Title of Invention	"A NOVEL HETEROCYCLEC CMPOUND XANTHONOXY PROPANOLAMINES"
Abstract	This invention relates to a novel heterocyclic compounds Xanthonoxy propanolamines having the formula: Process for the preparation of novel Xanthonoxy propanolamines comprising adding Epichlorohydrin to a solution of hydroxy Xanthones in an aqueous ethanol containing sodium hydroxide, heating the mixture under reflux at 50° to 80°C preferably at 60-75°C for 1-2 hours with continuous stirring followed by further stirring for 2-4 hrs, preferably for 3 hrs at 15° to 30°C, preferably at room temperature, pouring the products into ice water, separating out the oily layer and concentrating under reduced pressure to get the epoxy compounds as semisolid or oily residue.

Title of Invention

"A NOVEL HETEROCYCLEC CMPOUND XANTHONOXY PROPANOLAMINES"

Abstract

This invention relates to a novel heterocyclic compounds Xanthonoxy propanolamines having the formula: Process for the preparation of novel Xanthonoxy propanolamines comprising adding Epichlorohydrin to a solution of hydroxy Xanthones in an aqueous ethanol containing sodium hydroxide, heating the mixture under reflux at 50° to 80°C preferably at 60-75°C for 1-2 hours with continuous stirring followed by further stirring for 2-4 hrs, preferably for 3 hrs at 15° to 30°C, preferably at room temperature, pouring the products into ice water, separating out the oily layer and concentrating under reduced pressure to get the epoxy compounds as semisolid or oily residue.

