active pharmaceutical ingredient dipyridamole. In particular, it relates to efficient processes for the preparation of dipyridamole which are amenable to large scale commercial production and provide the required product with improved yield and purity. The present invention also relates to a novel crystallization method for the purification of dipyridamole.

AN IMPROVED PROCESS FOR THE PREPARATION OF DIPYRIDAMOLE

The present invention relates to an improved process for the preparation of Dipyridamole of formula (I) by reacting 2,6-Dichloro-4, 8-dipiperidinopyrimido (5,4- d) pyrimidine (DDH) with Diethanolamine (DEA) using l-Methyl-2-pyrrolidinone (NMP) as a solvent.

Use of radical-scavenging compounds for treatment and prevention of NO-dependent microcirculation disorders

A method of treatment of the human or non-human animal body for treating NO-dependent microcirculation disorders is disclosed, for example microcirculation disorders caused by metabolic diseases, such as elevated levels of homocystin-homocystein inflammatory reactions or autoimmune diseases, furthermore peripheral microcirculation disorders or microcirculation disorders associated with increased cell fragmentation, which method comprises administering to a human or non-human animal body in need of such treatment an effective amount of a pharmaceutical composition containing a substance which scavenges free radicals, e.g. a pyrimido-pyrimidine selected from Dipyridamole, Mopidamol and the pharmaceutically acceptable salts thereof, and the use such substance for the manufacture of a corresponding pharmaceutical composition, optionally in combination with an agent capable of increasing NO procution.

Prodrugs for the therapy of tumors and inflammatory disorders

Compounds of the formula Iglycosyl-Y[--C( Y)--X--] p --W(R) n --Z--C( Y)-active compound (I)are described which are suitable for the treatment of carcinomatous diseases, autoimmune diseases and chronic inflammatory diseases such as rheumatoid arthritis.

Structure-activity relationships of pyrimido-pyrimidine series of 5-lipoxygenase inhibitors

A series of pyrimido-pyrimidine compounds were synthesized and a SAR study was conducted for 5-LO inhibition using a broken cell preparation from RBL-1 cells. In this series compound 21 was found to be a potent 5-LO inhibitor in vitro.

Pharmaceutical composition and process of treatment

A process for alleviating proliferative skin diseases such as psoriasis, atopic dermatitis, etc. comprising administering to humans, or domesticated animals, topically and/or systemically a composition comprising a pharmaceutical carrier and at least one active compound selected from the groups, substituted alkyl zanthines, tricyclic antidepressants, organic nitrates, antihypertensives, anti-asthma agents and central nervous system depressants and combinations of certain compounds from specifically named groups of compounds.