Full Text	"Antihypertensive Activity of Novel Heterocyclic Compounds and the process of preparation thereof Field of Invention; The invention relates to xanthonoxy propanolamines having antihypertensive activity and the process of preparation thereof. Background of the Invention: Hypertension or High Blood Pressure is the name of a pathological condition in which blood pressure is persistently elevated. It is defined as a rise in the pressure of blood in the arteries, compared to a value known as ^normal" established by many scientific committees throughout the world. This persistent high blood pressure puts undue stress on the heart, blood vessels and other organs. It is now a major public health problem of largely unknown cause and yet a great concern of modern medical practice due to its doubtful and uncertain etiology. The people suffering from the disorder gradually come undjer the phenomena of secondary complications that may produce other vital-organ diseases. It contributes alone a number of cardio vascular diseases, which causes morbidity and premature death. The main causes of hypertension may be sleep apnea, drug induced or related causes, chronic kidney disease, primary aldosteronism, reno-vascular disease, chronic steroid therapy, cushing's syndrome, thyroid or parathyroid disease, coarctation of the aorta. B-Bjockers as a important antihvpertensive drugs; Standard drugs: Propranolol, Atenolol (IDR (Sept.-Oct. 2003; MIMS India Nov. 2005). (Figure Remove) OCH2CHCH2NHCH(CH3)2 OH PCH2CHCH2NHCH(CH3)2 OH CH2CONH2 Atenolol Propranolol Major Drawbacks and side effects of existing standard drugs (Propranolol and Atenolol), and other p-blocker drugs: The major clinical adverse effects of the most of antihypertensive ($-blockers have been found as CNS effects like fatigue, lethargy, decrease exercise tolerance, sleep disturbance, vivid dreams, hallucination, sinus bradycardia, any degree of heart attack and bronchospasm etc. For example, despite of good ^-blocking activity and reducing a number of heart attacks in the most patients with angina pectoris, propranolol is found carcinogenic with much CNS effect. Propothalol causes increase incidence of sarcoma in mice, whereas, tolamolol causes mammory aderno-carcinoma. Pamatolol induces hepatcarcinoma in rats. In addition, fatigue, tiredness, skin-rash, fever, depression, nightmare, renal dysfunction, nausea, epigastric distress, cold extremities and hypoglycemia are also associated with propranolol. Other cardioselective (J-blockers totamolol, practolol, metoprolol and acebutalol are generally hydrophilic P Atenolol or Metoprolol are not good inhibitor of "Renin-Release", thus, possibility of developing congestive cardiac failure (CCF) is greater with these cardioselctive agents, because, venous return is not reducted in the face of (-) inotropic and chronotropic effects. Bunalol exhibits uterine leio-myometa and liver adenomas in rats. In addition, bradycardia, nausea, vomiting, epigastric discomfort, skin rash, tiredness, fatigue, dizziness, leg pain, cold extremities because of peripheral arterial insufficiency are associated with Atenolol. Drug interactions of Propranolol and Atenolol: «»» Propranolol produces orthostatic with quinidine J Rifarnpicin, phenobarbitone, NSAID, thyroid hormones, smoking. All decrease antihypertensive of action of propranolol «!» Corticosteriods antagonize antihypertensive effect of propranolol J Sympathomimetic drug marks hypertension and bradycardia. ^* With insulin, hypoglycemic effect will be prolonged by propranolol and masking of the sympotoms of hypoglycemia in diabetes cases. > Increased level of lidocaine with propranolol leads to toxicity. »» With calcium channel blockers, it produces severe bradycardia especially in those patients with impaired left ventricular (LV) function. J Propranolol also antagonizes the action of theopylline in case of asthma. Thus, the observations regarding the above mentioned side effects of the existing ^-blocking antihypertensive agents tend for the search of novel type of drugs to lower the high blood pressure with a quality of more potency and devoid of adverse effect. The ideal {3-blockers for HTN should be long acting, cardioselctive and usefully effective in standard dose. They must have simple pharmacokinetics advantage such as, no liver metabolism, little protein binding, no lipid solubility (i.e lipid neutral) and no active metabolites. Inventors have therefore, prepared some novel heterocyclic compounds i.e., Xanthonoxypropanolamines, which contain (i); almost double antihypertensive activity, (ii): 4-5 times much faster onset of action, (iii): 4-5 times much longer duration of action, (iv): 2-3 times more active at lower does than the standard drugs i.e., I/4th dose than the standard, and (v): in good yield (more than 60-70%) without any significant toxicity, as no signs of toxicity were observed in the preliminary screening tests. Objects of the Invention: An bject of the invention is to produce novel drugs and a process for the preparation thereof with almost double anti-hypertensive activity in comparison to known drugs. Another object of the invention is to produce novel drugs which has 2-3 times more activity at V^th dose than the known drug. Further object is to produce novel drugs which modifies the onset of action 4-5 times faster than known drugs. Other object is to produce novel drugs which increases the duration of action for a substantially longer period than known drugs. Another object of the invention is to produce novel drugs which has a 60 to 70% yield. Yet another object of the invention is to produce novel drugs which does not produce toxicity. Statement of invention; 1. A process for the preparation of novel heterocyclic compounds Xanthonoxy propanolamines having the formula: OCH2CHCH2N-Y-R2 OH R5 O R3 (Figure Remove) Xanthonoxypropanolamines for use as a antihypertensive drug comprising the following steps of condensing the appropriate phenols i.e. heterocyclic aromatic compounds containing hydroxy groups with epichlorohydrin in the presence of alkali and ethanol at 50° to 80 c for 1-2 hours to obtain their epoxy derivatives, then opening ring of the epoxides with various amines referred in Table A by refluxing in ethanol with stirring at least 24 to 36 hrs at 40° to 70°C to afford the aryloxy propanolamines derivatives. Brief description of the accompanying drawings: Fig. 1: shows % inhibition of adrenaline effect of compound la, Ib and 3b as compared to standard drug Propranolol. Fig 2 and 3: show the % and actual decrease in BP by compounds Ib, la, 2b, 3b, 4b and Sb as compared to saline and standard drugs propranolol and Atenolol. Fig 4, Fig 5: show actual and % decrease in BP using i.p. dose of Ic, Id, 2h, 4t, 4n as compared to saline and standard drugs Propranolol, Atenolol. Fig 6, Fig 7: show actual and % decrease in BP by oral dose of compounds Ib, 2b, 3b and 4b as compared to saline and standard drugs Propranolol and Atenolol. Fig 8, Pig 9, Fig 10: show onset and duration of action of compounds (la, Ib, 3b) comparing with reference drugs (i.p. dose). Fig 11: shows onset and duration of action of compound Ib, 2b, 3b, 4b compared with the standard drugs (oral dose). Fig 12: show onset and duration of action of Propranolol (IP dose). Fig 13: shows onset and duration of action of Atenolol (IP dose). Fig 14: shows duration of action of Propranolol (oral dose). Fig 15: shows duration of action of Atenolol (oral dose). Fig 16: shows duration of action of Ib (oral dose). Fig 17: shows duration of action of 2b (oral dose). Fig 18: shows duration of action of 3b (oral dose). Fig 19: shows duration of action of 4b (oral dose). Fig 20, Fig 21: show actual increase in BP at two different doses by MPA (methyl prednisolone acetate). Fig 22: shows onset action of MPA. Detailed description of Invention; General Procedure; The appropriate phenols (i.e. heterocyclic aromatic compounds containing hydroxyl groups) were condensed with epichloro-hydrin in the presence of alkali and ethanol to obtain their epoxy deriyatives. Ring opening of the epoxides with various amines was achieved by refluxing in ethanol to afford the aryloxy propanolamines derivatives. Synthesis of Compounds: a) Di and tri hydroxy xanthones: A mixture of o-hydroxy benzoic acid 2, 4 dihydroxy benzoic acid, a phenol (such as catechol, pyrogallol, resorcinol), freshly fused zinc chloride (znc!2) and phosphorous oxychloride (Pocla) was heated on a water bath or on heating mantle (maintaining the temperature 55 to 70°C) for 1.5-2 hr, cooled and poured into ice-water carefully in order to avoid polymerization. The product was filtered off, washed with 2% sodium hydrogen carbonate solution (if needed) and water, dried and crystallized from ethanol. The recrystallization of compounds from ethyl alcohol furnished analytically pure products. b) Preparation of epoxy compounds (3-aryloxy-2, 3-epoxy propane) from the respective hydroxy-xanthones: Epichlorohydrin was added to a solution of hydroxy xanthones in an aqueous ethanol containing sodium hydroxide. The reaction mixtures were heated under reflux at 50° to 80°C, preferably at 60-75°C for 1-2 hrs with continuous stirring. The above mentioned reaction contents for each respective xanthones were stirred for further 2-4 hrs, preferably 3 hours at 15° to 30° C, preferably at room temperature. The products were poured into ice water, the oily layer was separated out and concentrated under reduced pressure (or aqueous layer was decanted after keeping overnight in a refrigerator and was left in open air for evaporation upto dryness). The epoxy compounds were mostly obtained as semi solid or oily residue. The purification of epoxy derivatives may be done by precipitation in acetone or methanol and hexane to obtain semi-solid compounds c) Preparation of [(alkyl/aryl-amino)-2 hydroxy-propoxy] Xanthones: The prepared epoxy derivatives of xanthones, in absoluate alcohol, were added slowly in large excess of different type of alkyl/aryl amines (referred in Table A). The molar ratio of amines and epoxides were generally taken as (500-100:1). The reaction mixtures were refluxed with stirring at least for 24 to 36 hrs at 40° to 70° preferably at 50-65°C. The mixtures were further stirred under reflux at room temperature for 1-2 days. The products were, then subjected to evaporate in the vacuum to remove the remaining amines. The resulting amino-alcohols were purified and recrystallized from ethyl alcohol. Screening of antihypertenaive activity of the novel compounds; The novel synthesized compounds for their antihypertensive activity were screened on both normal and methyl prednisolone acetate induced hypertensive albino rats through i.p route. While, the spontaneous hypertensive rats (SHR) were earlier used for the screening purpose in most of the cases. The change in systolic, diastolic and the mean blood pressure before and after the treatment of the drugs was measured on a digital LE-S100 Blood Pressure Meter in tail-cuff method non-invasively at full cautious state of the animals and compared with the standard drugs. The mean BP was also verified with the following calculation. Mean Arterial Blood Pressure (MAPS) = [Systolic + (2 x diastolic)] * 3 The synthesis of respective final or target compounds as (alkyl/aryl-amino)-2-hydroxy-propoxy]-Xanthones was performed on the basis of the general procedure. The characterization of the structure of the final compounds was established on the basis of UV, FT-IR, H NMR, 13C NMR, Mass spectral data and synthetic routes. The hypertension induction of blood pressure in the albino rats (Kyoto Wisfar Strain) weighing 250 gm (approx.) was done by the administration of methyl prednisolone acetate intraperitonially on the basis of a modified method of Karakoff in order to obtain the significant results and saving the time Graph (MP-1) and Graph (MP-2). The compound 3, 6-Di-[3-(iso-propyl-amino)-2-hydroxy-propoxy]-Xanthone (Ib) was observed more potent, because it decreased the both systolic and diastolic BP almost equally on the administration of drug at very low dose among all the compounds. Whereas 4-hydroxyl-3, 6-Di~[3-(iso-propyl-amino)-2-hydroxy-propoxy]-xanthone (3b) exhibited more significant systolic blood pressure in comparison diastolic BP (Table 2, 3 and Graph AC-1). (FigureRemove) OCH2CHCH2N-Y-R2 OH RS O R3 Xanthonoxypropanolamines Table A; Key to General structure; Ri Ra Rs R4 Rs H CH3 H H H H CH3 H H H H CH3 OH H H H CH3 H OH H H CHs H H OH H CHs OH H H C2H5 C2H5 H H H CHs CH3 H H H H C(CH3)s OH H H C2H5 C6H5 OH H H H 4-C6H4OCH3 OH H H S.No. X Y la OCH2CH(OH)CH2N(Ri)YR2 (CH2)x Ib OCH2CH(OH)CH2N(Ri)YR2 CH(CH3) H 2b OCH2CH(OH)CH2N(Ri)YR2 CH(CH3) H 3b OCH2CH(OH)CH2N(Ri)YR2 CH(CH3) H 4b CH3 CH(CH3) H 5b H CH(CH3) H Ic OCH2CH(OH)CH2N(Ri)YR2 Nil Id OCH2CH(OH)CH2N(Ri)YR2 Nil 2h OCH2CH{OH)CH2N(Ri)YR2 Nil 4n OCH2CH(OH)CH2N(Ri)YR2 Nil 4t OCH2CH(OH)CH2N(Ri)YR2 Nil Other two novel compounds of Ib series [compounds no. (Ic), (Id)] and three more compounds related to other series [compounds No. (2h), (4t) and (4n)] possessing also almost double activity have also been prepared and screened for their activity (Table 1, Graph AC-3 (Fig 4) and AC-4). (FigiS). The structures of pure synthesized novel compounds were elucidated on the basis of UV, FT-IR, 1H NMR, 13C NMR, Mass spectral data. The percentage yield of the novel compounds was also found more than 60-70%. Antihypertensive activity: 1. The antihypertensive activity of the novel compounds was found two times more than the standard drugs: e.g. Propranolol, Atenolol when the doses were administered through i.p route Graph AC-1 and AC-2) (Fig 2 and Fig 3). 2. The systolic blood pressure and the mean arterial blood pressure were found decreased two to three times more than the standard drugs. 3. The onset action of both compounds (la) and (Ib) was found two times faster than standard drugs. However, a quicker effect was found within the short period when the compounds were given through i.p. route (Graph On-1, On-2, On-3 and On-2a, On-2b, On-2c) (Fig 8, Fig 9, Fig 10, Fig 11, Fig 12, Fig 13). 4. The duration of action was also observed longer (lasted up to 48h) than standard drugs (lasted up to 4 h only) (Graphs DR1- j 6} (Fig 14-19). 5. The procedure for measuring the antihypertensive activity was also modified in the present work by using methyl prednisolone acetate induced hypertensive albino rats through i.p. route for the first time (Graph MP-1, MP-2 and MP-2) (Fig 20, 21, 22). Dose response: 1. These all novel compounds were found almost equally effective in both routes i.e. intraperitonialy as well as orally (Graph OR-1 and OR-2) (Fig 6 and Fig 7). 2. The doses used for the screening of novel synthetic compounds showed two or three times more activity than the standard drugs in very litter amounts (namely lAth of the standard drugs). Toxicological profiles j. The toxicological profiles of the compounds will be studies in detail after filing the patent. However, during the screening period, no death or any abnormal behavior of test animals (i.e. albino rats) was observed at the given dose described in the table (1,2 and 3). 2. No dangerous side effects or any such types of the signs were seen in the experimental animals till 15 days after the dosing of tested drugs. In contrast, the hypertension induced animals were observed more curative and active after 24-30 hr since dosing time, when they were treated through i.p route and after 4-6 days through oral dose of the same tested drugs. p-receptors blocking activity The novel compounds exhibited higher (3-adrenergic blocking activity higher than propranolol, as they blocked the effect of adrenaline through i.p. dose (GraphB-1) (Fig 1). The results obtained showed that the compound have the novelty and potentiality and could be used antihypertensive drugs in future. Table 1: Average effect of Standard Drugs and Test compounds (i. p route) with ± SD (Standard Deviation) Serial No. Compounds No. Dose in Pretreated BP after 1 hr of treatment decrease from pretreated BP % decrease inBP rag/kg ASBP AMBP ASBP AMBP ASBP AMBP systolic mean saline (0.9%) 5ml 115 ±7.8 104 ± 1.1 115 ±6.8 102 ±9.1 0 ±2 2 ±2 0 1.9 Propranolol 10 mg 111.5 ±8.5 % ±10.6 98 ±7 85±7.2 13 ±2.2 11 ±3 11.7 11.2 j Atenolol 10 mg 119 ±7.8 105±9 105+6 93 ±7.5 14 ±2 12 ±1.7 11.76 11.42 1 (Ib) 2.8 mg 117 ±4.7 104.6 ±4.5 95 ±2.6 78 ±4 22 ±2.5 26.5 ±2.1 18.8 25.40 2 (la) 3 mg 115.5 ±13 ICMhS ±1.7 103 1±1 80 ±1.2 13±1.4 21 ±2.7 1130 21 3 (2b) 3mg 111 ±2.2 96.4 ±2.8 97 ±1.4 70 ±2.5 14 ±3.2 26 ±2 12.6 273 4 (3b) 3mg 117 ±0.5 103 ±2.1 102 ±1 2 71,5± 1.2 15.2 ± 2 31.5±2.1 12.8 30.53 5 (4b) 3 mg 117 ±8.5 102 ±6.1 96±4.5 86 ±33 21 ±4.1 16 ±3.4 18 15.6 6 (5b) 3mg 110±1 96 ±4.1 99.4 ±0.8 75 ±3.5 11 ± 0.8 21 ±2.4 10 21.8 7 (1C) 4mg 107 ±2.6 95 ±1.6 89 ±6 67.4 ±6.4 18 ±5 27.6 ±5.2 16.8 29 8 (Id) 3 mg 113.5 ±23 101 ± 86 ±3.5 78 ±4 27.5 ±3 23 ±1 24.2 22.7 9 (2h) 4mg 107 ±2.6 92.5 ±2 99 ±0.5 69.5 ±2.8 8 ±2.7 23 ±3 7.4 24.8 10 (4t) 3.6 mg 109 ±2 95 ±2 104 ±1 71 ±1.7 5 ±1.2 24±2.2 4.5 23 11 (4n) 4mg 111 ±2.2 98 ±1.4 98 ±1.4 76 ±0.5 13.25 ±1.7 2210.95 113 22.9 ASBP = Average Systolic Blood Pressure, AMBP = Average Mean Arterial Blood Pressure Table 3: Actual and % decrease in systolic and mean BP by oral dose of standard drugs and test compounds Drugs/ compounds No. Dose (mg/kg) actual decrease in BP (inmmHg) % decrease in BP Saline (0.9%) 5ml «0faL ; ^ P&&I * .HP^ fihara«d&&» EHEP-lilflMSsS Mean 4 2.5 3 2.2 Propranolol 16 mg 15.5 12 11. .85 10.6 Atenolol 15 mg 15 14 11.07 11.11 (Ib) 3.5 mg 26 29 19.2 24.48 (2b) 4 mg n 15 25 11.34 20.66 (4b) 5mg 25 20 19 18 Table 2: Average effect of compounds/ reference drugs (administered orally), showing significant decrease in systolic and mean arterial BP with ± SD (standard deviations) Drugs/ Comp. No. Dose in mg/kg Pretreated BP BP after 4 days of treatment BP after 8 days of treatment change from pre-treated ASBP .XIJ^BI Assst; ........ JiSBP ASBP ASBP AMBP Saline 5ml i 132 ±4.3 i 112.5±3 130+4.5 11.512.6 12814.5 10912 4+1.5 210.8 1 Propranolol 16 mg I 13513 ! 11312.5 128.513 108.512 11911 10112.2 15.512 1211 i Atenolol 15 mg 14011 I 121.5+2 13211.6 113.511 124.511 10812.2 1511.7 1412 (Ib) 3.5 mg 14011.6 i 121 +1.3 I 124 13 102 12 113+1.7 9112 2612.5 2911.8 (2b) 4mg 1 14111.3 ] 12111 13211.2 10511 12511.3 9611 16+1.5 2511 (3b) 4mg 141 ±2.5 j 122 ±0.8 131 ±1.7 102.511 12311.7 8912.75 17.5+5 33 ±5 (4b) 5mg I 134.5+4 ! 11213 124+2.5 102.513 i 109 ±2.2 1 9212.5 1 25 +2.5 i 20 ±1 ASBP= Average Systolic Blood Pressure, AMBP = Average Mean Arterial Blood Pressure. Number of rats taken in each group = 4. We Claim: 1. A novel heterocyclic compounds Xanthonoxy propanolamines having the formula: (Formula Removed) Wherein X, Y, R1 to R5 are as herein described 2. The process for the preparation of novel Xanthonoxy propanolamines as claimed in claim 1 wherein Epichlorohydrin is added to a solution of hydroxy Xanthones in an aqueous ethanol containing sodium hydroxide, heating the mixture under reflux at 50° to 80°C preferably at 60-75°C for 1-2 hours with continuous stirring followed by further stirring for 2-4 hrs, preferably for 3 hrs at 15° to 30°C, preferably at room temperature, pouring the products into ice water, separating out the oily layer and concentrating under minimum pressure to avoid decomposition, polymerization and isomerization to other compounds and to get the epoxy compounds as semisolid or oily residue. 3. The process for the preparation of novel Xanthonoxy propanolamines as claimed in claim 2 wherein the epoxy derivatives of Xanthones in absolute alcohol is added slowly in large excess of different types of alkyl/arylamines, as herein described in a molar ratio of amines to epoxides as 500-100:1, refluxing the reaction mixture with stirring atleast 24 to 36 hrs at 40° to 70°C preferably at 50-65°C followed by further stirring under reflux at room temperature for 1-2 days, then subjecting the product to evaporate in the vacuum to remove the remaining amines. 4. The process of preparing hydroxy xanthones as claimed in claim 2 wherein the recrystalization from ethyl alcohol furnishes analytically pure products. 5. The process of preparing epoxy compounds as claimed in claim 2 wherein further purification is done by precipitation in acetone or methanol and hexane to obtain semi-solid compound. 6. The process of preparing alkyl/aryl amino 2 hydroxy-propoxy xanthones as claimed in claim 1 wherein the resulting amino alcohols are purified and recrystallized from ethanol.

Full Text

"Antihypertensive Activity of Novel Heterocyclic Compounds and the process of preparation thereof
Field of Invention;
The invention relates to xanthonoxy propanolamines having antihypertensive activity and the process of preparation thereof.
Background of the Invention:
Hypertension or High Blood Pressure is the name of a pathological condition in which blood pressure is persistently elevated. It is defined as a rise in the pressure of blood in the arteries, compared to a value known as ^normal" established by many scientific committees throughout the world. This persistent high blood pressure puts undue stress on the heart, blood vessels and other organs.
It is now a major public health problem of largely unknown cause and yet a great concern of modern medical practice due to its doubtful and uncertain etiology. The people suffering from the disorder gradually come undjer the phenomena of secondary complications that may produce other vital-organ diseases. It contributes alone a number of cardio vascular diseases, which causes morbidity and premature death.
The main causes of hypertension may be sleep apnea, drug induced or related causes, chronic kidney disease, primary aldosteronism, reno-vascular disease, chronic steroid therapy, cushing's syndrome, thyroid or parathyroid disease, coarctation of the aorta.

B-Bjockers as a important antihvpertensive drugs;
Standard drugs: Propranolol, Atenolol (IDR (Sept.-Oct. 2003; MIMS India Nov. 2005).
(Figure Remove)

OCH2CHCH2NHCH(CH3)2 OH
PCH2CHCH2NHCH(CH3)2 OH
CH2CONH2
Atenolol Propranolol

Major Drawbacks and side effects of existing standard drugs (Propranolol and Atenolol), and other p-blocker drugs:
The major clinical adverse effects of the most of antihypertensive ($-blockers have been found as CNS effects like fatigue, lethargy, decrease exercise tolerance, sleep disturbance, vivid dreams, hallucination, sinus bradycardia, any degree of heart attack and bronchospasm etc. For example, despite of good ^-blocking activity and reducing a number of heart attacks in the most patients with angina pectoris, propranolol is found carcinogenic with much CNS effect. Propothalol causes increase incidence of sarcoma in mice, whereas, tolamolol causes mammory aderno-carcinoma. Pamatolol induces hepatcarcinoma in rats. In addition, fatigue, tiredness, skin-rash, fever, depression, nightmare, renal dysfunction, nausea, epigastric distress, cold extremities and hypoglycemia are also associated with propranolol.

Other cardioselective (J-blockers totamolol, practolol, metoprolol and acebutalol are generally hydrophilic P Atenolol or Metoprolol are not good inhibitor of "Renin-Release", thus, possibility of developing congestive cardiac failure (CCF) is greater with these cardioselctive agents, because, venous return is not reducted in the face of (-) inotropic and chronotropic effects. Bunalol exhibits uterine leio-myometa and liver adenomas in rats. In addition, bradycardia, nausea, vomiting, epigastric discomfort, skin rash, tiredness, fatigue, dizziness, leg pain, cold extremities because of peripheral arterial insufficiency are associated with Atenolol.
Drug interactions of Propranolol and Atenolol:
«»» Propranolol produces orthostatic with quinidine
*J* Rifarnpicin, phenobarbitone, NSAID, thyroid hormones, smoking. All decrease antihypertensive of action of propranolol
«!» Corticosteriods antagonize antihypertensive effect of propranolol *J* Sympathomimetic drug marks hypertension and bradycardia.
^* With insulin, hypoglycemic effect will be prolonged by propranolol and masking of the sympotoms of hypoglycemia in diabetes cases.
*> Increased level of lidocaine with propranolol leads to toxicity.

*»» With calcium channel blockers, it produces severe bradycardia especially in those patients with impaired left ventricular (LV) function.
*J* Propranolol also antagonizes the action of theopylline in case of asthma.
Thus, the observations regarding the above mentioned side effects of the existing ^-blocking antihypertensive agents tend for the search of novel type of drugs to lower the high blood pressure with a quality of more potency and devoid of adverse effect.
The ideal {3-blockers for HTN should be long acting, cardioselctive and usefully effective in standard dose. They must have simple pharmacokinetics advantage such as, no liver metabolism, little protein binding, no lipid solubility (i.e lipid neutral) and no active metabolites.
Inventors have therefore, prepared some novel heterocyclic compounds i.e., Xanthonoxypropanolamines, which contain (i); almost double antihypertensive activity, (ii): 4-5 times much faster onset of action, (iii): 4-5 times much longer duration of action, (iv): 2-3 times more active at lower does than the standard drugs i.e., I/4th dose than the standard, and (v): in good yield (more than 60-70%) without any significant toxicity, as no signs of toxicity were observed in the preliminary screening tests.
Objects of the Invention:
An bject of the invention is to produce novel drugs and a process for the preparation thereof with almost double anti-hypertensive activity in comparison to known drugs.

Another object of the invention is to produce novel drugs which has 2-3 times more activity at V^th dose than the known drug.
Further object is to produce novel drugs which modifies the onset of action 4-5 times faster than known drugs.
Other object is to produce novel drugs which increases the duration of action for a substantially longer period than known drugs.
Another object of the invention is to produce novel drugs which has a 60 to 70% yield.
Yet another object of the invention is to produce novel drugs which does not produce toxicity.
Statement of invention;

1.

A process for the preparation of novel heterocyclic compounds Xanthonoxy propanolamines having the formula:

OCH2CHCH2N-Y-R2 OH
R5 O R3
(Figure Remove) Xanthonoxypropanolamines

for use as a antihypertensive drug comprising the following steps of condensing the appropriate phenols i.e. heterocyclic aromatic compounds containing hydroxy groups with epichlorohydrin in the presence of alkali and ethanol at 50° to 80 c for 1-2 hours to obtain their epoxy derivatives, then opening ring of the epoxides with various amines referred in Table A by refluxing in ethanol with stirring at least 24 to 36 hrs at 40° to 70°C to afford the aryloxy propanolamines derivatives.
Brief description of the accompanying drawings:
Fig. 1: shows % inhibition of adrenaline effect of compound la, Ib and 3b as compared to standard drug Propranolol.
Fig 2 and 3: show the % and actual decrease in BP by compounds Ib, la, 2b, 3b, 4b and Sb as compared to saline and standard drugs propranolol and Atenolol.
Fig 4, Fig 5: show actual and % decrease in BP using i.p. dose of Ic, Id, 2h, 4t, 4n as compared to saline and standard drugs Propranolol, Atenolol.
Fig 6, Fig 7: show actual and % decrease in BP by oral dose of compounds Ib, 2b, 3b and 4b as compared to saline and standard drugs Propranolol and Atenolol.
Fig 8, Pig 9, Fig 10: show onset and duration of action of compounds (la, Ib, 3b) comparing with reference drugs (i.p. dose).

Fig 11: shows onset and duration of action of compound Ib, 2b, 3b, 4b
compared with the standard drugs (oral dose).
Fig 12: show onset and duration of action of Propranolol (IP dose). Fig 13: shows onset and duration of action of Atenolol (IP dose). Fig 14: shows duration of action of Propranolol (oral dose). Fig 15: shows duration of action of Atenolol (oral dose). Fig 16: shows duration of action of Ib (oral dose). Fig 17: shows duration of action of 2b (oral dose). Fig 18: shows duration of action of 3b (oral dose). Fig 19: shows duration of action of 4b (oral dose).
Fig 20, Fig 21: show actual increase in BP at two different doses by MPA (methyl prednisolone acetate).
Fig 22: shows onset action of MPA. Detailed description of Invention;
General Procedure; The appropriate phenols (i.e. heterocyclic aromatic compounds containing hydroxyl groups) were condensed with epichloro-hydrin in the presence of alkali and ethanol to obtain their epoxy deriyatives. Ring opening of the epoxides with various amines was

achieved by refluxing in ethanol to afford the aryloxy propanolamines derivatives.
Synthesis of Compounds:
a) Di and tri hydroxy xanthones: A mixture of o-hydroxy benzoic
acid 2, 4 dihydroxy benzoic acid, a phenol (such as catechol,
pyrogallol, resorcinol), freshly fused zinc chloride (znc!2) and
phosphorous oxychloride (Pocla) was heated on a water bath or on
heating mantle (maintaining the temperature 55 to 70°C) for 1.5-2
hr, cooled and poured into ice-water carefully in order to avoid
polymerization. The product was filtered off, washed with 2%
sodium hydrogen carbonate solution (if needed) and water, dried
and crystallized from ethanol. The recrystallization of compounds
from ethyl alcohol furnished analytically pure products.
b) Preparation of epoxy compounds (3-aryloxy-2, 3-epoxy
propane) from the respective hydroxy-xanthones:
Epichlorohydrin was added to a solution of hydroxy xanthones in an aqueous ethanol containing sodium hydroxide. The reaction mixtures were heated under reflux at 50° to 80°C, preferably at 60-75°C for 1-2 hrs with continuous stirring. The above mentioned reaction contents for each respective xanthones were stirred for further 2-4 hrs, preferably 3 hours at 15° to 30° C, preferably at room temperature. The products were poured into ice water, the oily layer was separated out and concentrated under reduced pressure (or aqueous layer was decanted after keeping overnight in a refrigerator and was left in open air for evaporation upto dryness). The epoxy compounds were mostly obtained as semi solid or oily residue. The purification of epoxy derivatives may be

done by precipitation in acetone or methanol and hexane to obtain semi-solid compounds
c) Preparation of [(alkyl/aryl-amino)-2 hydroxy-propoxy] Xanthones: The prepared epoxy derivatives of xanthones, in absoluate alcohol, were added slowly in large excess of different type of alkyl/aryl amines (referred in Table A). The molar ratio of amines and epoxides were generally taken as (500-100:1). The reaction mixtures were refluxed with stirring at least for 24 to 36 hrs at 40° to 70° preferably at 50-65°C. The mixtures were further stirred under reflux at room temperature for 1-2 days. The products were, then subjected to evaporate in the vacuum to remove the remaining amines. The resulting amino-alcohols were purified and recrystallized from ethyl alcohol.
Screening of antihypertenaive activity of the novel compounds;
The novel synthesized compounds for their antihypertensive activity were screened on both normal and methyl prednisolone acetate induced hypertensive albino rats through i.p route. While, the spontaneous hypertensive rats (SHR) were earlier used for the screening purpose in most of the cases.
The change in systolic, diastolic and the mean blood pressure before and after the treatment of the drugs was measured on a digital LE-S100 Blood Pressure Meter in tail-cuff method non-invasively at full cautious state of the animals and compared with the standard drugs. The mean BP was also verified with the following calculation.

Mean Arterial Blood Pressure (MAPS) = [Systolic + (2 x diastolic)] * 3
The synthesis of respective final or target compounds as (alkyl/aryl-amino)-2-hydroxy-propoxy]-Xanthones was performed on the basis of the general procedure. The characterization of the structure of the final compounds was established on the basis of UV, FT-IR, *H NMR, 13C NMR, Mass spectral data and synthetic routes.
The hypertension induction of blood pressure in the albino rats (Kyoto Wisfar Strain) weighing 250 gm (approx.) was done by the administration of methyl prednisolone acetate intraperitonially on the basis of a modified method of Karakoff in order to obtain the significant results and saving the time Graph (MP-1) and Graph (MP-2).
The compound 3, 6-Di-[3-(iso-propyl-amino)-2-hydroxy-propoxy]-Xanthone (Ib) was observed more potent, because it decreased the both systolic and diastolic BP almost equally on the administration of drug at very low dose among all the compounds. Whereas 4-hydroxyl-3, 6-Di~[3-(iso-propyl-amino)-2-hydroxy-propoxy]-xanthone (3b) exhibited more significant systolic blood pressure in comparison diastolic BP (Table 2, 3 and Graph AC-1).
(FigureRemove)

OCH2CHCH2N-Y-R2 OH
RS O R3
Xanthonoxypropanolamines

Table A; Key to General structure;
Ri Ra Rs R4 Rs
H CH3 H H H
H CH3 H H H
H CH3 OH H H
H CH3 H OH H
H CHs H H OH
H CHs OH H H
C2H5 C2H5 H H H
CHs CH3 H H H
H C(CH3)s OH H H
C2H5 C6H5 OH H H
H 4-C6H4OCH3 OH H H
S.No. X Y
la OCH2CH(OH)CH2N(Ri)YR2 (CH2)x
Ib OCH2CH(OH)CH2N(Ri)YR2 CH(CH3) H
2b OCH2CH(OH)CH2N(Ri)YR2 CH(CH3) H
3b OCH2CH(OH)CH2N(Ri)YR2 CH(CH3) H
4b CH3 CH(CH3) H
5b H CH(CH3) H
Ic OCH2CH(OH)CH2N(Ri)YR2 Nil
Id OCH2CH(OH)CH2N(Ri)YR2 Nil
2h OCH2CH{OH)CH2N(Ri)YR2 Nil
4n OCH2CH(OH)CH2N(Ri)YR2 Nil
4t OCH2CH(OH)CH2N(Ri)YR2 Nil

Other two novel compounds of Ib series [compounds no. (Ic), (Id)] and three more compounds related to other series [compounds No. (2h), (4t) and (4n)] possessing also almost double activity have also been prepared and screened for their activity (Table 1, Graph AC-3 (Fig 4) and AC-4). (FigiS).

The structures of pure synthesized novel compounds were elucidated on the basis of UV, FT-IR, 1H NMR, 13C NMR, Mass spectral data.
The percentage yield of the novel compounds was also found more than 60-70%.
Antihypertensive activity:
1. The antihypertensive activity of the novel compounds was found
two times more than the standard drugs: e.g. Propranolol,
Atenolol when the doses were administered through i.p route
Graph AC-1 and AC-2) (Fig 2 and Fig 3).
2. The systolic blood pressure and the mean arterial blood
pressure were found decreased two to three times more than
the standard drugs.
3. The onset action of both compounds (la) and (Ib) was found
two times faster than standard drugs. However, a quicker effect
was found within the short period when the compounds were
given through i.p. route (Graph On-1, On-2, On-3 and On-2a,
On-2b, On-2c) (Fig 8, Fig 9, Fig 10, Fig 11, Fig 12, Fig 13).
4. The duration of action was also observed longer (lasted up to
48h) than standard drugs (lasted up to 4 h only) (Graphs DR1-
j 6} (Fig 14-19).
5. The procedure for measuring the antihypertensive activity was
also modified in the present work by using methyl prednisolone

acetate induced hypertensive albino rats through i.p. route for the first time (Graph MP-1, MP-2 and MP-2) (Fig 20, 21, 22).
Dose response:
1. These all novel compounds were found almost equally effective in
both routes i.e. intraperitonialy as well as orally (Graph OR-1 and
OR-2) (Fig 6 and Fig 7).
2. The doses used for the screening of novel synthetic compounds
showed two or three times more activity than the standard drugs
in very litter amounts (namely lAth of the standard drugs).
Toxicological profiles
j. The toxicological profiles of the compounds will be studies in detail after filing the patent. However, during the screening period, no death or any abnormal behavior of test animals (i.e. albino rats) was observed at the given dose described in the table (1,2 and 3).
2. No dangerous side effects or any such types of the signs were seen in the experimental animals till 15 days after the dosing of tested drugs. In contrast, the hypertension induced animals were observed more curative and active after 24-30 hr since dosing time, when they were treated through i.p route and after 4-6 days through oral dose of the same tested drugs.

p-receptors blocking activity
The novel compounds exhibited higher (3-adrenergic blocking activity higher than propranolol, as they blocked the effect of adrenaline through i.p. dose (GraphB-1) (Fig 1).
The results obtained showed that the compound have the novelty and potentiality and could be used antihypertensive drugs in future.

Table 1: Average effect of Standard Drugs and Test compounds (i. p route) with ± SD (Standard Deviation)

Serial No. Compounds No. Dose in Pretreated BP after 1 hr of treatment decrease from pretreated BP % decrease inBP
rag/kg ASBP AMBP ASBP AMBP ASBP AMBP systolic mean
saline (0.9%) 5ml 115 ±7.8 104 ± 1.1 115 ±6.8 102 ±9.1 0 ±2 2 ±2 0 1.9
Propranolol 10 mg 111.5 ±8.5 % ±10.6 98 ±7 85±7.2 13 ±2.2 11 ±3 11.7 11.2 j
Atenolol 10 mg 119 ±7.8 105±9 105+6 93 ±7.5 14 ±2 12 ±1.7 11.76 11.42
1 (Ib) 2.8 mg 117 ±4.7 104.6 ±4.5 95 ±2.6 78 ±4 22 ±2.5 26.5 ±2.1 18.8 25.40
2 (la) 3 mg 115.5 ±13 ICMhS ±1.7 103 1±1 80 ±1.2 13±1.4 21 ±2.7 1130 21
3 (2b) 3mg 111 ±2.2 96.4 ±2.8 97 ±1.4 70 ±2.5 14 ±3.2 26 ±2 12.6 273
4 (3b) 3mg 117 ±0.5 103 ±2.1 102 ±1 2 71,5± 1.2 15.2 ± 2 31.5±2.1 12.8 30.53
5 (4b) 3 mg 117 ±8.5 102 ±6.1 96±4.5 86 ±33 21 ±4.1 16 ±3.4 18 15.6
6 (5b) 3mg 110±1 96 ±4.1 99.4 ±0.8 75 ±3.5 11 ± 0.8 21 ±2.4 10 21.8
7 (1C) 4mg 107 ±2.6 95 ±1.6 89 ±6 67.4 ±6.4 18 ±5 27.6 ±5.2 16.8 29
8 (Id) 3 mg 113.5 ±23 101 ± 86 ±3.5 78 ±4 27.5 ±3 23 ±1 24.2 22.7
9 (2h) 4mg 107 ±2.6 92.5 ±2 99 ±0.5 69.5 ±2.8 8 ±2.7 23 ±3 7.4 24.8
10 (4t) 3.6 mg 109 ±2 95 ±2 104 ±1 71 ±1.7 5 ±1.2 24±2.2 4.5 23
11 (4n) 4mg 111 ±2.2 98 ±1.4 98 ±1.4 76 ±0.5 13.25 ±1.7 2210.95 113 22.9
ASBP = Average Systolic Blood Pressure, AMBP = Average Mean Arterial Blood Pressure

Table 3: Actual and % decrease in systolic and mean BP by oral dose of standard drugs and test compounds

Drugs/ compounds No. Dose
(mg/kg) actual decrease in BP
(inmmHg) % decrease in BP
Saline (0.9%) 5ml «0fa*L ;
^ P&&I * .HP*^ fihara«d&&»
EHEP-lilflMSsS Mean

4 2.5 3 2.2
Propranolol 16 mg 15.5 12 11. .85 10.6
Atenolol 15 mg 15 14 11.07 11.11
(Ib) 3.5 mg 26 29 19.2 24.48
(2b) 4 mg n 15 25 11.34 20.66
(4b) 5mg 25 20 19 18

Table 2: Average effect of compounds/ reference drugs (administered orally), showing significant decrease in systolic and mean arterial BP with ± SD (standard deviations)

Drugs/ Comp. No. Dose in mg/kg Pretreated BP BP after 4 days of treatment BP after 8 days of treatment change from pre-treated
ASBP .XIJ^BI* Assst; ........ JiSBP ASBP ASBP AMBP
Saline 5ml i
132 ±4.3 i 112.5±3 130+4.5 11.512.6 12814.5 10912 4+1.5 210.8
1
Propranolol 16 mg I
13513 ! 11312.5 128.513 108.512 11911 10112.2 15.512 1211
i
Atenolol 15 mg 14011 I 121.5+2 13211.6 113.511 124.511 10812.2 1511.7 1412
(Ib) 3.5 mg 14011.6 i 121 +1.3
I 124 13 102 12 113+1.7 9112 2612.5 2911.8
(2b) 4mg 1
14111.3 ] 12111 13211.2 10511 12511.3 9611 16+1.5 2511
(3b) 4mg 141 ±2.5 j 122 ±0.8 131 ±1.7 102.511 12311.7 8912.75 17.5+5 33 ±5
(4b) 5mg I 134.5+4 ! 11213 124+2.5 102.513 i 109 ±2.2 1 9212.5 1
25 +2.5 i 20 ±1
ASBP= Average Systolic Blood Pressure, AMBP = Average Mean Arterial Blood Pressure. Number of rats taken in each group = 4.

We Claim:
1. A novel heterocyclic compounds Xanthonoxy propanolamines having
the formula:
(Formula Removed)
Wherein X, Y, R1 to R5 are as herein described
2. The process for the preparation of novel Xanthonoxy propanolamines as claimed in claim 1 wherein Epichlorohydrin is added to a solution of hydroxy Xanthones in an aqueous ethanol containing sodium hydroxide, heating the mixture under reflux at 50° to 80°C preferably at 60-75°C for 1-2 hours with continuous stirring followed by further stirring for 2-4 hrs, preferably for 3 hrs at 15° to 30°C, preferably at room temperature, pouring the products into ice water, separating out the oily layer and concentrating under minimum pressure to avoid decomposition, polymerization and isomerization to other compounds and to get the epoxy compounds as semisolid or oily residue.
3. The process for the preparation of novel Xanthonoxy propanolamines as claimed in claim 2 wherein the epoxy derivatives of Xanthones in absolute alcohol is added slowly in large excess of different types of alkyl/arylamines, as herein described in a molar ratio of amines to epoxides as 500-100:1,
refluxing the reaction mixture with stirring atleast 24 to 36 hrs at 40° to 70°C preferably at 50-65°C followed by further stirring under reflux at room temperature for 1-2 days, then subjecting the product to evaporate in the vacuum to remove the remaining amines.
4. The process of preparing hydroxy xanthones as claimed in claim 2 wherein the recrystalization from ethyl alcohol furnishes analytically pure products.
5. The process of preparing epoxy compounds as claimed in claim 2 wherein further purification is done by precipitation in acetone or methanol and hexane to obtain semi-solid compound.
6. The process of preparing alkyl/aryl amino 2 hydroxy-propoxy xanthones as claimed in claim 1 wherein the resulting amino alcohols are purified and recrystallized from ethanol.

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Patent Number

250538

Indian Patent Application Number

2498/DEL/2006

PG Journal Number

02/2012

Publication Date

13-Jan-2012

Grant Date

09-Jan-2012

Date of Filing

20-Nov-2006

Name of Patentee

HAMDARD UNIVERSITY

Applicant Address

FACULTY OF PHARMACY, HAMDARD NAGAR, NEW DELHI-110062,INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. BAHAR AHMED	FACULTY OF PHARMACY, HAMDARD NAGAR, NEW DELHI-110062,INDIA
2	MR. ANWARUL-HAQUE SIDDIQUI	FACULTY OF PHARMACY, HAMDARD NAGAR, NEW DELHI-110062,INDIA

PCT International Classification Number

C07C

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA