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AU2002341289B2 - Benzoxazine and benzothiazine derivatives and pharmaceutical compositions containing them - Google Patents

Benzoxazine and benzothiazine derivatives and pharmaceutical compositions containing them Download PDF

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Publication number
AU2002341289B2
AU2002341289B2 AU2002341289A AU2002341289A AU2002341289B2 AU 2002341289 B2 AU2002341289 B2 AU 2002341289B2 AU 2002341289 A AU2002341289 A AU 2002341289A AU 2002341289 A AU2002341289 A AU 2002341289A AU 2002341289 B2 AU2002341289 B2 AU 2002341289B2
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AU
Australia
Prior art keywords
dihydro
oxazin
benzo
salts
acid
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AU2002341289A
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AU2002341289A1 (en
Inventor
Debnath Bhuniya
Ranjan Chakrabarti
Saibal Kumar Das
Javed Iqbal
Gurram Ranga Madhavan
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Dr Reddys Laboratories Ltd
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Dr Reddys Laboratories Ltd
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Priority claimed from PCT/IB2002/004275 external-priority patent/WO2003033481A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Description

00
O
00 BENZOXAZINE AND BENZOTHIAZINE DERIVATIVES AND
PHARMACEUTICAL
COMPOSITIONS CONTAINING THEM 00 Field of the Invention The present invention relates to novel antidiabetic, hypolipidemic, Santiobesity and hypocholesterolemic compounds, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them, to a process for preparing such compounds. More particularly, the present invention relates to novel alkyl carboxylic acids of the general formula as defined below, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them, to a process for preparing such compounds.
The present invention also relates to novel intermediates, processes for their preparation, their use in the preparation of the above said compounds and their use as antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds.
The compounds of the present invention lower plasma glucose, triglycerides, lower total cholesterol (TC) and increase high-density lipoprotein (HDL) and decrease low density lipoprotein (LDL), which have a beneficial effect on coronary heart disease and atherosclerosis.
The compounds of the present invention are useful in reducing body weight and for the treatment and/or prophylaxis of diseases such as atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful for the treatment of hyperlipidemia, hyperglycemia, hypercholesterolemia, lowering of atherogenic lipoproteins, VLDL (very low density lipoprotein) and LDL. The compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. The said compounds are also useful for the treatment and/or prophylaxis of leptin resistance, impaired glucose tolerance, disorders related to syndrome X such as hypertension, obesity, insulin resistance, WO 03/033481 PCT/IB02/04275 2 coronary heart disease and other cardiovascular disorders. These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, eating disorders, inflammation and for the treatment of cancer. The compounds of the present invention are also useful in the treatment and/or prophylaxis of the above said diseases in combination/concomittant with one or more HMG CoA reductase inhibitors, hypolipidemic/hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol and probucol; insulin, sulfonyl urea, metformin.
Background of the Invention Atherosclerosis and other peripheral vascular diseases effect the quality of life of millions of people. Therefore, considerable attention has been directed towards understanding the etiology of hypercholesterolemia and hyperlipidemia and development of effective therapeutic strategies.
Hypercholesterolemia has been defined as plasma cholesterol level that exceeds arbitrarily defined value called "normal" level. Recently, it has been accepted that "ideal" plasma levels of cholesterol are much below the "normal" level of cholesterol in the general population and the risk of coronary artery disease (CAD) increases as cholesterol level rises above the "optimum" (or "ideal") value. There is clearly a definite cause and effect-relationship between hypercholesterolemia and CAD, particularly for individuals with multiple risk factors. Most of the cholesterol is present in the esterified forms with various lipoproteins such as Low density lipoprotein (LDL), Intermediate density lipoprotein (IDL), High density lipoprotein (HDL) and partially as Very low density lipoprotein (VLDL). Studies clearly indicate that there is an inverse correlationship between CAD and atherosclerosis with serum HDL-cholesterol concentrations, (Stampfer et al., N. Engl. J. Med., 325 (1991), 373-381) and the risk of CAD increases with increasing levels of LDL and
VLDL.
WO 03/033481 PCT/IB02/04275 3 In CAD, generally "fatty streaks" in carotid, coronary and cerebral arteries, are found which are primarily free and esterified cholesterol. Miller et al., (Br. Med.
282 (1981), 1741 1744) have shown that increase in HDL-particles may decrease the number of sites of stenosis in coronary arteries of human, and high level of HDL-cholesterol may protect against the progression of atherosclerosis. Picardo et al., Arteriosclerosis 6 (1986) 434 441 have shown by in vitro experiment that HDL is capable of removing cholesterol from cells. They suggest that HDL may deplete tissues of excess free cholesterol and transfer it to liver, which is known as reverse cholesterol transport, (Macikinnon et al., J. Biol. chem. 261 (1986), 2548 2552). Therefore, agents that increase HDL cholesterol would have therapeutic significance for the treatment of hypercholesterolemia and coronary heart diseases
(CHD).
Obesity is a disease highly prevalent in affluent societies and in the developing world and is a major cause of morbidity and mortality. It is a state of excess body fat accumulation. The causes of obesity are unclear. It is believed to be of genetic origin or promoted by an interaction between the genotype and environment. Irrespective of the cause, the result is fat deposition due to imbalance between the energy intake versus energy expenditure. Dieting, exercise and appetite suppression have been a part of obesity treatment. There is a need for efficient therapy to fight this disease since it may lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility and many other psychological and social problems.
Diabetes and insulin resistance is yet another disease which severely effects the quality of large population in the world. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations.
In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably raises and develops into diabetes. Among the developed countries, diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia Clin. Invest., WO 03/033481 PCT/IB02/04275 4 (1985) 809 817; N. Engl. J. Med 317 (1987) 350-357; J. Clin. Endocrinol.
Metab., 66 (1988) 580 583; J Clin. Invest., 68 (1975) 957 969) and other renal complications (patent publication No. WO 95/21608). It is now increasingly being recognized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes mellitus. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link- Syndrome-X.
Hyperlipidemia is the primary cause for cardiovascular (CVD) and other peripheral vascular diseases. High risk of CVD is related to the higher LDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein) seen in hyperlipidemia. Patients having glucose intolerance/insulin resistance in addition to hyperlipidemia have higher risk of CVD. Numerous studies in the past have shown that lowering of plasma triglycerides and total cholesterol, in particular LDL and VLDL and increasing IIDL cholesterol help in preventing cardiovascular diseases.
Peroxisome proliferator activated receptors (PPAR) are members of the nuclear receptor super family. The gamma isoform of PPAR (PPARy) has been implicated in regulating differentiation of adipocytes (Endocrinology, 135 (1994) 798-800) and energy homeostasis (Cell, 83 (1995) 803-812), whereas the alpha (a) isoform of PPAR (PPARa) mediates fatty acid oxidation (Trend. Endocrin. Metab., 4 (1993) 291-296) thereby resulting in reduction of circulating free fatty acid in plasma (Current Biol. 5 (1995) 618 -621). PPARa agonists have been found useful for the treatment of obesity (WO 97/36579). It has been recently disclosed that compounds which are agonists for both PPARa and PPARy are suggested to be useful for the treatment of syndrome X (WO 97/25042). Similar effect between the insulin sensitizer (PPARy agonist) and HMG CoA reductase inhibitor has been observed which may be useful for the treatment of atherosclerosis and xanthoma (EP 0 753 298).
WO 03/033481 PCT/IB02/04275 It is known that PPARy plays an important role in adipocyte differentiation (Cell, 87 (1996) 377-389). Ligand activation of PPAR is sufficient to cause complete terminal differentiation (Cell, 79 (1994) 1147-1156) including cell cycle withdrawal. PPARy is consistently expressed in certain cells and activation of this nuclear receptor with PPARy agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristics of a more differentiated, less malignant state (Molecular Cell, (1998), 465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., 94 (1997) 237-241) and inhibition of expression of prostate cancer tissue (Cancer Research 58 (1998) 3344- 3352). This would be useful in the treatment of certain types of cancer, which express PPARy and could lead to a quite nontoxic chemotherapy.
Leptin resistance is a condition wherein the target cells are unable to respond to leptin signal. This may give rise to obesity due to excess food intake and reduced energy expenditure and cause impaired glucose tolerance, type 2 diabetes, cardiovascular diseases and such other interrelated complications. Kallen et al (Proc. Natl. Acad. Sci. (1996) 93, 5793-5796) have reported that insulin sensitizers which perhaps due to the PPAR agonist expression lower plasma leptin concentrations. However, it has been recently disclosed that compounds having insulin sensitizing property also possess leptin sensitization activity. They lower the circulating plasma leptin concentrations by improving the target cell response to leptin (WO 98/02159).
Prior Art A few alkyl carboxylic acids, their derivatives and their analogs have been reported to be useful in the treatment of hyperglydemia and hypercholesterolemia.
Some of such compounds described in the prior art are outlined below: In our international publication No. WO 99/08501 we have disclosed the compounds of general formula (Ha) WO 03/033481 PCT/IB02/04275 6 RI R 6 2 (CH 2 )n-(O)mAr R7 0 (5Hn() r OY~ (IIa) R H R5 O YRIO R4 R 9 0 wherein the groups R 1
R
2
R
3
R
4 and the groups R 5 and R 6 when attached to carbon atom, may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamnino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R 5 and R 6 may also represent an oxo group when they are attached to carbon atom; R 5 and R 6 when attached to nitrogen atom represent hydrogen, hydroxy, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aiyl, aralkyl, heterocyclyl,' heteroaryl, heteroaralkyl, acyl, acyloxy, amino, acylamino, monoalkylamino, dialkylamino, arylamrnino, aralkylamino, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylthio, carboxylic acid derivatives, or sulfonic acid derivatives; X represents a heteroatom selected from oxygen, sulfur, or NR11 where R 1 1 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl groups; Ar represents unsubstituted or substituted divalent single or fused aromatic or heterocyclic group; R7 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, unsubstituted or substituted aralkyl group or forms a bond together with the adjacent group R 8
R
8 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, unsubstituted or substituted aralkyl or R 8 forms a bond together with R 7
R
9 represents hydrogen, unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl, WO 03/033481 PCT/IB02/04275 7 alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R 1 0 represents hydrogen, unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen or NR 1 2 where R 1 2 represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl groups; and R 1 2 together may form a 5 or 6 membered cyclic structure containing carbon atoms, atleast one nitrogen atom and which may optionally contain one or more additional heteroatoms selected from oxygen, sulfur or nitrogen; the linking group to represented by may be attached either through a nitrogen atom or a carbon atom; n is an integer ranging from 1-4 and m is an integer 0 or 1.
An example of these compounds is shown in formula (IIb) 0> 0(1b cH2)2O (IIb) ii) International publication No. WO 00/64888 disclose the compounds of general formula (IIc)
R
1 R3 R5
R
-A Ar B E-Z (Ilc) 2 14 R R Ra R wherein Arl and AT2 are independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylcyclenyl or fused heteroarylheterocycly1; A is O, S, SO, SO 2 NR, NR 1 4
C(O)NR
14 NR' C(O)N(RI), C(R 1 4 chemical bond and the like; B is O, S, NR", a chemical bond, N(R 20 or C(0)N(R2 0 E is a chemical bond or an ethylene group; a is 0-6; b is 0-4; c is 0-4; d is 0-6; g is 1-5; h is 1-4; R 1 R, RS and R' are WO 03/033481 WO 03/33481PCT/lB02104275 independently hydrogen, halogen, alkyl, carbonyl, alkoxycarbonyl, Or aralkyl; R 2
,R,
R 6 and e 8 are independently -(CH2)q-X; q is 0-3; X is hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, carbonyl, alkoxycarbonyl, tetrazolyl, acyl, acylHNSO 2 and the like; Z is R 2 1 0 2 C, R 2 1 0C, cyclo-imide; CN, R 21
O
2
SHNCO,
R O 2 SNH, R NCO, RK 0-2,4-thiazolidinonyl or tetrazolyl.
An example of these compounds is shown in formula (ld) 0 N' 0 (lid) iii) International publication Nos. WO 95/03038 and WO 96/04260 disclose compounds of formula (11 e) H3
-COOH
bCH 2
R
wherein R3 represents 2-benzoxazolyl or 2-pyridyl and Rb represent CF 3
CIT
2 0C11 3 or C1-1 3 A typical example is (S)-3-[4-[2-[N-(2-benzoxazolyl)Nmethylamino] ethoxyjphenyl]-2-(2,2,2-trifluor~oethoxy)propanoic acid (11 f).
N CH 3 COOH t I I HK OCH 2
CF
3 (l) 0'
"Z
iv) International publication Nos. WO 94/13 650, WO 94/0 1420 and WO 95/17394 disclose the compounds of general formnula (IT g)
A-X-(CH
2 R 2(II g) wherein Al represent aromatic heterocycle, A 2 represents substituted benzene ring and A 3 represents moiety of formula (CH 2 wherein RI represents alkyl groups, m is an integer of 1-5; X represents substituted or unsubstituted Y represents C=0 or C=S, R 2 represents OR 3 where R 3 may be hydrogen, alkyl, aralkyl, or aryl group and n is an integer of 2-6.
An example of these compounds is shown in formula (11 h) WO 03/033481 PCT/IB02/04275 9 N CCO 2
CH
2
CH
3 N CH3 S/(IIh) N OPh v) International publication No. WO 00/49005 disclose the compounds of general fonnula (II i) 1 R- Het-L 1
L
2 y (I 1 i)
R
2 wherein Het is an optionally substituted, saturated partially saturated or fully unsaturated 8 to 10 membered bicyclic ring, R' is optionally substituted aryl or optionally substituted heteroaryl, R 2 is hydrogen halogen, lower alkyl or lower alkoxy, L' is an -R-R 4 linkage where R 3 is alkylene, alkenylene or alkynylene and Ri is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroarylidinyl,
C(=Z
2
)-NR
5
NR
5
-C(=Z
2
-Z
2
-C(=NOR
5
-NR
5 NRs-C(=Z )-NR s
SO
2
NR
5 NR-S0 2 -O-C(=0)-NR 5
L
2 is optionally substituted alkylene or alkenylene, Y is carboxy or an acid bioisostere and Z' is NR 5 and the corresponding N-oxides and their prodrugs and pharmaceutically acceptable salts and solvates.
An example of these compounds is shown in formula (II j)
H
H N O N (ii j N- COOH vi) International publication No. WO 94/12181 disclose the compounds of general formula (II k) X-Y-Z-Aryl-A-B (II k) aryl is a 6 membered aromatic ring containing 0, 1, 2 or 3 nitrogen atoms and either unsubstituted or substituted with R 8 and R 9 X represents NH 2 and the like or 4 to 10 membered mono or polycyclic aromatic or nonaromatic ring system and containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S either WO 03/033481 WO 03/33481PCT/lB02104275 unsubstituted or substituted; Y is selected from Ca-8 alkYl, C 4 10 cycloalkyl, Co-s alkyl-
NR
3 -CO-Co-s alkyl, Co-8alkyl-CONR 3 -Co-g alkyl, Co- 8 alkyl-O-Co-s alkyl, Co-S alkyl- S(O).-COs8 alkyl, (CII 2 )o-g aryl-(CH2)o-8, (CH 2 0 6 ary1-SO.-, (CH 2 02 8 aryl-CO-(CH 2 0 s, (CH 2 06 arIy-SO2-(CH2)0os-, (CH 2 0 6
NR
3 -(CH2)0os-, (CH 2 )o 0 6 aryl-CH(OH)-(CH2)o- (CH2)o-8-CON-H-(CH2)o8-,
CO.
8 alkyl-S0 2
-NW
3 -Co-s alkcyl, CO 08 alkyl-CO-CO 0 8 alkyl,
CO.
8 alkyl-CH(OH)-Co-8 alkyl, where n is an integer from 0-2; Z and A are independently chosen from (CH 2
(CH-
2 )mO(CH 2 (C11 2 )mNR 3 (CH2)., (C~I2)mNR(CH 2
(CH
2 )mCONR"(CH 2
(CH
2 )mCO(CH 2
(CH
2 )mCS(CH 2 )n,
(CH
2 )mSOz(CH 2
(CH
2 )mS(CH 2
(CH
2 )mSQ 2
(CH
2
(CH
2 )m1SO(CH, 2 )n,
(CH
2 )mSO 2
NR
3
(CH
2
(CH
2 )mNR 3
SO
2
(CH
2
(CH
2 )mCR 3
=CR
4 (CH,)n,
(CH
2 )mC=-C(CT-T)n, (CH2)mCH(OH)(CH 2 where m and n are each independently an integer from 0 to 6; Aryl is a 6 membered aromatic ring system containing 0, 1, 2, 3 or 4 N atoms and either unsubstituted or substituted with W 5 provided that when A is
(CH
2 the Aryl ring, bonded by Z and A must contain at least one heteroatom; B is R8R 12 0 9 1
(CH
2 0 1
-C-R
Z6 or R R Rio R 1
R',R
7
R
5
R
9
R"
0 and R" 1 are independently selected from hydrogen, fluorine, (C I S) alkyl, hydroxy, hydroxy(C1-6) alkyl, carboxy(CO.6)alkyl, (C 1 6 )alkyloxy, aryl(Co- 6 )alkYloxy, (C 3 -g)cycloalkyl, aryl(CO- 6 )alkyl, (Cl.
6 )alkylcarbonyloxy,
(CO-
6 )alkylamino(Co-6)alkyl and the like; R 1 2 is selected from hydroxy, (CI-s) alkyloxy, aryl (CO.
6 alkyl and the like; An example of those compounds is shown in formula (11 1) WO 03/033481 WO 03/33481PCT/lB02104275 vii) Internationtal publication No. WO 93/16697 and US patent No. 5,227,490 disclose the compounds of general formula (I1 m) RR (11rn) Z-Y-X COOR 3 R' is chosen from hydrogen, CI- 6 alkyl, aryl C 4 10 alkyl, aryl, carboxy, C 1 6 alkyloxy, carboxy CO- 6 alkyl, carboxy C 1 6 alkyloxy, hydroxy CO- 6 alkyl, CI- 4 alkylsulfonlyl Co- 6 alkyl, CO- 4 alkylamino CO- 6 alkyl, aryl CO- 1 0 alkylamino CO- 6 alkyl C 2 1 o acylarnio Co-6 alkyl, C 1 4 carboalkoxy CO- 6 alkyl halogen, R 2 is independently chosen from hydrogen, halogen, hydroxy, CI- 6 alkyl, wherein the alkyl group is substituted or unsubstituted, C 1 6 alkyloxy, aryl CO- 4 alkyl, aryl CO- 6 alkyloxy and the like; W 3 hydrogen, C 1 -6 alkYl, aryl C 1 10 alkyl; Z is NRAR 5 or a 4 9 membered mono or bicyclic ring system containing 1, 2 or 3 heteroatoms selected from N, 0 or S and either unsubstituted or substituted; Y is C 1 6 alkyl either unsubstituted or substituted,
C
4 -8 cycloalkyl, aryl, and the like; X is 0, S0, 502, S, CO, -NRCO-, CONR 4 CLz and the like; An example of these compounds is shown in fornula (11 n) COOC 2
H
HN -(CH 2 4 0 0 H In Few P-phenyl ct-hydroxysubstituted propionic acid derivatives have been reported which have been used as intennediates for the synthesis of target molecules.
Some of such compounds described in the prior art are outlined below: i) European Patent Application EP08 163 16 discloses compound of formula (Ho) WO 03/033481 PCT/IB02/04275 12 R1 n COOR 3 (11o)
OH
R
2 The compound of formula (va) was further converted to 1,2-ethanediaol derivative of the formula (IIp) R H OH (lp)
OH
R
2 These 1,2-ethanediaol derivatives are useful intermediates for the pharmaceuticals and agricultural chemicals.
ii) Japanese Patent Application JP 10017540 discloses compound of formula (IIq)
NH
2 S(Ilq) HO CO 2 BzI The compound of formula (IIr) was further converted to a compound of formula (vd) 0 o N (llr) Bo N O CO 2
BI
00 -13-
O
O
c Summary of the Invention It would be advantageous to develop novel compounds for the treatment and/or 00 prophylaxis of diseases related to increased levels of lipids, especially to treat hypertriglyceridemia and to lower free fatty acids, for the treatment and or prophylaxis of diseases described as Syndrome-X which include hyperlipidemia, 00 hyperinsulinemia, obesity, insulin resistance, insulin resistance leading to type 2 diabetes and diabetes complications thereof, for the treatment of diseases wherein M insulin resistance is the pathophysiological mechanism, for the treatment of Shypertension, atherosclerosis and coronary artery diseases with better efficacy, potency and lower toxicity.
It would therefore be advantageous to provide novel 3- -aryl-a-oxysubstituted alkylcarboxylic acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or their mixtures.
It would also be advantageous to provide novel P-aryl-aoxysubstituted alkyl carboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against PPARa and or PPARy, and optionally inhibit HMG CoA reductase, in addition to agonist activity against PPARa and or PPARy.
It would also be advantageous to provide novel P-aryl-aoxysubstituted alkyl carboxylic acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, without toxic effect or with reduced toxic effect.
It would also be advantageous to provide a process for the preparation of P-aryl-a-oxysubstituted alkyl carboxylic acids, their derivatives, their 0 14 analogs, their tautomeric forms, their stereoisomers, their polymorphs, their c. pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.
SIt would also be advantageous to provide pharmaceutical compositions of P-aryl-a-oxysubstituted alkyl carboxylic acids, their analogs, their derivatives, their tautomers, their stereoisomers, their polymorphs, their salts, O0 00 solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
SIt would also be advantageous to provide novel intermediates, a Sprocess for their preparation and use of the intermediates in process for preparation of P-aryl-oc-oxysubstituted alkoxy carboxylic acids, their derivatives, theirt analogs their tautomers, their stereoisomers, their polymorphs, their salts and their pharmaceutically acceptable solvates and their use as antidiabetic, hypolipdemic, antiobesity and hypocholesterolemic compounds.
00 14a CK The present invention provides the following items I to 21: 1. A compound of formula (I) 00 S/ RR 5
R
R 2 oR -Ar YR' 00 R NR 4
OR
or a tautomeric form thereof, or a stereoisomer thereof, or a polymorph thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein R 2 and R 3
R
4 when attached to the carbon atom, are same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, -aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R 3 and R 4 represents oxo or thioxo group when they are attached to carbon atom; R 3 and R 4 when attached to nitrogen atom represent hydrogen, hydroxy, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives, or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; W represents NR 2, -O-aryl-(CRoR" )o-NR12, where R1 2 represents hydrogen or substituted or unsubstituted group selected from alkyl, aryl or aralkyl groups; o is an integer ranging from 0-6; R' 0 and R" are same or different and represent hydrogen or unsubstituted or unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl group; Ar represents substituted or unsubstituted divalent 00 14b single or fused aromatic or heterocyclic group selected from divalent phenylene, naphthylene, pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl or benzoxazolyl group; Rs 5 represents hydrogen atom, hydroxy, alkoxy, halogen, alyl, substituted or unsubstituted aralyl group or forms a 00 bond together with the adjacent group R 6
R
6 represents hydrogen, hydroxy, alkoxy, halogen, alkyl group, acyl, substituted or unsubstituted aralkyl or R6 forms a bond M together with R 5
R
7 represents hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, C 10 aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R 8 represents hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NRY, where R 9 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, or heteroaralkyl groups or NR9 represents chiral amine, chiral amine alcohols derived from chiral amino acid; or R 8 and R9 together form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; m and n are integers ranging from 0-6.
2. A compound according to item 1, wherein the substituents on R' to Rare selected from halogen, hydroxyl, nitro, thio or unsubstinited. or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, alkoxyalkyl, aryloxyalkyl, arolkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamnino, arylamino, aminoalkyl, alkoxycarbonyl, alkylamino, alkylthio groups, carboxvlic acid or its derivatives or sulfonic acid or its derivatives; substituents on R 7 are selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives or sulfonic acid or its derivatives.
00 1 4c r~ A compound according to item 1, wherein R 2 and R R.
4 when attached n to the carbon atom, are same or different and represent hydrogen, halogen or alkyl; 00 one or both of R 3 and R 4 represent oxo or thioxo group when they are attached to carbon atom; R 3 and R 4 when attached to nitrogen atom represent hydrogen or alkyl; R 5represents hydrogen atom or forms a bond together with the adjacent group R 6; R6 00 (~KI represents hydrogen or forms a bond together with Ri; R7 represents hydrogen or substituted or unsubstituted alkyl, aryl or aralkyl; R.
8 represents hydrogen or M substituted or unsubstituted groups selected from alkyl, aryl or aralkyl; m and n are integers ranging from 0 2.
ri 1 4. A compound according to any one of items 1-3, which is selected from: Ethyl (3 ,4-dihydro-2H-benzo[b][1 ,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate; ()Ethyl {3 ,4-dihydro-2H-benzo[b] [1 4 ]oxazin-4-yl)propylainino} phenyl]-2-ethoxypropanoate Ethyl {3-(3,4-dihydro-2H-benzo[b] [1 4 ]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate; {3-(3,4-Dihydro-2H-benzo[b] 1, 4 ]oxazin-4-yl)propylamino) phenyl]-2ethoxypropanoic acid or its salts f{3 -(3,4-Dihydro-2H-benzo[b] 1,4]oxazin-4-yl)propylaminolphienyl]-2ethoxypropanoic acid or its salts 3 f{3-(3 ,4-Dihydro-2H-benzo[b] [I ,4]oxazin'-4-yl)propylaminolphenyl]-2ethoxypropanoic acid or its salts; Ethyl 3-[4-N-heptyl-N- {2-(3-oxo-3,4-dihydro-2H--benzo[b] 1,4]oxazin-4yl)ethylamino lphenyl]-2-ethoxypr'opanoate Ethyl 3-[4-N-heptyl-N- {2-(3-oxo-3,4-dihydro-2H-benzo[b][ 1 ,4]oxazin-4yl)etlhylamino} phenyl]-2-ethoxypropanoate; Ethyl 3-[4-N-heptyl-N- {2-(3-oxo-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)ethylamino }phenyl]-2-ethoxypropanoate; 00 1 4d W± 3-[4-N-Heptyl-N- {2-(3-oxo-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazini-4yl)ethylamino~phenyl]-2-ethoxypropanoic acid or its salts; 00 3 -[4-N-Heptyl-N- 2 3 -oxo-3,4.-dihydro-2H-benzo ,4]oxazin-4yl)ethylamino~phenyl]-2-ethioxypropanoic acid or its salts [4-N-Heptyl-N- {2-(3-oxo-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4- 00 yl)ethylaminolphenyl]-2-ethoxypropanoic acid or its salts; ()Methyl 2-ethoxy-3-[4- fN-heptyl-N-(2-(3,4-dihydro2Hbenzop]oxazin4yl-2oxoethyl)aminomethyl~phenyl]propanoate; ()Methyl 2-ethoxy-3 {N-heptyl-N-(2-(3 ,4-dihydro-2H-benzo [b]oxazin-4-yl)-2oxoethyl)aminomethyl}phenyl]propanoate Methyl 2-ethoxy-3-[4- {N-heptyl-N-(2-(3,4-dihydro2Hbenop,]oxazin-4y>2oxoethyl)arninoinethyllphenyl]propanoate ()2-Ethoxy-3-[4- {N-heptyl-N-(2-(3 ,4-dihydro-2H-benzo[b]oxazin-4-yl)-2oxoethyl)aminomethyl~phenyl]propanoic acid or its salts; N+ 2-Ethoxy-3-[4- {N-heptyl-N-(2-(3 ,4-dihydro-2H-benzo[b]oxazin-4-yl)-2oxoethyl)aminomethyl~phenyl]propanoic acid or its salts 2-Ethoxy-3-[4- {N-heptyl-N-(2-(3 ,4-dihydro-211-benzo[b]oxazin-4-yl)-2oxoethiyl)amninomethyl~phenyljpropanoic acid or its salts; ()Methyl 3 {5-(3,4-dihydro-2H-benzo[b] [1 4 phenyl]-2-ethioxypropanoate; Methyl 3 ,4-dihydro-2H-benzo[b] [1 4 phenyl]-2-ethoxypropanoate Methyl {5-(3,4-dihydro-2H-benzo[b] [1 ,4]oxazini-4-yl)-5-oxopentylamino} phenyl]-2-ethoxypropanoate; {5-(3,4-Dihydro-2H-benzo[b] 1,4]oxazin-4-yl)-5-oxopentyl amino) phenyl]- 2-ethoxypropanoic acid or its salts 00 1 4e ,4-Dihydro-2H-benzo [bl[1I, 4 ]oxazin- 4 -yl)-5-oxopentylamino} phenyl]- 2-ethoxypropanoic acid or its salts; 00 (5-(3,4-Dihydro-2H-benzo[b] [1 4 ]oxazin-4-yl)-5-oxopentylamino} phenyl]- 2-ethoxypropanoic acid or its salts; 00 Methyl 3 {3 -(3,4-dihydro-2H-benzo[b] [I, 4 ]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate.; Methyl 3-[3-f ,4-dihydro-2H-benzo[b] [1 4 ]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate; ()Methyl -(3,4-dihydro-2H-benzo[b] [I, 4 ]oxazin-4-yl)propylamino phenyl]- 2-ethoxypropanoate 3 {3-(3,4-Dihydro-2H-benzo[b] [1 4 ]oxazin-4-yl)propylamino} phenyl]-2ethoxypropanoic acid or its salts; ,4-Dihydro-2H-benzo[b] [1 4 ]oxazin-4-yl)propylamino~phenyl]-2ethoxypropanoic acid or its salts ,4-Dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propylamino~phenyl]-2ethoxypropanoic acid or its salts; Methyl 3 (3 -(7-fluoro-3 ,4-dihydro-21{-benzo[b] 1,4]oxazin-4-yl) propylaminolphenyl]-2-ethoxypropanoate H+ Methyl {3 -(7-fluoro-3 ,4-dihydro-2H-benzo[b][ 1,4]oxazin-4-yl) propylamino~phenyl]-2-ethoxypropanoate Methyl {3 -(7-fluoro-3 ,4-dihydro-2H-benzo[b][ I,4]oxazin-4-yl) propylamino~pbenyl]-2-ethoxypropanoate; W± {3-(7-Fluoro-3,4-dihydro-2H-benzo[b][ 1,4]oxazin-4-yI)propylamino} phenyl]-2-ethoxypropanoic acid or its salts M+ {3-(7-Fluoro-3 ,4-dihydro-2H-benzo[b][l ,4]oxazin-4-yI)propylamino} phenyl]-2-ethoxypropanoic acid or its salts 00 1 4f 3- {3-(7-Fluoro-3 ,4-dihydro-2H-benzo[b][ [1,4]oxazin-4-yl)propylamino phenyl]-2-ethoxypropanoic acid or its salts; 00 M± Methyl 2-ethoxy-3-[4- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propyloxy)benzyl} aminophenyllpropanoate; 00 N+ Methyl 2-ethoxy-3-[4- ,4-dihydro-2H-benzo [1 ,4]oxazin-4yl)propyloxy)benzyl} am inophenyl]propanoate; Methyl 2-ethoxy-3-[4- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propyloxy)benzyl} aminophenyl]propanoate; (Ni W± Methyl 2-ethoxy-3 ,4-dihydro-21--benzo[b] [1 ,4]oxazin-4yl)propyloxy)benzyl} aminophenyl]propano ate Methyl 2-ethoxy-3-13 ,4-dihydro-2H-benzo[b] 1,4]oxazin-4yl)propyloxy)benzyl~arninophenyl]propanoate Methyl 2-ethoxy-3-[3- -(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propyloxy)benzyl} aminophenyl]propanoate; W± 2-Ethoxy-3-[4- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propyloxy) berizyl) aminophenyljpropanoic acid or its salts 2-Ethoxy-3-[4- -(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propyloxy) benzyl) aminopbenyl]propanoic acid or its salts 2-Ethoxy-3 {4-(3-(3,4-dihydro-2H-benzo[bj [1 ,4]oxazin-4-yl)propyloxy) benzyl Iaminophenyl]propanoic acid or its salts; 2-Ethoxy-3-[3 {4-(3-(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propyloxy) benzyl} amninophenyl]propanoic acid or its salts; (H 2-Ethoxy-3 -(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propyloxy) benzyl aminophenyl]propanoic acid or its salts; 2-Ethoxy-3-[3- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propyloxy) benzyl} aminophenyl]propanoic acid or its salts; 00 1 4g W± Ethyl 2-ethoxy-3 {3-(3,47dihydro-2H-benzo [b][1I,4]thiazin-4yl)propylaminolphenyl]propanoate; 00 0 H Ethyl 2-ethoxy-3 f{3 -(3,4-dihydro-2H-benzo[b] 1,4]thiazin-4- C*N yI)propylaminolphenyl]propanoate; 00 Ethyl 2-ethoxy-3-[4-,{3-(3,4-dihydro-2H-benzo [1 ,4]thiazin-4yl)propylaminolphenyl]propanoate; W± 2-Ethoxy-3-[4- ,4-dihydro-2H-benzo ,4]thiazin-4yI)propylarnino~phenyl]propanoic acid or its salts 2-Ethoxy-3-[4- ,4-dihydro-2H-benzo[b][ 1,4]thiazin-4yl)propylamino Iphenyl]propanoic acid or its salts; 2-Ethoxy-3-[4-{3 ,4-dihydro-2H-benzo[b] [1 ,4]thiazin-4yl)propylamino) phenyl]propanoic acid or its salts; Ethyl 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b] [I,4]oxazin-4-yl) cthylamino~phenyl]propanoate N+ Ethyl 2-ethioxy-3-[4-{2-(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) ethylamino} phenyl]propanoate Ethyl 2-ethoxy-3-[4-{ 2-(3 ,4-dihydro-2H-benzo[b] 1,4]oxazin-4-yl) ethylaminol phenyl]propanoate M± 2-Ethoxy-3-[4- {2-(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)ethylamino} phenyl]propanoic acid or its salts N+ 2-Ethoxy-3-[4- {2-(3,4-dihydro-2H-benzo [bl]l ,4]oxazin-4-yl)ethylamino} phenyl]propanoic acid or its salts 2-Ethoxy-3 {2-(3,4-dihydro-2H-benzo[b][ 1 ,4]oxazin-4-yl)ethylamnino} phenyl]propanoic acid or its salts 00 1 4h ()Methyl 2-ethoxy-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yI)ethoxy} 00 phenylaminomethyl]phenyl]propanoate; ()Methyl 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1 ,4]oxazin-4-yl)ethoxy} phienylaminomethyflphenyllpropanoate Methyl 2-ethoxy-3-[4-[4- {2-(3,4-dihydro-2H-benzo[b][ 1,4]oxazin-4-yl)ethoxy} 00 ri phenylaminornethyl]phenyljpropanoate; M± 2-Ethoxy-3-[4-[4- {2-(3,4-dibydro-2H-be-nzo[b] [1 ,4]oxazin-4-yl)ethc-xy,) phenylaminomethyl]phenyl~propanoic acid or its salts +)2-Ethoxy-3-[4-[4- ,4-dihydro-21--benzo[b] [1 ,4]oxazin-4-yl)ethoxy} phenylaminomethyl]phenyl]propanoic acid or its salts; 2-Ethoxy-3- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)ethoxy} phenylaminomethyl]phenyl]propanoic acid or its salts; Ethyl -(7-fluoro-3 ,4-dihydro-2H-benzo[b][l ,4]oxazin-4-yl) propylamino~phenyl]-2-ethoxypropanoate N+ Ethyl {3-(7-fluoro-3 ,4-dihydro-2H-benzo[b][1 ,4]oxazin-4-yl) propylaminolphenyl]-2-ethoxypropanoate Ethyl {3 -(7-fluoro-3 ,4-dihydro-2H-berzo[b][1 ,4]oxazin-4-yl) propylamino~phenyl]-2-ethoxypropanoate M± Ethyl -(7-fluoro-3,4-dihydro-2H-benzo ,4]oxazin-4-yl) propylamino~phenyl]-2-rnethoxypropanoate H+ Ethyl 3 -(7-fluoro-3,4-dihydro-2W--benzo[b] [1 ,4]oxazin-4-yl) propylamino~phenyl]-2-methoxypropanoate Ethyl {3-(7-fluoro-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propylamino }phenyl] -2-methoxypropanoate M± {3-(7-Fluoro-3 ,4-dihydro-.2H-benzo[b][El,4]oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoic acid or its salts 00 1 4i H± 3 {3-(7-Fluoro-3,4-dihydro-211-benzo [1 4 ]oxazin-4-yl)propylamino phenyl]-2-methoxypropanoic acid or its salts 00 {3 -(7-Fluoro-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-4-yl)propylarnino phenyl]-2-methoxypropanoic acid or its salts 00 Ethyl -(2-methyl-7-fluoro-3 ,4-dihydro-2H-benzo[b][1 ,4]oxazin-4-yl) propylamino~phenyl]-2-ethoxypropanoate Ethyl {3 -(2-methyl-7-fluoro-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-.yl) propyl amino) phenyl]-2-ethoxypropanoate Ethyl {3-(2-rnethyl-7-fluoro-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propylamino~phenyl]-2-ethoxypropanoate W 3- {3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo jb] [1 ,4]oxazin-4yl)propylamino} phenyl]-2-ethoxypropanoic acid or its salts 3 {3-(2-methyl-7-Fluoro-3,4-dihydro-2H--benzo [1 ,4]oxazin-4yl)propylarnino} phenyl]-2-ethoxypropanoic acid or its salts 3 {3 -(2-methyl-7-Fluoro-3,4-dihydro-2H--benzo[b] [1 ,4]oxazin-4yl)propylamino} phenyl[J-2-ethoxypropanoic acid or its salts Ethyl {3-(2-rnethyl-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propyl amino) phenyl] -2-ethoxypropanoate N+ Ethyl {3-(2-methyl-3 ,4-dihydro-2H-benzo[b][1 ,4]oxazin-4-yI) propylamino~phenyl]-2-ethoxypropanoate 0- Ethyl {3 -(2-methyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-4-yl) propylaminolphenyl]-2-ethoxypropanoate W± 3 {3-(2-methyl-3,4-dihydro-2H-benzo jb] [1 ,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid or its salts N± 3 {3-(2-methyl-3,4-dihydro-2H-benzo[b][l ,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid or its salts 00 1 4j {3 -(2-methyl-3 ,4-dihydro-21--benzo[b] 1, 4 ]oxazin-4-yl)propyl amino} phenyl]-2-ethoxypropanoic acid or its salts 00 M± Ethyl {3 -(2-methyl-3 ,4-dihydro-2H-benzo[b][ 1,4]oxazin-4-yl) propylaminolphenyl]-2-methoxypropanoate 00 ri (H Ethyl 3 {3-(2-methyl-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propylamino~phenyl]-2-methoxypropanoate Ethyl 3 {3 -(2-methyl-3 ,4-dihydro-2H--benzo[b] [1 ,4]oxazin-4-yl) propylaminolphenyl]-2-methoxypropanoate M± {3-(2-methyl-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propylamino} phenyl]-2-methoxypropanoic acid or its salts 3 {3-(2-methyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-4yl)propylarnino~phenyl]-2-methoxypropanoic acid or its salts {3-(2-methyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-4yl)propylaminolphenyl]-2-methoxypropanoic acid or its salts M± Ethyl 3 (3 -(2-propyl-3 ,4-dihydro-2H-benzo[b] 1 ,4]oxazin-4-yl) propylamino~phenyl]-2-ethoxypropanoate Ethyl 3 {3-(2-propyl -3 ,4-dihydro-2H-b enzo 1,4]oxazin-4-yl) propylarnino~phenylj-2-ethoxypropanoate Ethyl 3 3-(2-propyl-3 ,4-dihydro-2H-benzo[b] 1,4]oxazin-4-yI) propylamino~phenyl]-2-ethoxypropanoate 3 f{3-(2-propyl-3 ,4-dihydro-2H-benzo 1,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid or its salts H± 3 f{3-(2-propyl-3,4-dliydro-2H-benzo[b] [1 oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid or its salts 3 -(2-propyl-3 ,4-diliydro-2H-benzo[b][1I,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid or its salts 00 14k Ethyl (2S)-3 {3-(2-propyl-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yI) propyl amino) phenyl]-2-rnethoxypropanoate 00 Ethyl f{3-(2-propyl-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propylamino} phenyl]-2-methoxypropanoate 0 Ethyl (2S)-3 {3-(2-propyl-3 ,4-dihydro-2H--benzo[b] 1,4]oxazin-4-yl) 00 propylamino~phenyl 3-2-methoxypropanoate -(2-propyl-3,4-dihydro-2H-benzo[b][ 1,4]oxazin-4-yl)propylarnino} pheiiyl]-2-methoxypropanoic acid and its salts ()3-[4-f{3-(2-propyl-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propylarnino} phenyl]-2-methoxypropanoic acid and its salts 0- 3 f{3 -(2-propyl-3,4-dihyclro-2H-benzo[b] [1 ,4]oxazin-4-yI)propylamino} phenyl]-2-methoxypropanoic acid and its salts ()Ethyl 2-isopropoxy-3-[4- {3-(7-fluoro-3 ,4-dihydro-2H-benzo[b][1I,4]oxazin-4-y1) propylamino} phenyl] propanoate Ethyl 2-isopropoxy-3-74- {3-(7-fluoro-3 ,4-dihydro-2H-benzo[b][ 1,4]oxazin-4-yl) propylamninolphenyl] propanoate Ethyl 2-isopropoxy-3-[4- {3-(7-fluoro-3 ,4-dihydro-2H-benzo[b][ 1,4]oxazin-4-yl) propylaminolphenyl] propanoate M± 2-Isopropoxy-3-[4- {3 -(7-fluoro-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propylaminolphenyl]propanoic acid and its salts.
N± 2-Isopropoxy-3 -(7-fluoro-3 ,4-dihydro-2H-benzo[b] [I,4]oxazin-4-yl) propylamino~phenyl]propanoic acid and its salts 2-Isopropoxy-3-[4- {3 -(7-fluoro-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propylamino~phenyl]propanoic acid and its salts Ethyl {3-(2-methyl-7-fluoro-3 ,4-dihydro-2H--benzo[b] [1 ,4]oxazin-4-yl) propylaniino} phenyl]-2-methoxypropanoate 00 141 Ethyl 3-I4-{3 -(2-methyl-7-fluoro-3 ,4-dihydro-2H--benzo[b] [1 ,4]oxazin-4-yl) propylamino~phenyl]-2-methoxypropanoate Ethyl {3-(2-1-ethyl-7-fluoro-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yI) propylamino) phenyl]-2-methoxypropanoate 00 M± {3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propylaminolphenyl]-2-methoxypropanoic acid and its salts N+ 3.44- {3-(2-niethyl-7-fluoro-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propylamino~phenyl]-2-methoxypropanoic acid arid its salts {3 -(2-methyl-7-fluoro-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propylamino~phenyl]-2-methoxypropanoic acid and its salts [2S,N( IR)]-N-(2-hydroxy-l -phenylethyl)-2-ethoxy-3-[4- ,4-dihydro-2Hbenzo[b] [I,4]oxazin- 4-yl)propylaminolphenyl]propanamide; [2R,N( IR)]-N-(2-hydroxy-1 -phenylethyl)-2-ethoxy-3-[4- ,4-dihydro-2Hbenzo[b][ [1,4]oxazin-4-yl)propylamino~phenyl]propanamide 2SN( lR)]-N-(2-hydroxy- l-phenylethyl)-2-ethoxy-3 -44-f 3-(7-fluoro-3 ,4-dihydro-2Hbenzo[b] [1 ,4]oxazin-4-yl)propylamino~phenyl]propanide [2R,N(IlR)]-N-(2-hydroxy-1 -phenylethyL)-2-ethoxy-3-[4- {3-(7-fluoro-3 ,4-dihyclro-Hbenzo 1,4]oxazin-4-yl)propylamnino~phenyljpropanamide [2SN( lR)]-N-(2-hydroxy-l1-phenylethyl)-2-ethoxy-3-[4- ,4-dihydro-2Hbenzo[b] [1 ,4]oxazin-4-yl)propylamino~phenyl]propanamide hydrochloride salt; [2R,N(1 R)]-N-(2-hydroxy-l1-phenylethyl)-2-etoxy-3-14-{3 -(3,4-dihydro-2Hbenzo[b] I ,4]oxazin-4-yl)propylaminolphenyl]propanamide hydrochloride salt; A compound according to item 1 wherein the pharmaceutically acceptable salt is Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; NN'-diacetylethylenediamine, betaine, 00 14m caffeine, 2-diethylamino ethanol, 2-dimethylaminoethanol, N-ethylmorpholine, Nethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, 00 methylgiucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, -tromethamine, diethanolamine, meglumine, ethylenediamine, N,N'-diphenylethylenediamine, NN'- 001 dibenzylethylenediar-nine, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamnine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine; alkyiphenylamine, glycinol, phenyl glycinol; glycine, alanine, valine, leucine, r~l 1 isoleucine, norleucrne, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, omithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids; D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammnoniumi salts and aluminum salts; sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, berizenesulfoniates, ascorbates, glycerophosphates, ketoglutarates, ammonium or substituted ammonium salts or aluminiumn salt.
6. A process for the preparation of the compound of formula (I)
RRG
11101) A yCR R )n-W-(CR 10R m1 Y 8
(I
R2 N 4OR 7 as defined in item 1 which comprises a. reacting the compound of formula (111a) R NR where L' is a leaving group and all other symbol ar as defined above with a compound of formula (111b) 00 14n 0R 5 00
HW-(CRR
11 )m-Ar YR 9 (III b)
OR
7 Swhere W represents NR 1 2 or -O-aryl-(CRl 0 R ')o-NR12 and all symbols are as defined C above to yield a compound of formula defined above; 1 5 or C b. Reacting a compound of formula (II c) 0 R 1 X R3 R R R 4 (III c R2 NR 4 where all symbols are as defined above with a compound of formula (IIId)
R
5 L -CRR11i-W-(CR1R11)m-Ar YR 9 (111 d)
OR
7 where L' is a leaving group, W represents NR 1 2 or -O-aryl-(CRo'R")o-NR 1 2 and all other symbols are as defined above to produce a compound of formula or c. Reacting a compound of formula (IIe)
R
1 X R 3 (CRo R1 )n-W-(C1R'VR )m-Ar-CHO (III e) R2
N'R
4 where W represents NR 1 2 or -O-aryl-(CR'OR"))-NR 1 2 and all symbols are as defined above with a compound of formula (IIIf) R O 2 C P(O)(OR13)2 (llf)
OR
7 where R 1 3 represents (Ci-C 6 )alkyl and all other symbols are as defined above to yield compound of formula defined above, 00 O 140 and optionally, converting the compound of formula obtained in any of the processes described above into a pharmaceutically acceptable salt thereof or 00 Spharmaceutically acceptable solvate thereof; or 00 5 d. Reducing a compound of formula (IVa) S"3 0 X R 3
O
S(CR'10R")1-W-(C R 1 0 R1 )-Ar YR (IVa) 2 N 4 Y R SR OR 7 which represents a compound of formula where R 5 and R 6 together represent a bond and Y represents an oxygen atom and all other symbols are as defined above, to yield a compound of the formula where R 5 and R 6 each represent hydrogen atom and all other symbols are as defined above; or e. Reacting a compound of formula (IIIe) 1 X R3 -(CRoR" 1 n-W- C R
R"
m -Ar-CHO (IIIe) 24 R2 N R4 where W represents NR 1 2 or -O-aryl-(CR'OR")o-NR' 2 and all other symbols are as defined above with a compound of formula (IVb) 6 R 5 C0 2
R
8 (IVb)
OR
7 where R 5 represents hydrogen and all other symbols are as defined above to yield compound of formula defined above; or f. Reacting a compound of formula (LIg) 00 1 4 p R XR 3 S)n- (CR R )o-L (III g)
OR
2 N R 4
O
where L' is a leaving group, n and o are integers ranging from 0-6 and all other 00 symbols are as defined above, with a compound of formula (IIIb)
R
5
SHW-(CR
1
R
11 )m-Ar YR 9 (II b)
SOR
7 where W represents NR 2 and all other symbols are as defined above to yield a compound of formula where W represents -C(=0)-(CRI o
RI")
o
-NR'
2 and all other symbols are as defined above; or g. Reacting a compound of formula (IIli) 1
R
3 R,(CR1OR')n-O-
-(CR
10 R)-G (lli) R2N R4
H
where n and p are integers ranging from 0-6, G' is CHO or NH 2 and all other symbols are as define above with a compound of formula (IIIh)
R
5
O
2 10 11 A (Illh)
G-(CR
1 R
YR
8
OR
7 where q is an integer ranging from 0-6, G 2 is CHO or NH 2 and all other symbols are as defined above to yield a compound of formula where W represents -O-aryl-
(CR
10
R
11 )o-NR 1 2 and all other symbols are as defined above; or h. i. Reacting a compound of formula (I) 00 S14q C3 1 R 3 00 -(CRoR")n-W-(CRR")--Ar YR 8 RH
R
4
OR
7 where all symbols are as defined above and Y represents oxygen or YR 8 represents a 00 halogen atom or COYR 8 represent a mixed anhydride group and all other symbols are as defined above with an amine of formula NHR 8
R
9 where R 8 and R 9 are as defined above and optionally; ii. Resolving the compound of formula obtained above into stereoisomers; or i. Hydrolysing a compound of formula (I) 1 RR
RR
3
R
5 60 X/ R O R2 (CR R R Arm YR H R 4
OR
where R 8 represents unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl group and all other symbols are as defined above to a compound of formula wher R 8 represents hydrogen.
optionally coverting the compound of formula obtained in any of the processes described above into a pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate thereof.
7. An intermediate of formula (IIId)
R
6 0 L (CROR"1)-W-(CR 1
OR
1 1 Ar (li l d) OR7 or a tautomeric form thereof, or a stereoisomer thereof, or a polymorph thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein L' is a leaving group; 0 14r 0 .W represents NR 2 -C(=O)-(CRi o R")o-NR 2 -O-aryl-(CR°R' ')o-NRI2, where R 1 2 represents hydrogen or 00 substituted or unsubstituted group selected from alkyl, aryl or aralkyl groups; o is an integer ranging from 0-4; Ro 1 and R" are same or different and represent hydrogen or unsubstituted or unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl 00 group; Ar represents substituted or unsubstituted divalent single or fused aromatic or heterocyclic group; R 5 represents hydrogen atom, hydroxy, alkoxy, halogen, alkyl, M substituted or unsubstituted aralkyl group or forms a bond together with the adjacent group R 6
R
6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, 10 substituted or unsubstituted aralkyl or R 6 forms a bond together with R 5
R
7 represents hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R 8 represents hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NR 9 where R 9 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, or heteroaralkyl groups; or R 8 and R 9 together form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; m and n are integers ranging from 0-6.
8. An intermediate of formula (IIIg)
R
1
R
3 Y/ 0 H R4 or a tautomeric form thereof, or a stereoisomer thereof, or a polymorph thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein R 2 and R 3
R
4 when attached to the carbon atom, are same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, 00 14s cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, n heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, 00monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, 00 aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R 3 and R 4 represent oxo or thioxo group when they are attached to carbon atom; R 3 and R 4 when attached to nitrogen atom represent hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, to cycloalkyl, alkoxy, cycloalkoxy, alyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives, or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; R' 0 and R" are same or different and represent hydrogen or substitutedor unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl group; L' is a leaving group; n and o are integer ranging from 0-6.
9. An intermediate of formula (IIi) 1 R 3 R2(CRoR ),-O-II-(CR1R11),-G (Illi) R N 4 H R4 or a tautomeric form thereof, or a stereoisomer thereof, or a polymorph thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein R 2 and R 3
R
4 when attached to the carbon atom, are same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, o0 14t 0 Sheteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, Smonoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, 00 aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic- acid or its 0 derivatives; one or both of R 3 and R 4 represent oxo or thioxo group when they are attached to carbon atom; R 3 and R 4 when attached to nitrogen atom represent hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, 0 cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, C 10 acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives, or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; R 1 and R" are same or different and represent hydrogen or substituted or unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl group; G' is CHO or
NH
2 n and p are integers ranging from 0-6.
A pharmaceutical composition which comprises a compound according to any one of items 1-5 and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
11. A pharmaceutical composition which comprises a compound according to any one of items 1-5 and a HMG CoA reductase inhibitor; fibrate; nicotinic acid; cholestyramine; cholestipol; probucol or their combination and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
12. A pharmaceutical composition as claimed in item 10 or 11 in the form of a tablet, capsule, powder, syrup, solution or suspension.
13. A method of preventing or treating hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering a compound 00
O
O according to any one of items 1-5 or a pharmaceutical composition according to item 10 or 11 to a patient in need thereof.
14. A method according to item 13, wherein the disease is type II diabetes, 00 impaired glucose tolerance, dyslipidemia, disorders related to Syndrome X including hypertension, obesity, insulin resistance, coronary artery disease and other cardiovascular disorders, renal diseases including glomerulonephritis, 00 glomeruloscierosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy; retinopathy, disorders related to endothelial cell activation, Spsoriasis, polycystic ovarian syndrome (PCOS), dementia, diabetic complications, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer, osteoporosis or inflammation.
A method for the treatment and/or prophylaxis of disorders related to Syndrome X, which comprises administering a compound according to any one of items 1-5 or a pharmaceutical composition according to item 10 or 11 to a patient in need thereof.
16. A method of reducing total cholesterol, body weight, blood plasma glucose, triglycerides, LDL, VLDL or free fatty acids or increasing HDL in the plasma comprising administering a compound according to any one of items or a pharmaceutical composition according to item 10 or 11 to a patient in need thereof.
17. The use of a compound according to any one of items 1-5 in the preparation of a medicament for the prevention or treatment of hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases in which insulin resistance is the underlying pathophysiological mechanism.
18. The use according to item 17, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidemia, disorders related to Syndrome X including hypertension, obesity, insulin resistance, coronary artery disease and other cardiovascular disorders; renal diseases including glomerulonephritis, glomeruloscierosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy; retinopathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), dementia, diabetic 00
O
O complications, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer, osteoporosis or inflammation.
00 19. The use of a compound according to any one of items 1-5 in the preparation of a medicament for the treatment and/or prophylaxis of disorders related to Syndrome X.
00 20. The use of a compound according to any one of items 1-5 in the preparation of a medicament for reducing total cholesterol, body weight, blood N plasma glucose, triglycerides, LDL, VLDL or free fatty acids or increasing HDL in the plasma.
21. The intermediate according to item 7 or 8, wherein the leaving group L' is halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate or hydroxy.
00 Detailed Description of the Invention 3-Aryl-a-oxysubstituted propionoic acids of the present invention. having the 00 general formula (I)
R
3 R X'(CRio-( YR (I) 00 X-II iY R \4 7R HR R
OR
their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically (N acceptable solvates wherein R and R 3
R
4 when attached to the carbon atom, may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aloxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyallcyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, araloxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R 3 and R 4 may represent oxo or thioxo group when they are attached to carbon atom; R 3 and R 4 when attached to nitrogen atom represent hydrogen, hydroxy, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalcyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives, or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; W represents NR' 2 2 -O-aryl-(CR'oR")),- 12 12 NR 2, where R represents hydrogen or substituted or unsubstituted group selected from alcyl, aryl or aralkyl groups; o is an integer ranging from 0-6; R' 0 and R" may be same or different and represent hydrogen or unsubstituted or substituted group WO 03/033481 PCT/IB02/04275 16 selected form alkyl, alkoxy, aryl or aralkyl group; Ar represents substituted or unsubstituted divalent single or fused aromatic or heterocyclic group; R 5 represents hydrogen atom, hydroxy, alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group or forms a bond together with the adjacent group R6; R 6 represents hydrogen, hydroxy, alkoxy, halogen, alkyl group, acyl, substituted or unsubstituted aralkyl or forms a bond together with Rs; R 7 may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R8 may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NR 9 where R 9 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, or heteroaralkyl groups or NR 9 represents chiral amine, chiral amine alcohols derived from chiral amino acid; R s and
R
9 together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; m and n are integers ranging from 0-6.
Suitable groups represented by R2, R, R 4 may be selected from hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxy, cyano, nitro, formyl, substituted or unsubstituted (Ci-C 1 2 alkyl group especially linear or branched (C 1 -Clo) alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl and the like; cyclo(C 3
-C
6 )alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; (Ci-C 6 )alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may be substituted; cyclo(C 3
-C
6 )alkoxy group such as..cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, the cycloalkoxy group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aryloxy group such as phenoxy, naphthyloxy and the like, the aryloxy group may be substituted; aralkyl such as benzyl, phenethyl, C 6 H5CH 2
CH
2
CH
2 naphthylmethyl and the like, the aralkyl group may be substituted; aralkoxy group such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy and the like, WO 03/033481 WO 03/33481PCT/lB02104275 17 the aralkoxy group may be substituted; heterocyclyl groups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and the like, the heterocyclyl group may be sub stituted; heteroary1' group such as pyridyl, thienyl, funyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, beuzopyranyl, benzofuryi and the like, the heteroaryl group may be substituted; heteroaralkyl group such as furanethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted; hecteroaryloxy and heteroaralkoxy, wherein heteroaryl and heteroaralkyl moieties are as defined earlier and may be substituted; acyl group such as acetyl, propionyl, benzoyl and the like, the acyl group may be substituted; acyloxy group such as OCCMe, QOCEt, OOCPh and the like, which may be substituted; acylamino groups such as NHCOCH 3 NH4COC 2 H1 5
NHCOC
3
H
7
NHCOC
6
H
5 and the like, which may be substituted; monoalkylamino group such as
-NTTCH
3
NHC
2 1T 5
NH-C
3 1I 7
NHC
6 H1 13 and the like, which may be substituted; dialkylamino group such as N(CH 3 2
NCH
3
(C.
2
H
5
N(C
2
H
5 2 and the like, which j 5 may be substituted; arylamino group such as HNC 6
H
5
NCH
3
(C
6
H
5
NH-C
6
II
4
CII
3 NIfC 6
HT
4 -Ial and the like, which may be substituted; aralkylam-ino group such as 2 NH, C6H 5
CH
2
CH
2 NH, C6H5CH 2
NCH
3 and the like, which may be substituted; amino group; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and the like, which may be substituted; aryloxycarbonyl group such as phenoxycarbonyl, naphthyloxycarbonyl and the like, the aryloxycarbonyl group may be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may be substituted; alkoxyalkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, the alkoxyalkyl group may be substituted; aryloxyalkyl group such as C61H 5
OCH
2
C
6
H
5
OCH
2
CII
2 naphthyloxymethlyl and the like, which may be substituted; aralkoxyalkyl group such as C 6 HsCH 2 OC1I 2
C
6 11 5
CH
2
OCH
2
CU
2 and the like, which may be substituted; hydroxy(Ci-C 6 )alkyl, which may be substituted; thio (CI-C 6 )alkyl, which may be substituted; (C 1
-C
6 )alkylthio which may be substituted; alkoxycarbonylamino group such as NHCOOC 2
H
5
NIHCOOCH
3 and the like, which may be substituted; aryloxycarbonylamino group such as
NHCOOC
6
II
5
NCH
3
COOC
6
H
5
NC
2
H
5
COOC
6
H
5
NHCOOC
6
H
4
CH
3
NHCOOC
6
H
4
OCH
3 and the like, which may be substituted; aralkoxycarbonylamino WO 03/033481 PCT/IB02/04275 18 group such as NHCOOCH 2
C
6
H
5
NHCOOCH
2
CH
2
C
6
H
5
N(CH
3
)COOCH
2
C
6 Hs,
N(C
2 Hs)COOCH 2 C6H5, NHCOOCH 2
C
6
H
4
CH
3
NHCOOCH
2
C
6
H
4 0CH 3 and the like, which may be substituted; carboxylic acid or its derivatives such as amides, like
CONH
2 CONHMe, CONMe 2 CONHEt, CONEt 2 CONHPh and the like, the carboxylic acid derivatives may be substituted; sulfonic acid or its derivatives such as S02NH 2 SONHMe, SO 2 NMe 2
SO
2
NHCF
3 and the like, the sulfonic acid derivatives may be substituted.
When the groups represented by R 1 to R4 are substituted, the substituents may be selected from halogen, hydroxy, nitro, thio or unsubstituted or substituted groups to selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl, alkylamino, alkylthio groups, carboxylic acids or its derivatives or sulfonic acid or its derivatives. These groups are as defined above.
It is preferred that the substituents on R 1 to R 4 represent halogen atom such as fluorine, chlorine or bromine; alkyl group such as methyl, ethyl, iso-propyl, n-propyl, n-butyl; cycloalkyl group such as cyclopropyl; aryl group such as phenyl; aralkyl group such as benzyl; (C 1
-C
3 )alkoxy, benzyloxy, hydroxy, acyl or acyloxy groups.
Suitable groups represented by X may be selected from oxygen or sulfur.
Suitable groups represented by Ar may be selected from substituted or unsubstituted groups selected from divalent phenylene, naphthylene, pyrrol, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like. The substituents on the group represented by Ar amy may be selected from linear or branched optionally halogenated (C 1 -Cs)alkyl, optionally halogenated
(C
1
-C
3 )alkoxy, halogen, acyl, amino, acylamino, thio or carboxylic or sulfonic acids and their derivatives. The substituents are defined as they are for R'-R 4 It is more preferred that Ar represent substituted or unsubstituted divalent, phenylene, naphthylene, benzofuryl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl groups.
Suitable groups represented by R 5 may be selected from hydrogen, hydroxy,
(C
1
-C
6 alkyl groups such as methyl, ethyl, propyl and the like; (C 1
-C
3 )alkoxy group WO 03/033481 PCT/IB02/04275 19 such as methoxy, ethoxy, propoxy and the like; halogen atom such as fluorine, chlorine, bromine or iodine; aralkyl such as benzyl, phenethyl and the like, which may be unsubstituted or substituted or R 5 together with R 6 represents a bond. The substituents are selected from halogen, hydroxy or alkyl groups.
Suitable R 6 may be hydrogen, hydroxy, (C 1
-C
6 )alkyl groups such as methyl, ethyl, propyl and the like; (C 1
-C
3 )alkoxy such as methoxy, ethoxy, propoxy and the like; halogen atom such as fluorine, chlorine, bromine or iodine; (C 2 -Co 1 )acyl group such as acetyl, propanoyl, butanoyl, pentanoyl, benzoyl and the like; aralkyl such as benzyl, phenethyl and the like, which may be unsubstituted or substituted or R 6 together with R s forms a bond. The substituents are selected from halogen, hydroxy or alkyl groups.
Suitable groups represented by R 7 may be selected from hydrogen, linear or branched (C 1
-C
16 )alkyl, preferably (C 1
-C
12 )alkyl group such as methyl, ethyl, npropyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like, the alkyl group may be substituted; (C 3
-C
7 )cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl group such as benzyl, phenethyl and the like, wherein the alkyl moiety may contain (Ci-C6) atoms, wherein the aryl moiety may be substituted; heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl and the'like, the heteroaryl group may be substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may be substituted; linear or branched (C 2
-C
16 )acyl group such as acetyl, propanoyl, butanoyl, benzoyl, octanoyl, decanoyl and the like, which may be substituted; (C 1
-C
6 )alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl and the like, the alkoxycarbonyl group may be substituted; aryloxycarbonyl such as phenoxycarbonyl, naphthyloxycarbonyl and the like, the aryl group may be substituted; (C 1
-C
6 )alkylaminocarbonyl, the alkyl group may be substituted; arylaminocarbonyl such as PhNHCO, naphthylaminocarbonyl and the like, the aryl moiety may be substituted. The substituents may be selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, WO 03/033481 PCT/IB02/04275 cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives or sulfonic acid or its derivatives. The substituents are as defined above.
Suitable groups represented by R8 may be selected from hydrogen, linear or branched (CI-C 16 )alkyl, preferably (C 1
-C
12 )alkyl group such as methyl, ethyl, npropyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like, the alkyl group may be substituted; (C 3 -Cy)cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl and the like, the heteroaryl group may be substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted;.
aralkyl group such as benzyl, phenethyl and the like, the aralkyl group may be substituted; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may be substituted. The substituents on R may be selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, aiylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives. The substituents are as defined above.
Sutiable groups represented by R may be seleted from hydrogen, linear or branched (C-C 1 6 )alkyl, preferably (C 1 -Clz)alkyl group, such as methyl, ethyl, npropyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, heptyl, octyl and the like;hydroxy(CI-C)alkyl; aryl group such as phenyl, naphthyl and the like; aralkyl group such as benzyl, phenethyl the like; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like; heteroaryl group such as pyridyl, thienyl, pyrrolyl, furyl and the like; heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like. The substituents may be selected from hydroxy, halogen, nitro, amino, alkyl, alkoxy or aryl.
WO 03/033481 PCT/IB02/04275 21 Suitable chiral amines represented by NR may be selected from ethyiphenylamine, naphthylethylamine, phenylglycinol, cinchonidine, ephedrine, N-octylglucaramine, N-methylglucaraminc and the like; chiral amine alcohols such as phenyl glycinol, valine, tert-leucine and the like.
Suitable ring structures formed by R8 and R 9 together may be selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like.
Sutiable groups represented by Ro 10 and R 1 may be selcted from hydrogen, or substituted or unsubstituted linear or branched (C 1
-C
12 )alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, to heptyl, octyl, nonyl, decyl and the like; (C-C 6 )alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl such as benzyl, phenethyl, C 6
H
5
CH
2
CH
2
CH
2 naphthylmethyl and the like.
The substituents may be selected from hydroxy, halogen, nitro or amino.
Suitable groups represented by R 12 may be selected from hydrogen or substituted or unsubstituted linear or branched (C 1
-C
12 )alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl group such as benzyl, phenethyl
C
6
H
5
CH
2
CH
2
CH
2 naphthylmethyl and the like.the substituents may be selected from hydroxy, halogen, nitro or amino.
Suitable n is an integer ranging from 0 to 6.
Suitable m is an integer ranging from 0 to 6.
Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts 'of organic bases such as N,N'-diacetylethylenediaminle, betaine, caffeine, 2diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine,
N-
ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, glycinol, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, adamentyl amine, diethanolamine, meglumine, ethylenediamine, WO 03/033481 WO 03/33481PCT/lB02104275 22 N,N'-diphenylethylenediamine, N,N'-dibenzylethyleflediamifle, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclohexylamine, metforinin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiarme, aminopyrimidine, aminopyridine, purile, spermidine, and the like; chiral bases like alkyiphenylamine, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, inethionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchiorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinatts, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
Particularly useful compounds according to the present invention includes: Ethyl 3-14- {3 -(3,4-dihydro-2H-benzo ibill ,4]oxazin-4-yl)propylanfoI phenyl]-2-ethoxypropafloate Ethyl 34[4- {3-(3,4-dihydro-2H-benzo~b]Ll ,4]oxazin-4-yl)propylamiio} phenyl]-2-ethoxypropanoate; ()Ethyl 3-L4- ,4-dihydro-2H-benzojb][1 ,4]oxazin-4-yl)ptopylaflmo} phenyl]-2-ethoxypropano ate; ,4-Dihydro-2H-belzo[b][1,4]oxazin-4-yl)propylamiflphenyl]- 2 ethoxypropanoic acid or its salts ,4-Dihydro-2H-benzoll] [1 ,4]oxazin-4-yl)propylamfino}phenyl]- 2 ethoxypropanoic acid or its salts; 3- {3-(3,4-Dihydro-2H-benzotbl [1 ,4]oxazin-4-yl)propylaminolphel]- 2 ethoxypropanoic acid or its salts WO 03/033481 WO 03/33481PCT/lB02104275 23 Ethyl 3-[4-N-heptyl-N- {2-(3-oxo-3,4-dihydro-2H-benzo[b] [1 .4]oxazin-4yl)ethylamino }pheny1l-2-ethoxypropafloate; Ethyl 3 [4-N-heptyl-N- -oxo-3,4-dihydro-2H-belzo[b] 1,4] oxazin-4yl)ethylamino lphnyl-2-ethoxypropanoate Ethyl 3-4Nhpy--{-3-xo34dhdo2-ez b 1,41oxazin-4yl)ethylaminophel12-ethoxypropaloate; W± 3-[4-N-Heptyl-N- {2-(3-oxo-3,4-dihydro-2H-benzoIbl[1 ,4]oxazin-4yl)ethylaminophenyl]-2-ethoxypropaloic acid or its salts H+ 3-[4-N-Heptyl-N- {2-(3-oxo-3 ,4-dihydro-2H-benzolblil,4]oxazifl-4yl)ethylaminophenyl]-2-ethoxypropaloic acid or its salts; 3-[4-N-Heptyl-N- {2-(3-oxo-3 ,4-dihydro-211-benzo[b] [1 ,4]oxazin-4yl)ethylamiopheyl]-2-thoxypropaloic acid or its salts; (Methyl 2-ethoxy-3-44- Nhpy--2(,-iyr-2-ez~~xzn4y)2 oxoethyl)aminomethylPhellpropafloate (Methyl 2-ethoxy-3-[4- Nhpy--2(,4dhdo2-eio~~xzn4y)2 oxoethiyl)aminomethylphelyl]propafoate Methyl 2-ethoxy-3-[4- Nhpy--2(,-iyr-2-ez~lxzn4y)2 oxoethyl)aminomethiyl}pheliylpropanoate; M± 2-Ethoxy-3-[4- {N-heptyl-N-(2-(3 ,4-dihydro-2H-benzo[b]oxazifl4-yl)- 2 oxoethyl)aminomethylphelyl]propaloic acid or its salts 2-Ethoxy-3-II4-{N-hepty1-N-(2-(3 ,4-dihydro-2H-beflzo[b1oxazif4yi)-2 oxoethyl)aminomethyl lpeljpropanoic acid or its salts; ()2-Ethoxy-3 Nhpy--2(,-iyr-2-ez~~xzn4y)2 oxoethyl)aminonethyll phelyl]ptopafloic acid or its salts; ()Methyl 3 {5-(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)-5-oXOpeltylafifno} phenyl]-2-ethoxypropaloate WO 03/033481 WO 03/33481PCT/lB02104275 24 Methyl 34[4- ,4-dihydro-2H-bflzolbl [1 ,4]oxazin-4-yl)-5-oxopentylaflilo} phenyl]-2-ethoxypropanoate Methyl 3 ,4-dihydro-2H-benzo~b] [1 ,4]oxazin-4-yl)-5-oxopentylani- "o pheny11-2-ethoxypropanoate; ,4-Dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)-5-oxopeltylamilo} phenyl- 2-ethoxypropanoic acid or its salts ,4-Dihydro-2H-belzo[b]Iil,4]oxazin-4-yl)-5-oxopentYlaifno} phenyl]- 2-ethoxypropanoic acid or its salts 34[4- ,4-Dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)-5-oxopentylamilo} phenyl]- 2-ethoxypropanoic acid or its salts Methyl 3 ,4-dihydro-2H-benzo [1 ,4]oxazini-4-yl)propylamilo} phenyll-2-ethoxypropafloate Methyl 3 ,4-dihydro-2H-benzo[b]Iil,4]oxazin-4-yl)propylanoI phenyl]-2-ethoxypropalo ate Methyl 3 ,4-dihydfo-211-benzo[b] [1 ,4]oxazin-4-yl)popylamilo} phenyl]- 2-ethoxypropanoate 3-L3 {3 ,4-Dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propylamilphell- 2 ethoxypropanoic acid or its salts;- 3-[3-f{3 ,4-Dihydro-21--beuzo [I ,4]oxazin-4-yl)propylamilplhenfl]- 2 ethoxypropanoic acid or its salts {3-(3,4-Dihydo-2H-beilzoI~b][l ,4]oxazin-4-yl)propylamfilo phefllL 2 ethoxypropanoic acid or its salts; Methyl {3-(7-fluoro-3 ,4-dihydro-2H-benzo~b [1,4]oxazin-4-yl) propylaminophenyl]-2-ethoxypropafloate; H+ Methyl {3-(7-fluoro-3 ,4-dilhydro-21{-benzollbl[1 ,4]oxazin-4-yl) propylaminolphenyl]-2ethoxypropanoate; WO 03/033481 WO 03/33481PCT/lB02104275 Methyl {3-(7-fluoro-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propylarninolphenyl-2-ethoxypropafloate; W± 3-114- {3 (7-Fluoro-3,4-dihydro-2{-bezo1 i,4]oxazin-4-yl)propylamiloI phenyl]-2-ethoxypropaloic acid or its salts N+ {3-(7-Fluoro-3,4-dihydro-2H-benzo[b]1 ,4]oxazini-4-yl)piopylam-iilo phenyl] -2-ethoxypropaloic acid or its salts; 3-L4- {3-(7-Fluoro-3,4-dihydro-2H-benzo~b]1i,4]oxazin-4-yl)propylamiloI phenyl]-2-ethoxypropaloic acid or its salts; W± Methyl 2-ethoxy-3-f4-{4-(3-(3,4-dihydro-2Hbelzo[b]1 l,4]oxazin-4yl)propyloxy)benzyll amninophenyl]propanoate; Methyl 2-ethoxy-3-[4- {4-(3-(3,4-dihydro-2H-benzo~bIL1,4]ox5.zif-4yl)propyloxy)benzyl} aminophenyl]propanoate Methyl 2-ethoxy-3-[4- ,4-dihydro-2H-benzolbl[1 ,4]oxazin-4yl)propyloxy)belzyl} aminophenyilpropalo ate Methyl 2-ethoxy-3 ,4-dihydro-2H-benzo[bl 1,41oxazin-4yl)propyloxy)belzyll aminophenyllpropaloate; Methyl 2-ethoxy-3-13- ,4-dihydro-2H-belzo b] 1,4loxazin-4yl)propyloxy)benzyl} aminoplienyllpropafloate; Methyl 2-ethoxy-3 f{4-(3-(3,4-dihydro-2H-belzo[b] 1,4]oxazin-4yl)propyloxy)bfll aminoplienyl]proparioate; 2-Ethoxy-3 {4-(3-(3,4-dihydro-2H-belzo~b1 Li,4]oxazin-4-yl)prOpyloxy) benzyll aminophelyl]popalic acid or its salts; 2-Ethoxy-3 ,4-dihydro-2H-benzo~lJ1 [1 ,4]oxazin-4-yl)propyloxy) benzyl) aminophenylipropanoic acid or its salts; 2-Ethoxy-3 {4-(3-(3,4-dihydro-2H-bflzo~b1 [1 ,4]oxazin-4-yl)propyloxy) benzyl) aminophenyljpropaloic acid or its salts WO 03/033481 WO 03/33481PCT/lB02104275 26 2-Ethoxy-3-[3- {4-(3-(3,4-dihydrO-2H-bflZOIh] [1 ,4]oxazin-4-yl)propyloxy) benzyl} aminophenyllpropanoic acid or its salts; 2-Ethoxy-3-[3- -(3,4-dihydro-2H-benzolbl 1,4joxazin-4-yl)propyloxy) benzyl} aminophenyl]propanoic acid or its salts 2-Ethoxy-3-13- ,4-dihydro-211-benzo[b][l1;4loxazin-4-yl)propylOXy) benzyl aninophenyljpropanoic acid Or its salts; W± Ethyl 2-ethoxy-3-[4- {3-(3,4-dihydro-2H-belzo~b][1,4]thiaZifl-4 yl)propylaminolphenyl]propaloate; 0o Ethyl 2-ethoxy-3-[4-{3 ,4-dihiydro-2H-benzo [hI[1,4lthiazin-4yl)propylamino) phenyl]PrOPaflOate EthylI 2-ethoxy-3 ,4-dihydro-211-benzoibj [1 ,4]thiazin-4yl)propylamino phelYl]POPalOate; 2-Ethoxy-3 {3-(3,4-dihydro-2H--benzO 1,4]thiazin-4yl)propylamino, phellJTOPalOiC acid or its salts; 2-Ethoxy-3-[4- ,4-dihydro-2H-benzO[b] [I ,4]thiazin-4yl)propylaminopheflyl]prOPalOiC acid or its salts; 2-Ethoxy-3-14- ,4-dihydro-2H-benzO[bI[l ,4]thiazin-4yl)propylamino) phellPrOPalOic acid or its salts; Ethyl 2-ethoxy-3-[4- 2-(3 ,4-dihydro-211-benzohbllll,4]oxazin-4-yl) ethylaminolphenylprOpalOate; Ethyl 2-ethoxy-3 ,4-dihydro-ZH-benzO~b] [1,4]oxazin-4-yl) ethylaminolphenyllprlpalOate; Ethyl 2-ethoxy-3-[4- 2-(3,4-dihydro-2H-belZO[bI 1,4lloxazin-4-yl) ethylaminolphenyl]POPalOate; M± 2-Ethoxy-3-[4- ,4-dihydro,-2H-bnZOI~bI [1 ,4loxazin-4-yl)ethylamino} phenyl]propanoic acid or its salts WO 03/033481 WO 03/33481PCT/lB02104275 27 2-Ethoxy-3-L4- f{2-(3 ,4-dihydio-2H-benzo[bl 1,4lloxazin-4-yl)ethylamino} phenyllpropanoic acid or its salts; 2-Ethoxy-3-[4-{2-(3 ,4-dihydro-2H-belzo~bi[l ,4]oxazin-4-yl)ethylamilo} phenyl]propanoic acid or its salts; ()Methyl 2-ethoxy-3 -1444-{2-(3 ,4-dihydro-2H-benzo~b] [1 ,4]oxazin-4-yl)ethoxy} phenylaminometlllpelyl]propaloate; Methyl 2-ethoxy-3 -[4-[4-{2-(3,4-diydro-2H-beflzoIb1 [1 ,4]oxazin-4-yl)ethoxy} phe-nylaminiomethyllpieylpropafloate Methyl 2-ethoxy-3-444- ,4-dihydro-2H-benzo[bl III,4]oxazini-4-yl)ethoxy} phenylanhinomethyl]phelylpropalo ate 2-Ethoxy-3-4-14- ,4-dih-ydro-2H-ielzo[bII1 ,4]oxazi-n-4-yl)ethoxyI phenylarniinomethyl]phelyl]propafoic acid or its salts 2-Ethoxy-3-14-14- ,4-dihydro-21-belzo[b]i[l,4]oxazin-4-yl)ethoxy} phenylaminomethyllpheyl]Propaloic acid or its salts 2-Ethoxy-3-14-[4- {2-(3,4-dihydro-2H-benzoI1l,4]oxazin-4-yl)ethoxy} phenylaminomethyllpheYl]PTopaloic acid or its salts; Ethyl -(7-fluioro-3,4-dihydro-2H-belzoLb][l ,4]oxazini-4-yl) p~opylamiriolphenyl-2ethoxy1propanoate Ethyl {3-(7-fluoro-3 ,4-dihydro-2H-benzol~bl [l,4]oxazin-4-yl) propylaminolphenyll-2ethoxypropa-noate Ethyl 34[4- {3-(7-fluoro-3 ,4-dihydro-211-benzo[bl[l ,4]oxazin-4-yl) propylariniolphenyl-2ethoxypropanoate Ethyl 34[4- {3 -(7-tli-oro-3 ,4-dihydro-2H-belzo~b] 1,4]oxazin-4-yl) propylamino }phenyl]-2-metoxypropafloate N+ Ethyl 34[4- {3-(7-fluoro-3,4-dihydro-2H-belzo[b] [I ,4]oxazin-4-yl) propylamiophenyll-2metloxyp12opanoate WO 03/033481 WO 03/33481PCT/lB02104275 Ethyl 3 -(7-fluoro-3 ,4-dihyd-ro-211-benzo[b][1 ,4]oxazin-4-yl) propylaminolphenyl]-2-ethoxypropaloate W± {3-(7-Fluoro-3,4-dihydro-2H-belzoIbl Li ,4]oxazin-4-yl)propylamino}l phenyll-2-rnethoxypopaloic acid or its salts {3 -(7-Fluoro-3 ,4-dihydro-2H-benzo [bi Li ,4]oxazin-4-yl)propylamino} phenyl]-2-methoxypropaloic acid or its salts {3 -(7-FlUOrO-3 ,4-dihydro-2H-benzolbl[1 ,4]oxazin-4-yl)propylamino} phenyl]-2-rnethoxypropaloic acid or its salts Ethyl {3-(2-methyl-7-fluoro-3 ,4-dih-ydro-2H-benzo[bI[1 ,4]oxazin-4-yl) prol~ylaminolphenyl]-2-ethoxypropanoate Ethyl {3-(2-rnethyl-7-fluoro-3 ,4-dihydro-2H-beflzo[b][1,4]oxazin-4-yl) propylaminolpenylI-2-ethoxypropaloate Ethyl 3-[4-{3-(2-methyl-7-fluoro-3 ,4-dihydro-2H-benzo[b][l ,4loxazin-4-yi) propylaminolphenyl]-2-ethoxypropaloate W± {3-(2-methyl-7-Fluoro-3,4-dihydro-2Hbezo[b[1 ,4joxazin-4yl)propylamino} phenyll-2-ethoxypropaloic acid or its salts 3 {3-(2-methyl-7-Fluoro-3 ,4-dihydro-2H-belzo[b] [1 ,4]oxazin-4yl)propylarnino} phenyl]-2-ethoxypropaloic acid or its salts 3 {3 -(2-methyl-7-Fluoro-3 ,4-dihydro-2H-benzo[b [1 ,4]oxazin-4yl)propylamiiio} phanyl]-2-ethoxypropaloic acid or its salts Ethyl 3 13-(2-methyl-3 ,4-dihydro-2H-beflzo[bl[l ,4]oxazini-4-yl) propylaminopheiyl]2ethOXYPTopafloate Ethyl {3-(2-methyl-3 ,4-dihydro-2H-benzoLb] [1 ,4]oxazin-4-yl) propylaminolphenyl-2-ethoxypropanoate Ethyl 3-4- 3-2mty-,-iyr-Hbnob ,4]oxaz-in-4-yl) propylaminolpheyllY2-thoxypropan~oate WO 03/033481 WO 03/33481PCT/lB02104275 29 W± 3-[14- f 3-(2-methyl-3 ,4-dihydro-2H-benzo[b][l ,4]oxazin-4-yl)propylainoIfO plienyl]-2-ethoxypropanoic acid or its salts 3-[4-f 3-(2-methyl-3 ,4-dihydro-2H-benzo[bI[l,4]oxazin-4-yl)propylamilo} phenyl]-2-ethoxypropaloic acid or its salts 34[4- {3 (2-methyl-3,4-dihydro-2H-belzoIb][l ,4]oxazin-4-yl)propylaniinoI phenyl]-2-ethoxypropaloic acid or its salts M± Ethyl 3 -(2-methyl-3,4-dihydro-2H1-belzorb] [1 ,4]oxazin-4-yl) propylaminolphenyl2-nethoxypropaloate Ethyl -(2-methyl-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propylaminophenyl]-2-methoxypropafloate Ethyl {3-(2-methyl-3 ,4-dihydro-2H-benzo [hi Ii,4]oxazin-4-yl) propylaminolphenyl]-2methoxypropaloate {3 -(2-rnethyl-3 ,4-dihyLdro-2H1-benzo[bl [I,4]oxazin-4yl)propylaminolphelyl]-2-methoxypropafloic acid or its salts H+ 3-114- {3-(2-methy-3,4-dihydro-2H-bezoIb]1[1 ,43oxazin-4yl)propylaminophel-2-methoxypropanoic acid or its salts 344- {3-(2-methyl-3,4-dihydro-2H-bflzo[b] [1 ,4]oxazin-4yl)propylaminophenyl]2-methoxypro1)anoic acid or its salts MEthyl 3-14-f -rpl-,-iydo2-enob ,4]oxazin-4-yl) propylaninopenyl]-2-ethoxypropanoate H+ Ethyl {3-(2-propyl- 3 ,4-dihydro-2H-benzollbl[1 ,4]oxazin- 4 -yl) propylaminolphenyl]-2ethoxypropanoate Ethyl 3-[4-{3-(2-propyl- 3 ,4-dihydro -2H-benzo[b]11,4]oxazin-4-yi) propylamino-jphenyl-2-ethoxypropanoate M3-[4- {3-(2-propy1-3,4-dihydro-2H-elzo~b1[1 ,4]oxazin-4-yl)propylamilfl phenyl]-2-ethoxypropaloic acid or its salts WO 03/033481 WO 03/33481PCT/lB02104275 3-[4-{3-(2-propyl-3 ,4-dihydro-2H-benzo~b] [1 ,4]oxazin-4-yl)propylainoIO phenyl]-2-ethoxypropaoic acid or its salts 34[4- {3-(2-propyl-3 ,4-dihydro-2H-benzoI~b][l,4]oxazin-4-yl)propylalioI phenyl1-2-ethoxypropaloic acid or its salts Ethyl f{3-(2-propyl-3,4-dihydro-2-bezo1b]Il,4]oxazin-4-yl) propylaminolphenyl]p2fethoxypropanoate Ethyl {3-(2-propyl-3,4-dihiydro-2H-belzo[bI [1 ,4]oxazin-4-yl) propylaminophenyl]2-1nethoxypTopanoate Ethyl (2S)-3 f3 -(2-propyl-3 ,4-dihydro-2H-beflzo[b] [1 ,4]oxazin-4-yl) propylaniinolphenyl1-2-metioxypropanoate W± 34[4-{3 -(2-propyl- 3 ,4-dihydro-2H-benzoIb[Il,4]oxazin-4-yl)propylamfiloI phenyl-2-methoxypropaloic acid and its salts 3 -(2-propyl-3,4-dihydro-2H-benzo[b][ i ,4]oxazin-4-yl)propylamlil pheniy11-2-methoxypropaloiC acid and its salts {3-(2-propy1-3,4-dihydro-2H-belzo[b[Il,4]oxazin-4-yl)propylamio} phenyl]-2-methoxypropaloic acid and its salts Ethyl 2-isopropoxy-3-[ 4 3 -(7-fluoro-3 ,4-dihydro-2H-belzoIbII1 ,4]oxazin- 4 -yl) propyiaminolphenyl] propanoate Ethyl 2-isopropoxy- 3 -1 4 {3-(7-fluoro-3 ,4-dihydro-2H-bezoI~bl 1,4]oxazin-4-yl) propylaminoipheflyl] propanoate Ethyl 2-isopropoXy- 3 -1 4 {3 -(7-fluoro-3 ,4-dihydo-2H-beizoI~b] [1 ,4]oxazin-4-yl) propylamino~phenyl] propanoate 2-Isopropoxy- 3 -14- {3 (7-f-iuoro-3,4-dihydro-2l-bezo~b]1,4]oxazin-4-yl) propylaminolphnylpropaloic acid and its salts M+ 2-Isopropoxy- 3 -1 4 {3 (7-fluoro-3,4-dihydro-2H-belzo[b [1 ,4]oxa.ii--4-yl) propylaminolphenllpropanoic acid and its- salts WO 03/033481 WO 03/33481PCT/lB02104275 31 2-Isopfopoxy- 3 -(7-fluaoro3,4-dihydfo-2I-belzo[b][1 ,4]oxazin-4-yl) propylaminolphenYlPropaloic acid and its salts Ethyl 3 -(2-mnethyl-7-fluoro-3 ,4-dihydro-2H-benzo[bI[1 ,4loxazin- 4 -yl) propylaminolphenyl]-2-methoxypropanoate Ethyl {3-(2-methyl-7-fluoro- 3 ,4-dihydro-2H-belzoIbl [1 ,4]oxazin-4-yl) propylaminolphenyl-2-methoxypropanoate Ethyl {3-(2-metyl-7-fluorO-3 ,4-dihydro-211-benzo[b][1 ,4]oxazin-4-yl) propylamino }phenyl1-2-methoxypropafloate M± -ehl7floo34dhdr-Hbn b[1 ,4]oxazin-4yl)propylaniflo Iphelnyl 2-methoxypropanoic acid and its salts 3 {3-(2-methy1-7-fluoro-3 ,4-dihydro-2H-belzO [bI [1 ,4joxazin-4yl)propylarninolphelylP-2lethoxypropanoic acid and its salts {3-(2-methyl-7-fluoro-3 ,4-dihydro-2H--beflzo[b][l ,4]oxazini- 4 yl)propylamiflpheflyl-2-methoxypropanoic acid and its salts [2S,'N(lR)]-N-(2-hydroxy-1 -phenylethyl)-2-ethoxy- 3 [i 3 ,4-dihydro-2Hbenzollb][1 4 ]oxazin-4-y1)propylamtifolphelUpropanamide; [2R,N(1R)-N-(2-iydoxy-1-phenylethyl)-2-efioxy- 3 4 -{3-(3,4-dihydto-2Hbenzolb] [1 4 ]oxazin-4-yl)ptOpYlamlifl}phenylIIpropanamide; 2S,N(1R)-N-(2-hydToxy- -pheniyletliyl)-2-Cthoxy- 3 4 (7-fluoro-3,4-dihydro-2Hbeiizo[b] 1, 4 loxazin-4-yl)propylamiil}phe1ylHpropanamide II2R,N(1R)1-N-(2-hydroxy-l-plienylethyl)-2-ethoxy- 3 -(7-fluoro-3 ,4-dihydro-Hbenzollb][1 4 ]oxazin-4-yl)propylamiflphefllpropanamide [2SN(IR)]-N-(2-hydroxy-l phenylethyl)-2-ethoxy- 3 -4{3 -(3,4-dihydro-2Hbenzo[b][l 4 ]oxazin-4-yl)propylamilphefllpropanamide hydrochloride salt; WO 03/033481 WO 03/33481PCT/lB02104275 32 [2R,N(1,R)II-N-(2-hydroXY-1 -phenylethyl)-2-ethoxy-3-[4-{3 -(3,4-dihydro-2Hbenzo[b] [1 ,4]oxazin-4-yl)propylamnino}phel1]propafamide hydrochloride salt; According to another embodiment of the present invention, the compound of general formula where Wi and R6 together represent a bond; Y represent oxygen or sulfur and W represents NR" 2 -O-aryl-(CR 1 0 R' 1 )O4NR] 2 and all other symbols are as defined above may be prepared by one or more of processes shown in Scheme- I below.
Rr;1 X/ R H R HW-(CRlOR11)mAr R YR 8 (Il1b) OR' L'(RR YR 8 (11id) OR~ 1 oate 3
R
1 -(CRR 1
-CHO
H R4 (Ille) R 8 0 2 C jP(O)(0R 13 2 OR 7 (uhlf) Scheme I Route The reaction of a compound of the general fonnula (111a) where Ll is a leaving group such as halogen atom, inethanesulfoniate, trifluoromethanesulfoflate, ptoluenesulfonate, p-nitrobenznensufolate, acetate, slfate, phosphate, hydroxy and the like, and all other symbols are as defined above with compound of formula (11Th) where W represents INR'1 2 -0-aryl-(CR 1 0 R' 1 )O)NR 1 2 and all other symbols are as defined above to yield compound of general formula where all symbols are as defined above may be carried out in the presence of a base such as metal carbonates like sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate WO 03/033481 PCT/IB02/04275 33 and the like; metal bicarbonates like sodium bicarbonate, potassium bicarbonate, cesium bicarbonate and the like; metal hydrides like NaH or KH; metal hydroxides, like sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide and the like; alkoxides such as NaOMe, NaOEt, K BuO" and the like; organic bases such as guanidine, triethyl amine, pyridine, N-methyl morpholine and the like or mixtures thereof. The reaction may be carried out in the presence of solvents such as THF, dioxane, DMF, DMSO, DME, toluene, benzene, acetone, dimethyl acetamide, acetonitrile and the like or mixtures thereof. Phase transfer catalyst such as tetraalkylammonium halides or hydroxides may be employed. The reaction temperature may range from 0 OC to 150 OC, preferably at a temperature in the range of 10 °C to 120 When L1 represents, hydroxy group, the reaction may also be carried out using Mitsunobu conditions using reagents lie DEAD, DIAD and the like.
The compound of formula (IIIa) was obtained by reacting compound of the formula (IVc) R1 R 3 R I (rVe) H R where all symbols are as defined earlier, with a compound of formula (IVd)
L
1
(CR
1 ioRl)n- L1 (IV d) where L 1 and all other symbols are as defined above.
Route The reaction of a compound of general formula (IIIc) where all symbols are as defined above with a compound of general formula (IIId) where L' is a leaving group such as halogen atom, methanesulfonatc, trifluoromethanesulfonate, ptoluenesulfonate, p-nitrobenznensulfonate, acetate, sulfate, phosphate, hydroxy and the like, and all other symbols are as defined above to yield compound of general formula where all symbols are as defined above may be carried out in the presence of a base such as metal carbonates like sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and the like; metal bicarbonates like sodium bicarbonate, potassium bicarbonate, cesium bicarbonate and the like; metal WO 03/033481 PCT/IB02/04275 34 hydrides like NaH or KH; metal hydroxides, like sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide and the like; alkoxides such as NaOMe, NaOEt, K+BuO and the like; organic bases such as guanidine, triethyl amine, pyridine, N-methyl morpholine and the like or mixtures thereof The reaction may be carried out in the presence of solvents such as THF, dioxane, DMF, DMSO, DME, toluene, benzene, acetone, dimethyl acetamide, acetonitrile and the like or mixtures thereof. Phase transfer catalyst such as tetraalkylammonium halides or hydroxides may be employed. The reaction temperature may range from 0 °C to 150 preferably at a temperature in the range of 10 °C to 100 When L' represents, hydroxy group, the reaction may be also be carried out using Mitsunobu conditions using reagents lie DEAD, DIAD and the like.
Route The reaction of a compound of the general formula (IIIe) where all symbols are as defined above with a compound of formula (IIIf) where R 13 represents (Ci-C 6 )alkyl group and all other symbols are as defined earlier to yield compound of general formula where R 5 and R 6 together represent a bond and all other symbols are as defined above may be carried out in the presence of a base such as metal hydride such as NaH or KH; organolithiums such as CH 3 Li, BuLi and the like; alkoxides such as NaOMe, NaOEt, K+BuO- and the like or mixtures thereof. The reaction may be carried out in the presence of solvents such as diethyl ether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide and the like or mixtures thereof.
HMPA may be used as cosolvent. The reaction temperature may range from -78 °C to 50 preferably at a temperature in the range of -10 oC to 30 OC. The reaction is more effective under anhydrous conditions. The compound of general formula (IIIf) may be. prepared according to the procedure described in the literature (Annalen.
Chemie, (1996) 53, 699).
According to another embodiment of the present invention, the compound of the general formula where R 5 represents hydrogen atom, hydroxy, alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group; R 6 represents hydrogen, hydroxy, alkoxy, halogen, alkyl group, acyl, substituted or unsubstituted aralkyl; Y represents oxygen and W represents NR 12 -O-aryl-(CR'OR )o-NR 12 and all other WO 03/033481 PCT/IB02/04275 symbols are as defined above may be prepared by one or more of processes shown in Scheme-II below.
R
1 R/ o r -(CRORll)-W-(CR1R1)n-- Ar YR R^^'\XR4
OR
7 H (IVa) Route 4
R
1 X/ R5 0 C 1 C10R)1-W-(CR 10Rn11--Ar YR i
I
R
4
OR
Route 5
(I)
1 R 3 R2 (CR10R11)nW_(CRioR )m _Ar-L 2 Rs CO2R 8 (,Vb) R2 4
OR
7 H R (Ille) Scheme I Route The reduction of compound of the formula (IVa) which represents a compound of formula where R 5 and R 6 represent a bond and Y represents oxygen atom and all other symbols are as defined earlier, obtained as described earlier in Scheme-I, to yield a compound of the general formula where R 5 and R 6 each o1 represent hydrogen atom and all symbols are as defined earlier, may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts may be used. The reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate, methanol, ethanol, isopropanol and the like. A pressure between atmospheric pressure and 80 psi may be employed. High pressures may be used to reduce the reaction time. The catalyst may be preferably 5-10 Pd/C and the amount of catalyst used may range from 1-50 w/w. The reaction may also be carried out.by employing metal solvent reduction such as magnesium, samarium in alcohol or sodium amalgam in alcohol, preferably methanol. The hydrogenation may be carried out in the presence of metal catalysts containing chiral ligands to obtain a compound of formula in optically active form. The metal catalyst may contain Rhodium, Ruthenium, Indium and the like. The chiral ligands may preferably be chiral WO 03/033481 PCT/IB02/04275 36 phosphines such as (2S,3S)-bis(diphenylphosphino)butane, 1,2bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane, )-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butane and the like.
Any suitable chiral catalyst may be employed which would give required optical purity of the product Route The reaction of a compound of the general formula (IIIe) where L' is a leaving group such as halogen atom, methanesulfonate, trifluoromethanesulfonate, ptoluenesulfonate, p-nitrobenznensulfonate, acetate, sulfate, phosphate, hydroxy and the like, and all other symbols are as defined above with a compound of formula (IVb) where R 5 represents hydrogen and all other symbols are as defined earlier to yield compound of general formula where R 5 and R 6 represent a hydrogen atom and all other symbols are as defined above may be carried out in the presence of a base such as metal hydride such as NaH or KH; organolithiums such as CH 3 Li, LiN(iPr) 2 LiHMDS, LiN(Et) 2 NaHMDS, KHMDS, BuLi and the like; alkoxides such as NaOMe, NaOEt, t-BuO'K and the like or mixtures thereof. The reaction may be carried out in the presence of solvents such as diefhyl ether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide and the like or mixtures thereof. HMPA may be used as cosolvent. The reaction temperature may range from -78 "C to 50 oC, preferably at a temperature in the range of -10 °C to 30 oC. The reaction is more effective under anhydrous conditions According to another embodiment of the present invention, the compound of the general formula where Y represents oxygen or sulfur and W represents C(=O)-(CRoR 1 1 2 where o is an integer ranging from 0-6 and all other symbols are as defined above may be prepared by a process which comprises reacting the compound of formula (IIIg) 1
R
3 R X (CRo r" T T -(CR R C (CR 11 R (l|g) WO 03/033481 PCT/IB02/04275 37 where L 1 is a leaving group such as halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenznensulfonate, acetate, sulfate, phosphate, hydroxy and the like, and all other symbols are as defined above with compound of formula (IIIb)
R
5 6 HW-(CRiR 1 Ar R Y (Il1b)
OR
7 where W represents NR 1 2
R
1 2 represents hydrogen and all other symbols are as defined above in the presence of a base such as metal carbonates like sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and the like; metal bicarbonates like sodium bicarbonate, potassium bicarbonate, cesium bicarbonate and the like; metal hydrides like NaH or KHi; metal hydroxides, like sodium hydroxide, potassium hydroxide, calcium hydroxide and the like; alkoxides such as NaOMe, NaOEt, K BuO and the like; organic bases such as guanidine, triethyl amine, pyridine, N-methyl morpholine and the like or mixtures thereof The reaction may be carried out in the presence of solvents such as THF, dioxane, DMF, DMSO, DME, toluene, benzene, acetone, dimethyl acetamide, acetonitrile and the like or mixtures thereof. Phase transfer catalyst such as tetraalkylammonium halides or hydroxides may be employed. The reaction temperature may range from 0 °C to 150 OC, preferably at a temperature in the range of 10 °C to 120 OC. When L 1 represents, hydroxy group, the reaction may be also be carried out using Mitsunobu conditions using reagents lie DEAD, DIAD and the like.
According to yet another embodiment of the present invention, the compound of the general formula where Y represents oxygen and W represents -O-aryl- (CR'IR")o-NR2-; and all other symbols are as defined above may be prepared by a process which comprises reacting the compound of formula (IIIi)
R
1 xR3 11 X\10011 -CR1oR1l-G 1 (Illi) WO 03/033481 PCT/IB02/04275 38 where n and p are integers ranging from 0-6, G 1 represents NH 2 or formyl and all other symbols are as defined above with compound of formula (IIIh)
R
5
O
G -(CR0 R)q- ArYR 8 (h)
OR
7 where q is an integer ranging from 0-6, G 2 represent NH 2 or formyl and all other symbols are as defined above using solvents such as CH 2
CI
2 CHC13, chlorobenzene, benzene, THF, in the presence of catalyst such as p-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF 3 -OEt 2 and the like. The reaction may also be carried out using activated molecular sieves. The temperature of the reaction may range from 10 OC to 100 oC, preferably at a temperature in the range from 10 °C to The imine product initially produce may be reducing using Na(CN)BH 3 -HCI (ref: Hutchins, R. O. et al. J. Org. Chem. 1983, vol. 48, 3433-3428), H2-Pd/C, H 2 -Pt/C, H2-Ph/C and the like in solvents such as methanol, ethanol and the like.
The compound of formula where R 8 represents hydrogen atom may be prepared by hydrolysing, using conventional methods, a compound of formula (I) where R 8 represents all groups defined earlier excluding hydrogen. The hydrolysis may be carried out in the presence of a base such as Na 2
CO
3 and a suitable solvent such as methanol, ethanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 20 'C 40 preferably at 25 oC The reaction time may range from 2 to 12 h, preferably from 4 to 8 h.
The compound of general formula where Y represents oxygen and R 8 represents hydrogen or lower alkyl group may be converted to compound of formula where Y represents NR 9 by reaction with appropriate amines of the formula
NHRR
9 where R 8 and R 9 are as defined earlier to yield a compound of formula (I) where Y represents NR 9 and all other symbols are as defined earlier. Alternatively, the compound of formula where YR 8 represents OH may be converted to. acid halide, preferably YR 8 Cl, by reacting with appropriate reagents such as oxalyl chloride, thionyl chloride and the like, followed by treatment with amines of the formula NHRsR 9 where R 8 and R 9 are as defined earlier. Alternatively, mixed anhydrides may be prepared from compound of formula where YR 8 represents 00 39 OH and all other symbols are as defined earlier by treating with acid halides such acetyl chloride, acetyl bromide, pivaloyl chloride, dichlorobenzoyl chloride and the 00 like. The reaction may be carried out in the presence of suitable base such as pyridine, triethylamine, diisopropyl ethylamine and the like. Solvents such as 0 5 halogenated hydrocarbons like CHC13 or CH 2
CI
2 hydrocarbons such as benzene, 00 C,1 toluene, xylene and the like may be used. The reaction may be carried out at a Stemperature in the range of -40 C to 40 OC, preferably at a temperature in the range Sof 0 OC to 20 OC. The acid halide or mixed anhydride thus prepared may further be Streated with appropriate amines of the formula NHR 8
R
9 where R 8 and R 9 are as to defined earlier to yield a compound of formula where Y represents NR 9 and all other symbols are as defined earlier.
In still another embodiment of the present invention the novel intermediate of formula (IIIb)
R
5 6 0 HW-(CRloR 1 YR8
OR
7 their tautomeric forms, their stereoisomers, their salts, their solvates wherein W represents NR 1 2
R
1 2 represents hydrogen, R' 1 and R 1 may be same or different and represent hydrogen or substituted or unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl group; Ar represents substituted or unsubstituted divalent single or fused aromatic or heterocyclic group; R s represents hydrogen atom, hydroxy, alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group or forms a bond together with the adjacent group R6; R 6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, substituted or unsubstituted aralkyl or R 6 forms a bond together with R; R 7 may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R 8 may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NR 3 where R 3 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, WO 03/033481 PCT/IB02/04275 hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, or heteroaralkyl groups; R 8 and R 13 together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; m and n are integers 0-6 is provided.
The novel intermediate of formula (IIIb) where m is 0 and all other symbols are as defined above may be prepared by reducing the compound of formula (IIIj)
O
0 2 N-ArO C 2
R
8 (111j)
OR
7 where R 7
R
8 and Ar are as defined above in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts may be used. The reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst may be preferably 5-10 Pd/C and the amount of catalyst used may range from 1-50 w/w. The reaction may also be carried out by employing metal solvent reduction such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol. The hydrogenation may be carried out in the presence of metal catalysts containing chiral ligands to obtain a compound of formula in optically active form. The metal catalyst may contain Rhodium, Ruthenium, Indium and the like. The chiral ligands may preferably be chiral phosphines such as (2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2methoxyphenylphenylphosphino)ethane, (-)-2,3-isopropylidene-2,3-dihydroxy-l,4bis(diphenylphosphino) butane and the like. (Ref: Principles of Asymmetric Synthesis, Tet. Org. Chem. Series Vol 14, pp 3 1 1 -316, Ed. Baldwin J. The compound of formula (IIIj) may be prepared by reacting the compound of formula (11Hm) 0 2 N-Ar-CHO (Ilm) where Ar is as defined above with compound of formula (IlIf) WO 03/033481 PCT/IB02/04275 41
R
8 0 2 C P()(OR13) 2 (|llf)
OR
7 where R 1 3 represents (Ci-C 6 )alkyl group and all other symbols are as defined earlier in the presence of a base such as metal hydride such as NaH or KH; organolithiums such as CH 3 Li, BuLi and the like; alkoxides such as NaOMe, NaOEt, t-BuOK and the like or mixtures thereof. The reaction may be carried out in the presence of solvents such as diethyl ether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide and the like or mixtures thereof HMPA may be used as cosolvcnt. The reaction temperature may range from -78 OC to 50 OC, preferably at a temperature in the range of -10 °C to 30 oC. The reaction is more effective under anhydrous conditions. The compound of general formula (III b) may be prepared according to the procedure described in the literature (Annalen. Chemie, (1996) 53, 699).
In yet another embodiment of the present invention, the compound of formula (IIIb) where m is 0 and all other symbols are as defined above may be prepared by diazotizing the compound of formula (IIIk) to a compound of formula (III1) and reducing the compound of formula (III1) to yield compound of formula (IIIb). The reaction shown in scheme-III below:
R
5 60
R
5 12N--(CR1R11) Ar-8 0 2 N-(CRR)m Ar- YR N-(CR R Ar YR
NH
2
(III)
(I1lk) R O
WH-(CR
0
R
11 )m-Ar R-R
OR
7 (IIIb) Scheme-III The diazotiaziaon of the compound of the formula (IIIk) to obtain compound of formula (III1) may be carried out using diazotizing agent such as sodium nitrite, WO 03/033481 PCT/IB02/04275 42 isoamyl nitrite, potassium nitrite, ammonium nitrite and the like under acidic conditions using acids such as sulfuric acid, HC1, acetic acid and the like, in an organic solvent such as alcohols such as methanol, ethanol, propanol and the like; 1,4-dioxane, THF, acetone and the like. Etherifying the resiude using alkyl sulfates such as diethyl sulphate, dimethylsulphate and the like or alkyl halides such as ethyl iodide, methyliodide and the like, in the presence of solvents such as hydrocarbons like toluene, benzene and the like or DMF, DMSO, acetonitrile, THF, methyl isobutyl ketone (MIBK) and the like, in alkali bases such as sodium carbonate, potassium carbonate, sodium methoxide, sodium hydride, potassium hydride and the like.
The reduction of compound of the formula (III1) to yield a compound of the general formula (IIIb) may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts may be used. The reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst may be preferably 5-10 Pd/C and the amount of catalyst used may range from 1-50 w/w. The reaction may also be carried out by employing metal solvent reduction such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol. The hydrogenation may be carried out in the presence of metal catalysts containing chiral ligands to obtain a compound of formula in optically active form. The metal catalyst may contain Rhodium, Ruthenium, Indium and the like. The chiral ligands may preferably be chiral phosphines such as (2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenyl phenylphosphino)ethane, (-)-2,3-isopropylidcnc-2,3-dihydroxy-1,4bis(diphenylphosphino) butane and the like. (Ref Principles of Asymmetric Synthesis, Tet. Org. Chem. Series Vol 14, pp 3 1 1 -316, Ed. Baldwin J. In yet another embodiment of the present invention, the compound of formula (IIIb) where m is 1-6, and all other symbols are as defined above may be prepared by following the process described in scheme-IV below WO 03/033481 PCT/IB02/04275 43 R0 2 C- P(O)(OR 1 2
R
7 0 (CRIR" -Ar-CHO OR7 (f R 7 0 (Illn) CHO-(CRiR 1 1 )mTAr CO 2 R'R 7--(CRoR1 1 Ar~ CO 2
R
8 1 O 7 R I 7 O R
OR
(Ip) (lllo) (lllq)
R
5
HW-(CR
1 0 R")m -Ar YR8
OR
7 (lllb) Scheme-IV The reaction of a compound of the general formula (IIIf) defined above with a compound of formula (IIIn), to yield compound of formula (IIIo) may be carried out in the presence of a base such as metal hydride like NaH or KH; organolithiums such as CH 3 Li, BuLi and the like; alkoxides such as NaOMe, NaOEt, t-BuO-K and the like or mixtures thereof. The reaction may be carried out in the presence of solvents such as diethyl ether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide and the like or mixtures thereof. HMPA may be used as cosolvent. The reaction temperature may range from -78 OC to 50 OC, preferably at a temperature in the range of -10 °C to 30 oC.
The reduction of compound of the formula (IIIo) to yield a compound of the formula (IIIp) may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts may be used. The reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst may be preferably 5-10 Pd/C WO 03/033481 PCT/IB02/04275 44 and the amount of catalyst used may range from 1-50 w/w. The reaction may also be carried out by employing metal solvent reduction such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol. The hydrogenation may be carried out in the presence of metal catalysts containing chiral ligands to obtain a compound of formula in optically active form. The metal catalyst may contain Rhodium, Ruthenium, Indium and the like. The chiral ligands may preferably be chiral phosphines such as (2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2methoxyphenylPhenylphosphino)ethane, (-)-2,3-isopropylidene-2,3-dihydroxy-1,4bis(diphenylphosphino) butane and the like.
The reaction of a compound of general formula (IIIp) with a compound of formula (IIIq) may be carried out using solvents such as CH 2 Cl 2
CHCI
3 chlorobenzene, benzene, THF, in the presence of catalyst such as p-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF 3 -OEt 2 and the like. The reaction may also be carried out using activated molecular sieves. The temperature of the reaction may range from 10 °C to 100 preferably at a temperature in the range from 10 °C to 60 The imine product initially produce may be reducing using Na(CN)BH 3 HCI (ref: Hutchins, R. O. et al. J. Org. Chem. 1983, vol. 48, 3433-3428), H2-Pd/C,
H
2 -Pt/C, H 2 -Ph/C and the like in solvents such as methanol, ethanol and the like.
In yet another embodiment of the present invention, the compound of formula (IIIb) where m is 0 or 1 and all other symbols are as defined above may be prepared by diazotizing the compound of formula (IIIk) to a compound of formula (Va), decomposition of compound of formula (Va) to a compound of formula (III1) in the presence of alcohol such as R7OH and reducing the compound of formula (III1) to yield compound of formula (IIIb). The reaction sequence is shown in scheme-V below: WO 03/033481 PCT/IB02/04275
R
5 6O R 5 0
O
2 N-(CRi'R')-Ar- Y
R
8 2
N-(CR
0
R
1 1 )-Ar YR Y_4 YON R
NH
2
N
(Illk)
N
(Va)
R
5 O
R
5
O
2
N-(CR
10 R")n-Ar- YR 8 Y HW-(CR1 R")n-Ar 5 YR
OR
7
OR
7 (Illb) (1111) Scheme-V The diazotiaziaon of the compound of the formula (IIIk) where m is 0, R 6 is hydrogen and all other symbols are as defined above, to obtain compound of formula (Va) may be carried out using diazotizing agent such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and the like in the presence of catalytic amont of carboxylic acid such as acetic acid, propionic acid and the like, in suitable solvent such as chloroform, chlorobenzene, dichloroethane and the like or a mixture thereof at a temperature in the range of room temperature and reflux temperature of the solvent employed for a period in the range of 0.5 to 16 h.
Decomposing the arylalkyl diazo acetate of the formula (Va) to obtain a compound of formula (IIIl) where R 7 is as defined earlier excluding hydrogen and all other symbols are as defined earlier can be promoted by a suitable catalyst such as Rh(II)acetate, salt/complex of Cu(I) or Rh(II) and the like (Bio. Org. Med. Chem.
Lett., 1996, 2121-2126) in the presence of an alcohol of the formula The reduction of compound of the formula (IIII) to yield a compound of the general formula (IIIb) where all symbols are as defined earlier may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts may be used. The reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst may be preferably 5-10% Pd/C and the amount of catalyst used may range from 1-50% w/w. The reaction may also be carried out by employing metal solvent WO 03/033481 PCT/IB02/04275 46 reduction such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol. The hydrogenation may also be carried out using ammonium formate, cyclohex-l,4-diene type of hydrogen donor under pd/c conditions using solvents such as methanol, ethanol, ethyl acetate and the like.
In yet another embodiment of the present invention, the compound of formula (IIIb) in its enantiomerically pure form, where m is 0, R 5
R
6 H and all other symbols are as defined above may be prepared by following the process described in scheme-VI below:
RRSO
(CROR"
1 )m-Ar YR (CR1R")-Ar YR 8
H
2 N (Vib) HO (Via) 6 0 (CR1OR1)m-Ar R 60 yR8 7
YR
8 (Vic) R o 0 2
N-CR
1 0
R
1 )mAr YR HW(CR V 0 R -l YR 8
R
7 0 Ro 7 0 (VId) (lllb) Scheme-VI The diazotization of the compound of the formula (Via) where all symbols are as defined above to obtain compound of formula (VIb) may be carried out by using diazotizing agent such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and the like under aqueous acidic conditions using acids such as sulfuric acid, HC1, acetic acid and the like, in an organic solvent such as alcohols such as methanol, ethanol, propanol and the like; 1,4-dioxane, THF, acetone and the like.
One pot esterification and etherification of compound of general formula (VIb) to a compound of general formula (Vic) may be carried by initial di deprotonation of (VIb) using a suitable base such as NaH, KH, KOH or like, in a WO 03/033481 PCT/IB02/04275 47 suitable solvent such as toluene, benzene, diethylether, THF, DMF, DME HMPA, and like, followed by treatment with alkyl halide such as ethyl iodide or methyl iodide and like. Other alkylating agents such as Et 3 0 BF4-, Me30+BF 4 dialkylsulfate may also be used. Reaction temperature may vary from 0 oC to 100 oC.
Nitration of the compound of formula (VIc) to a compound of formula (VId) where n is 0 and all other symbols are as defined above, may be carried out using nitrating agents such as fuming nitric acid, N 2 0 5 a mixture of cone. Nitric acid and cone. Sulfuric acid or a mixture of nitric acid and acetic anhydride in the presence of a solvent or under neat condition at a temperature in the range of -10'C to room temperature for a period in the range of 0.5 to 4 h. (Ref: Org. Synth. Col. Vol. I, 396) Reduction of compound of the formula (VId) to a compound of formula (IIIb), may be carried out in the presence of gaseous hydrogen or hydrogen donors such as ammonium formate, cyclohex-1,4-diene and the like and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts may be used in the presence of solvents such as methanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. A pressure between atmospheric pressure and 80 psi may be employed.
The catalyst may be preferably 5-10 Pd/C and the amount of catalyst used may range from 1-50 w/w. Alternatively, the reaction may also be carried out by employing metal solvent reduction such as magnesium, iron, tin, samarium, indium, sodium amalgam in alcohol, or other suitable solvents preferably methanol.
In yet another embodiment of the present invention, the compound of formula (IIIb) in its enantiomerically pure form, where m is 0, R 5
R
6 H and all other symbols are as defined above may be prepared by following the process described in scheme-VII below: WO 03/033481 PCT/IB02/04275 48 R O R 5
R
0 1 R
R
0 2 N-(CRIR)m-Ar- YR8 02N-(CR 1
R
11 )m-Ar YR H2N H HO H (Vila) R(VIRb) O2N--(CRI°R11)-Ari yR8 (Vilc)
R
5 R60R 5
O
O
2
N-(CROR
1 ")m-Ar YR 8 HW-(CRAr YR 8
PR
7 OH
R
7 0 IH (Illb) (Vlld) Scheme VII The diazotization of the compound of formula (VIIa) where all symbols are as defined above to obtain a compound of formula (VIIb) may be carried out using diazotizing agents such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and the like under aqueous acidic conditions using acids such as sulfuric acid, hydrochloric acid, acetic acid and the like, in presence of an optional co solvent like alcohols such as methanol, ethanol, propanol and the like; or ethers such as 1,4-dioxane, THF, and the like; or ketones such as acetone, methyl ethyl ketone and the like.
Esterification of the compound of formula (VIIb) to a compound of formula (VIIc) may be done using an appropriate alcohol of formula Rs-OH where R 8 represents lower alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, tbutyl and the like in presence of suitable catalyst such as, cone. sulfuric acid, dry HC1, BF 3 -OEt 2 and the like. The reaction may be carried out at reflux temperature of the alcohol employed. Alternatively reagents like diazomethane or Et30+BF 4 or Me 3 0+BF 4 and the like may also be used for esterification.
Selective O-alkylation of the compound of formula (VIIc) to the compound of formula (VIId) may be done using alkyl sulfates such as diethyl sulfate, dimethyl sulfate and the like or alkyl halides such as ethyl iodide, methyl iodide, n-propyl WO 03/033481 PCT/IB02/04275 49 iodide, n-propyl bromide, isopropyl iodide and the like, in solvents such as hydrocarbons like toluene, benzene and the like or acetonitrile, tetrahydro furan, dimethyl formamide, dimethyl sulfoxide, and the like, in the presence of molecular sieves and alkali bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium hydride, potassium hydride, sodium or potassium hydroxide and the like. Heavy metal oxides such as Ag2O, PbO, HgO and the like may be of particular use to carry out alkylation when alkyl halides are used as alkylation reagent. Phase transfer catalysts such as tetraalkylammonium hydroxide or tetraalkylammonium halides such as tetrabutylammonium chloride, tetrabutylammonium bromide and the like may also be employed.
Reduction of compound of the formula (VIId) to a compound of formula (IIIb), may be carried out in the presence of gaseous hydrogen or hydrogen donors such as ammonium formate, cyclohex-l,4-diene and the like and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts may be used in the presence of solvents such as methanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. A pressure between atmospheric pressure and 80 psi may be employed.
The catalyst may be preferably 5-10 Pd/C and the amount of catalyst used may range from 1-50 w/w. Alternatively, the reaction may also be carried out by employing metal solvent reduction such as magnesium, iron, tin, samarium, indium, sodium amalgam in alcohol, or other suitable solvents preferably methanol.
In yet another embodiment of the present invention, the compound of formula (IIIb) in its enantiomerically pure form, where m is 0, R s
R
6 H and all other symbols are as defined above may be prepared by following the process described in scheme-VIII below: WO 03/033481 PCT/IB02/04275
S
R6 O R R6O
O
2 N- CROR 1 )m-Ar Y 6 R8 0 2
N-(CROR
1 )m-Ar YR
H
2 N "H HO 'H (Vila) (Vllb)
R
5 R60 R 5 R60
O
2 N-(CR'R)mAr YRs H 2 N-(CRR")m-Ar YR 8 C) H H (Villa)
R
5 O R 8
O
Bn2N-(CRioR")m-Ar R YR 8 Bn 2
N-(CR
10 RI)m-Ar R OH HO H HO H (Villb) (VIllc) R -O R 5 6O Bn 2
N(CR
1 R R R R 8 SBn2N-(CR 1 R")m-Ar YR 8 -HW-(CRlR )m-Ar YR
R
7 d H Rd /H (Vllld) (Illb) Scheme VIf The diazotization of the compound of formula (VIIa) where all symbols are as defined above to obtain a compound of formula (VIIb) may be carried out using diazotizing agents such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and the like under aqueous acidic conditions using acids such as sulfuric acid, hydrochloric acid, acetic acid and the like, in presence of an optional co solvent like alcohols such as methanol, ethanol, propanol and the like; or ethers such as 1,4-dioxane, THF, and the like; or ketones such as acetone, methyl ethyl ketone and the like.
Esterification of the compound of formula (VIlb) to a compound of formula (VIIc) may be done using an appropriate alcohol of formula R-OH where R 8 represents lower alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, tbutyl and the like in presence of suitable catalyst such as, cone. sulfuric acid, dry HC1, BF 3 -OEt 2 and the like. The reaction may be carried out at reflux temperature of the alcohol employed. Alternatively reagents like diazomethane or Et 3 0+BF 4 or Me 3 0 BF 4 and the like may also be used for esterification.
WO 03/033481 PCT/IB02/04275 51 Reduction of compound of the formula (VIIc) to a compound of formula (VIIIa), may be carried out in the presence of gaseous hydrogen or hydrogen donors such as ammonium formate, cyclohex-1,4-diene and the like and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixture of catalysts may be used in the presence of solvents such as methanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. A pressure between atmospheric pressure to 80 psi may be employed.
The catalyst may be preferably 5-10 Pd/C and the amount of catalyst used may range from 1-50 w/w. Alternatively, the reaction may also be carried out by employing metal solvent reduction such as magnesium, iron, tin, samarium, indium, sodium amalgam in alcohol, or other suitable solvents preferably methanol.
N,N-dibenzylation of the compound of formula (VIIIa) to the compound of formula (VIIIb) may be done using benzyl halides such as benzyl bromide, benzyl chloride and the like in solvents such as hydrocarbons like toluene, benzene and the like or acetonitrile, tetrahydro furan, dimethyl formamide, dimethyl sulfoxide, and the like, in the presence of alkali bases such as sodium carbonate, potassium carbonate, sodium or potassium hydroxide and the like. Phase transfer catalysts such as tetraalkylammonium hydroxide or tetraalkylammonium halides such as tetrabutylammonium chloride, tetrabutylammonium bromide and the like may also be employed. The reaction may be carried out in the range of room temperature to the reflux temperature of the solvent employed.
Hydrolysis of the compound of the formula (VIIIb) to the compound of formula (VIIIc) using aqueous alkali metal bases such as lithium carbonate, sodium carbonate, potassium carbonate or potassium bicarbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide and the like, in suitable co-solvents such as methanol, ethanol, THF and like or mixtures thereof The reaction time may range from 0.5 h to 24 h, preferably 0.5 h to 3-4 h and reaction temperature may range from 0 °C to 80 °C.
One pot esterification and etherification of the compound of the formula (VIIIc) to the compound of formula (VIIId) where R 5
R
6 may be done by treating with bases such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like, in solvents such as hydrocarbons like toluene, benzene and the like, dialkyl ethers such as diethyl ether, 00 52
(N
tetrahydro furan and the like or dimethyl formamide, HMPA followed by treatment _n with alkyl halides such as ethyl iodide, methyl iodide, n-propyl iodide, n-propyl 0 bromide, isopropyl iodide and the like, or alkyl sulfates such as diethyl sulfate, dimethyl sulfate and the like or alkylating agents such as Et 3
O+BF
4 Me 3 0+BF 4 and the like. The reaction time may range from 2 h to 20 h and reaction temperature may 00 Crange from 0 OC to 80 °C.
Debenzylation of the compound of the formula (VIIId) to the compound of Sformula (IIIb) may be carried out in the presence of gaseous hydrogen or hydrogen donors such as ammonium formate, cyclohex-l,4-diene and the like and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixture of catalysts may be used in the presence of solvents such as methanol, ethanol, dioxane, acetic acid, ethyl acetate 'and the like. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst may be preferably 5-10 Pd/C and the amount of catalyst used may range from 1-50 w/w.
The novel intermediate of formula (IIIb) where W represents NR 1 2 and R' 2 represents hydrogen that can be used to prepare the compounds of the present invention and process for preparing the intermediate (IIIb) is described and'claimed in our PCT application entitled "Novel P-phenyl-ao-oxysubstituted propionic derivatives: process for its preparation and their use in the preparation of pharmaceutically important compounds" filed on the same day as this application.
In still another embodiment of the present invention the novel intermediate of formula (IIId) R 6 0
R
s
O
L
1
_(CR
1 R")n-W-(CR 1 0
R
11 Ar
YR
8 (llld)
OR
7 their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates wherein L' is a leaving group such as halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p- 00 O 53 r nitrobenznensulfonate, acetate, sulfate, phosphate or hydroxy; W represents NR 1 C(=O)-(CRoR" o
-NR
12 -O-aryl-(CR'OR' )o-NR2, where R' 2 represents hydrogen or 00 substituted or unsubstituted group selected from alkyl, aryl or aralkyl groups; o is an integer ranging from 0-4; Ro 1 and R" may be same or different and represent hydrangea or unsubstituted or unsubstituted group selected form alkyl, alkoxy, aryl 00 or aralkyl group; Ar represents substituted or unsubstituted divalent single or fused aromatic or heterocyclic group; R s represents hydrogen atom, hydroxy, alkoxy, CM halogen, alkyl, substituted or unsubstituted aralkyl group or forms a bond together O with the adjacent group R 6
R
6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, substituted or unsubstituted aralkyl or R 6 forms a bond together with R 5
R
7 may be hydrogen or substituted or unsubstituted groups selected from alkyl, .cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R 8 may be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NR 9 where R 9 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, or heteroaralkyl groups; R 8 and R 9 together may form a substituted or or 6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; m and n are integers ranging from 0-6 is provided.
.In yet another embodiment of the present invention the novel intermediate of formula (IIIg) 1
R
3 1 -(CRoR" )nC-(CRoR
)-L
1 (llg) H R4 their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates wherein R 2 and R 3
R
4 when attached to the carbon atom, may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, 00 54 formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, 00 heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, 00 alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its 0 derivatives; one or both of R 3 and R 4 may represent oxo or thioxo group when they are attached to carbon atom; R 3 and R 4 when attached to nitrogen atom represent hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives, or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; R' 0 and R" may be same or different and represent hydrogen or substituted or unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl group; L' is a leaving group such as halogen atom, methanesulfonate, trifluorominethanesulfonate, ptoluenesulfonate, p-nitrobenznensulfonate, acetate, sulfate, phosphate or hydroxy; n and o are integer ranging from 0-6 is provided.
In yet another embodiment of the present invention the novel intermediate of formula (IIIi)
NR
3 R2 (CRoR' (lli) H R their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates wherein R 2 and R 3
R
4 when attached to the carbon atom, WO 03/033481 PCT/IB02/04275 may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R 3 and R 4 may represent oxo or thioxo group when they are attached to carbon atom; R 3 and R 4 when attached to nitrogen atom represent hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives, or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; Ro 1 and R 11 may be same or different and represent hydrogen or substituted or unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl group; G 1 is CHO or
NH
2 is provided, n and p are integer ranging from 0-6.
It is appreciated that in any of the above mentioned reactions, any reactive group in the substrate molecule may be protected according to conventional chemical practice. Suitable protecting groups in any of the above mentioned reactions are tertiarybutyl dimethyl silylchloride, methoxymethyl chloride etc, to protect hydroxyl group, N-Boc, N-Cbz, N-Fmoc etc, for protection of amino group, acetal protection for aldehyde, ketal protection for ketone and the like. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
The pharmaceutically acceptable salts are prepared by reacting the compound of formula with 1 to 4 equivalents of a base such as sodium hydroxide, sodium WO 03/033481 PCT/IB02/04275 56 methoxide, sodium hydride, potassium hydroxide, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol, toluene etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guanidine, adamentyl amine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, ptoluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane and the like. Mixtures of solvents may also be used.
The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically the compound of formula where YR 8 represents OH may be converted to a 1:1 mixture of diastereomeric amides by treating with chiral amines, amino acids, amino alcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolyzing the pure diastereomeric amide.
Pharmaceutically acceptable solvates of the compounds of formula (I) forming part of this invention may be prepared by conventional methods such as 00 0D 57
O
dissolving the compound of formula in solvents such as water, methanol, ethanol Sand the like, preferably water and recrystallizing by using different crystallization 00 techniques.
Various polymorphs of a compound of general formula forming part of this invention may be prepared by crystallization of compound of formula under 00 different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various C modes of cooling, ranging from very fast to very slow cooling during 0crystallizations. Polymorphs may also be obtained by heating or melting the C 10 compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
The present invention provides a pharmaceutical composition, containing the compounds of the general formula as defined above, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the .like, useful for the treatment and or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful for the treatment of hyperlipidemia, hyperglycemia, familial hypercholesterolemia, hypertriglyceridemia, lowering of atherogenic lipoproteins, VLDL and LDL. The compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy.
The compounds of general formula are also useful for the treatment prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease, and other cardiovascular disorders. These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, 00 58 retinopathy, arteriosclerosis, xanthoma, inflamation and for the treatment of cancer.
The compounds of the present invention are useful in the treatment and or 00 prophylaxis of the above said diseases in combination concomittant with one or more HMG CoA reductase inhibitors; cholesterol absorption inhibitors; antiobesity drugs; lipoprotein disorder treatment drugs; hypoglycemic agents: insulin; 00 C\I biguanides; sulfonylureas; thiazolidinediones; dual PPARa and y or a mixture Sthereof. The compounds of the present invention in combination with HMG CoA Sreductase inhibitors, cholesterol absorption inhibitors, antiobesity drugs, hypoglycemic agents can be administered together or within such a period to act synergistically.
The present invention also provides a pharmaceutical composition, containing the compounds of the general formula as defined above, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates and one or more HMG CoA reductase inhibitors; cholesterol absorption inhibitors; antiobesity drugs; lipoprotein disorder treatment drugs; hypoglycemic agents: insulin; biguanides; sulfonylureas; thiazolidinediones; dual PPARa and y or a mixture thereof in combination with the usual pharmaceutically employed carriers, diluents and the like.
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from 1 to 20%, preferably 1 to 10% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compound of formula can be combined with a suitable solid or liquid carrier or diluent to form WO 03/033481 PCT/IB02/04275 59 capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like. For parenteral administration, the polymorphic form can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds. Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
For nasal administration, the preparation may contain the polymorphic forms of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes.
Tablets, dragees or capsules having talc and or a carbohydrate carried binder or the like are particularly suitable for any oral application. Preferably, carriers for tablets, dragees or capsules include lactose, corn starch and or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical- tablet production method is exemplified below: Tablet Production Example a) 1) Active ingredient 30 g 2) Lactose 95 g 3) Corn starch 30 g 4) Carboxymethyl cellulose 44 g Magnesium stearate 1 g 200 g for 1000 tablets WO 03/033481 PCT/IB02/04275 The ingredients 1 to 3 are uniformly blended with water and granulated after drying under reduced pressure. The ingredients 4 and 5 are mixed well with the granules and compressed by a tabletting machine to prepare 1000 tablets each containing 30 mg of active ingredient.
a) 1) Active ingredient 30 g 2) Calcium phosphate 90 g 3) Lactose 40 g 4) Corn starch 35 g Polyvinyl pyrrolidone 3.5 g 5) Magnesium stearate 1.5 g 200 g for 1000 tablets The ingredients 1 to 4 are uniformly moistened with an aqueous solution of and granulated after drying under reduced pressure. Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing mg of ingredient 1.
The compound of fonnula as defined above are clinically administered to mammals, including man via either oral, nasal, pulmonary, transdermal or parenteral, rectal, depot, subcutaneous, intravenous, intrauretheral, intramuscular, intranasal, ophthalmic solution or ointment. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or absorption following oral administeration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally. By either route, the dosage is in the range of about 0.01 to about 100 mg/kg body weight of the subject per day or preferably about 0.01 to about 30 mg/kg body weight per day administered singly or as divided dose. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dose.
WO 03/033481 WO 03/33481PCT/lB02104275 61 The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Preparation 1 Ethyl 2-ethoxy-3-(4-auhiflOPhel)propafloate CEt
H
2 NI QOt Step (i) Wittig salt from triethyl 2-ethoxyphosphonoacetate (26.5 g, 1.5 eq, 99.3 mmol) and NaH (50 in oil) (5.3 g, 2 eq, 132.4 mamol) was prepared in THIF (350 ml) at 0 'C.
To this solid 4-nitrobenzaldehyde (10 g, 1 eq, 66.2 mmol) was added in portions at 0 0 C and the resulting solution was stirred at RT for. 16 h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NU 1 CI. The crude contains ethyl 4-nitro-2-ethoxyciflfamate in both Z and E stereoisomers (11 g).
Step (Ri) Ethyl 4-nitro-2-ethoxyciflnamate obtained in step was hydrogenated using Pd (1 112 (60 psi) (11 g) in ethyl acetate (150 ml) at RT and chromatographed using ethyl acetate hexane to yield the title compound as viscous oil (9.41 g, yield 11H NMR (200 MHz, CDCl 3 5:1.16 J=7.0Hz, 311), 1.22 J=7.OHz, 3H1), 2.90 (d, J=6.3Hz, 211), 3.30 (bs, 2H, NH 2 3.35 (in, 111), 3.55 (in, 11H), 3.94 J=6.3Hz, 11H), 4.15 J=7.OHz, 211), 6.62 J=8.3H4z, 2H1), 7.03 J 8.0Hz, 2H).
IR (neat) cm- 1 3 372, 173 8.
Mass m/ t z 238 192 (M 0C 2 11 5 Preparation 2 3-(3,4-Dihydro-2H-belzo bI 11,41 oxazin-4-yl)propyI bromide O$J Br WO 03/033481 WO 03/33481PCT/lB02104275 62 A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (3.0 g, 1 eq, 22.2 mmol), 1,3dibromopropane (22.5 ml, 10 eq, 222 mmcl) and anhydrous sodium carbonate (7.05 g, 3 eq, 66.6 mmol) in dry DMF (200 ml) was heated at'70 'C for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to yield the title compounds as "liquid mass (2.6 g, 47%).
1 H NMR (200 MHz, CDCI 3 5: 2.10 2.30 (in, 211), 3.37 1=4.4Hz, 2H), 3.40 3.56 (in, 4H), 4.25 J=4.3Hz, 211), 6.60 6.90 (mn, aromatics, 411).
Mass m/z 255 (M( 7 9 256 (M( 79 257 (IV(Br 81 258 (M(Br 8 1 Preparation 3 Ethyl 2-ethoxy-3- [4-{N-heptyl-N-(2'-bromoethyl)}aminophenyllpropanoate N C O 2 Et Et Step (i) A mixture of ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (5 g, 1 cq, 21 mmcl) obtained in preparation 1, heptyibromide (18.8 g, 5 eq, 105 mmol), and anhydrous
K
2 C0 3 (14.5 g, 5 eq, 105 mmol), was heated at 70 'C in DMF (100 ml), for 16 h.
The reaction mixture was diluted with ethyl acetate, Washed with water and brine.
The residue was chromatographed using a mixture of ethyl acetate and'hexane as diluent to afford monoheptylated product as thick liquid (3.85 gum, yield 111 NMR (200 MHz, CDCI 3 0.88 (bt, 1=6.3Hz, 3H), 1.05-1.42 (mn, 15H1), 1.42- 1.68 (in, 2H), 2.90 1=6.6Hz, 211), 3.08 3=6.8Hz, 2H), 3.22-2.42 (in, 111), 3.44- 3.64 (in, 111), 3.94 J=6.8Hz, 111), 4.1 J=7.OHz, 2H), 6.55 J=8.3Hz. 2H), 7.04 J=8.3Hz, 211).
IR (neat) em- 1: 3 396, 1747.
Mass m/z 335 290 (M-0C 2
H
5 WO 03/033481 WO 03/33481PCT/lB02104275 63 Step (Ri) The mono heptylated product (3 g, 1 eq, 8.98 nimol) obtained in step was treated with excess dibromoethane (10 eq) in presence of anhydrous K 2 C0 3 (3.72 g, 3 eq, 27 mmol), in DMF (40 ml), and heated at 70 'C for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The residue was chromatographed using a mixture of ethyl acetate and hexanie as diluent to yield ethyl 2-ethoxy-3-[4- {N-heptyl-N-(2'-bromoethyl)} aminophenyl]propanoate as thick liquid (1.98 g, yield 'H NMR (200 MHz, CDCl 3 5: 0.88 (bt, J=6.3Hz, 3H), 1.05-1.42 (in, 14H), 1.4 2- 1.68 (in, 2H), 2.90 J=6.6Hz, 211), 3.28 J=7.3Hz, 2H), 3.30-3.45 (mn, 311), 3.50- 3.70 (mn, 3H), 3.96 J=6.8Hz, IH), 4.17 J=7.OHz, 211), 6.57 J=8.3H-z, 2H), 7.09 J=8.3Hz, 2H).
IR (neat) cin 1 1747.
Mass in/z 442 (M( 7 9 444 (M(Br 81 Preparation 4 2-(3,4-Dihydro-2H-benzojbI 11,41oxazin-4-y)carboxymethylchloride 3,4-Dihydro-211-benzo[b][,4]oxazine (1.52 g, 1 eq, 11.3 iniol), triethyl amine (4.73 ml, 3 eq, 33.9 nm'ol) and catalytic amount of DMAP was taken in dry DCM ml). To this mixture 2-chloroacetyl chloride (1.8 ml, 2 eq, 22.6 iniol) was added at 0 'C and the reaction mixture was stirred at 0 'C for 4 h. The reaction mixture was diluted with DCM and washed with dil. aqueous HCl, followed by NaHCO 3 and brine. The organic layer was dried over anhydrous Na 2
SO
4 and concentrated on rotavap or. The crude compound was chromatographed using ethyl acetate and hexane to yield the title compounds as waxy solid (1.54 g, yield 1H NMR (200 MHz, CDCI 3 5: 3.98 J=4.4Hz, 2H), 4.25 4.40 (in, 411), 6.90 7.20 (aromatics, 411).
IR (neat) cm-1: 1655.
WO 03/033481 PCT/IB02/04275 64 Mass m/z 212 (M( 35 214 (M(C1 7 Preparation Methyl 3-[4-formylphenyl]-2-ethoxypropanoate
CO
2 Me
O
t: OEt
H
Step (i) Wittig salt from triethyl 2-ethoxyphosphonoacetate (25.6 g, 2.0 eq, 96 mmol) and NaH (3.84 g, 2 eq, 96 mmol) was prepared in THF (240 ml) at 0 oC. To this terepthalaldehyde monodiethylacetal (10 g, 1 eq, 48 mmol) was added dropwise at 0 C. The resulting solution was stirred at RT for 24 h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NH 4 C1. The residue was chromatographed (ethyl acetate and hexane) to obtain ethyl 4'-(diethoxymethyl)-2ethoxycinnamate in both Z and E stereoisomers (13.9 g, 90% yield).
Step (ii) A dry methanolic (20 ml) solution of ethyl 4'-(diethoxymethyl)-2-ethoxycinnamate g, 1 eq, 15.5 mmol), obtained in step was added to dry methanol (60 ml) containing activated magnesium turnings (7.44 g, 20 eq, 310 mmol) and was allowed to stir. Eventually the reaction mixture becomes vigorous requiring reflux condenser.
Once the magnesium gets consumed to yield Mg(OMe) 2 (takes 3-4 it was stirred at RT for 16 h. The reaction mixture was acidified carefully with cone HC1, stirred for 2 h at RT. Finally ethyl acetate was added and the organic layer was thoroughly washed with water and brine and dried over anhydrous Na 2
SO
4 The residue was chromatographed (EtOAc/hexane) to afford the title compound as viscous oil (2.92 g, yield 'H NMR (200 MHz, CDC13) 5: 1.14 J=6.8Hz, 3H), 3.00-3.20 2H), 3.22-3.41 1H), 3.48-3.67 1H), 3.73 3H), 4.06 (dd, J=7.8, 5.4Hz, 1H), 6.40 (d, J=8.3Hz, 2H), 7.81 J=8.3Hz, 2H), 9.99 1H).
IR (neat) cm-: 1751, 1701.
WO 03/033481 WO 03/33481PCT/lB02104275 Mass m/z 237 LM±1].
Preparation 6 Methyl 2-ethoxy-3-[4-(N-heptylamilomety1)phelpropafloate 'CO 2 Me H N I :1 O E t Step (i) Methyl 3 -[4-formylpheanyl]-2-ethoxypropaloate (2 g, 1 eq, 8.51 mmol) obtained in preparation 5, heptylamine (978 mg, 1 eq, 8.51 mmol) and cat. amount of p- TsOH.H 2 0 were taken in DCM (40 ml), along with few pieces of activated io molecular sieves (4 The reaction mixture was filtered through celite after 24 h, at RT and the filtrate was diluted with DCM and was washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate to yield crude methyl 2-ethoxy- 3-4-(N-heptyliminonethyl)phelyl]propanoate Step (ii) The crude methyl 2-etlioxy-3-[4-(N-heptyliminomethyl)phenyl~propaiio ate obtained in step above (2.95 was dissolved in methanol (40 ml), and treated with cone.
HCl (850 iii, 1 eq, 8.51 mmol) and sodium cyanoborohydride (535 mg, 1 eq, 8.51 mmol) at 0 The progress of the reaction was monitored by TLC. After 2-3 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The residue was chromatographed using methanol and chloroform to afford the title compound (1.71 g, yield 60%) as viscous liquid.
1H NMR (200 MHz, CDCl 3 5: 0.86 (bt, J=6.3Hz, 3H1), 1.14 J=6.8Hz, 3H1), 1.20- 1.40 (in, 911), 1.50-1.70 (in, 21-1), 2.60 J=7.4Hz, 2H), 2.98 J=6.3Hz 2H1), 3.22- 3.41 (mn, 111), 3.48-3.67 (mn, 1H), 3.71 3H), 3.89 2H), 4.02 J=6.3Hz, 111), 7.23 J==7.8I1z, 2H), 7.30 J=7.8Hz, 2H).
WO 03/033481 PCT/IB02/04275 66 IR (neat) cm-: 3500 1748.
Mass m/z 336 Preparation 7 Methyl 2-ethoxy-3-(4-aminophenyl)propanoate
'CO
2 Me
H
2 N OEt Ethyl 4-nitro-2-ethoxycinnamate (10 g, 1 eq, 37.7 mmol) obtained in step of preparation 1, was treated with activated magnesium turnings (18 g, 20 eq, 754 mmol) in dry methanol (400 ml). The reaction mixture was refluxed for 2-3 h, and allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and quenched with cold aqueous ammonium chloride. The organic layer was washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound as liquid (6 g, yield 72%).
'H NMR (200 MHz, CDC13) 5: 1.64 J=6.8Hz, 3H), 2.90 J 6.3 Hz, 2H), 3.22 3.42 1H), 3.42 3.65 2H), 3.70 3H), 3.96 J 6.8 Hz, 1H), 6.61 J 8.3 Hz, 2H), 7.00 J 8.3 Hz, 2H).
IR (neat) cm- 3350 1735.
Mass m/z 224 Preparation 8 5-(3,4-Dihydro-2H-benzo [1,4]oxazin-4-yl)-5-oxopentyl bromide Step (i) To a mixture of 5-bromo pentanoic acid (4.63 g, 1 eq, 25.6 mmol) and oxalyl chloride (11.2 ml, 5 eq, 128 mmol) in hexane (5ml), DMF (10 pl) was added and the reaction mixture was heated at 70 °C for 3 h. The excess oxalyl chloride and hexane WO 03/033481 PCT/IB02/04275 67 were removed by distillation and the residue was distilled under high vacuum to yield 5-bromo pentanoyl chloride as light yellow liquid (2.1 g, yield 41%).
Step (ii) To a solution of 3,4-dihydro-2H-benzo[b]oxazine (500 mg, 1 eq, 3.7 mmol), triethylamine (1.54 ml, 3 eq, 11.1 mmol) and catalytic amount of DMAP in dry DCM (20 ml) was added 5-bromo pentanoyl chloride (870 gl, 2 eq, 7.40 mmol) at 0 The reaction mixture was stirred at 0 'C for 4 h and then diluted with excess ethyl acetate. The ethyl acetate layer was washed with dil. HC1, water and then with brine. The residue was chromatographed with ethyl acetate and hexane to yield the title compound liquid (535 mg, yield 53%) as viscous liquid.
'H NMR (200 MHz, CDC13) 6: 1.70 2.00 4H), 2.63 (bt, J 5.9Hz, 2H), 3.39 (t, J=5.8Hz, major rotamer 1.2H), 3.53 J=6.3Hz, minor rotamer 0.8H), 3.94 (t, J=4.4Hz, 211), 4.29 J=4.9Hz, 2H), 6.80 -7.20 (aromatics, 4H).
IR (neat) cm': 2936, 1660.
Mass m/z 298 [M( 79 300 [M(aBBr)+l].
Preparation 9 Methyl 2-ethoxy-3-(3-aminophenyl)propanoate
H
2 N C0 2 Me OEt Step (i) Wittig salt from triethyl 2-ethoxyphosphonoacetate (34.3 ml, 2 eq, 132 mmol) and NaH (50 in oil) (6.28 g, 2 eq, 132 mmol) was prepared in THF (350 ml) at 0 °C.
To this solid 3-nitrobenzaldehyde (10 g, 1 eq, 66 mmol) was added in portions at 0 The resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NH 4 C1. The crude contains ethyl 4-nitro-2-ethoxycinnamate in both Z and E stereoisomers (15 g, yield 86%).
WO 03/033481 PCT/IB02/04275 68 Step (ii) The crude compound (15 g, 1 eq, 56.6 mmol) obtained in step was dissolved in methanol (250 ml). To this ammonium formate (35.6 g, 10 eq, 566 mmol) and 10 Pd/C (40 g) was added and the reaction mixture was stirred at RT for 16 h. The catalyst was filtered and the methanol was condensed on rotavapour. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed to yield methyl 2-ethoxy meta amino cinnamate as and (Z) isomers (10 g, yield Step (iii) Methyl 2-ethoxy meta amino cinnamate (10 g, 1 eq, 42.5 mmol) obtained in step (ii) was treated with magnesium (20.4 g, 20 eq, 850 mmol) and dry methanol (500 ml).
The reaction mixture was refluxed for 2-3 h, and allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and quenched with cold aqueous ammonium chloride. The organic layer was washed with water and brine.
The residue was chromatographed using ethyl acetate and hexane to afford the title compound as viscous liquid (8.06 g, yield 1H NMR (200 MHz, CDC13) 8: 1.15 J=6.8Hz, 31), 2.96 J=6.9Hz, 2H), 3.22 3.42 1H), 3.42 3.65 2H), 3.70 3H), 4.01 J=6.4Hz, 1H), 6.50 6.62 (aromatics, 3H), 7.06 J=7.8Hz, 1H).
IR (neat) cm- 1 3360, 1738.
Mass m/z 224 Preparation 3-(7-Fluoro-3,4-dihydro-2H-benzo [1,4]oxazin-4-yl)propylbromide I N '-NBr WO 03/033481 PCT/IB02/04275 69 Step (i) To a solution of 2-nitro-5-fluorophenol (5 g, 1 eq, 31.6 mmol) and ethyl 2bromoacetate (3.8 ml, 1.1 eq, 34.8 mmol) in dry acetone (160 ml) was added anhydrous potassium carbonate (8.7 g, 2 eq, 63.2 mmol) and stirred at RT for 16 h.
The reaction mixture was filtered through celite and then condensed on rotavapour.
The residue, was diluted with ethyl acetate and washed with water and brine to yield crude compound (6 g, yield which was used in step (ii).
Step (ii) The crude compound obtained in step (6 g, 1 eq, 28.8 mmol) was taken in dry methanol (150 ml). To this iron powder (8.06 g, 5 eq, 144 mmol) and glacial acetic acid (25 ml, 15 eq, 432 mmol) was added and heated at 110 OC for 4 h. The solvents were removed from the reaction mixture and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous ammonium chloride, water and brine. The residue was chromatographed to yield 3-oxo-7-fluoro-3,4-dihydro-2Hbenzo[b][1,4]oxazine as solid (2.2 g, mp 204-206 yield 46%).
'H NMR (200 MHz, CDC13+DMSO-d 6 8: 4.52 2H), 6.60 6.70 2H), 6.88 (dd, J=8.3 and 5.8Hz, 1H), 10.63 (bs, 1H).
IR (KBr) cm-l: 1677, 1622.
Mass m/z 168 Step (iii) 3-Oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (2.2 g, 1 eq, 13.1 mmol) obtained in step (ii) in dry THF (10 ml) was added drop wise to a refluxing THF ml) containing LAH (1.5 g, 3 eq, 39.5 mmol). It was further refluxed for 3 h and quenched with ethyl acetate. To this water (1.5 ml), 15 sodium hydroxide (1.5 ml) and water (4.5 ml) were added sequentially. Once Al(OH) 3
.H
2 0 precipitated out, it was filtered though celite. The filtrate was condensed on rotavapour and chromatographed (ethyl acetate and hexane) to yield 7-fluoro-3,4-dihydro-2Hbenzo[b][1,4]oxazine (1.3 g, yield 65%) as yellow oil.
WO 03/033481 WO 03/33481PCT/lB02104275 1H NMR (200 MHz, CDC1 3 6: 2.80 (bs, 1H), 3.38 J=4.4Hz, 2H1), 4.24 (t, J=4.4Hz, 211), 6.48 6.56 (aromatics, 3H).
IR (neat) cm': 3395 2957, 1606.
Mass m)'Z 154 (M+I1).
Step (iv) A mixture of 7-fluoro-3,4-dihiydro-2H-benzohb][1 ,4]oxaziine (1.3 g, 1 eq, 8.49 mnmol) obtained in step (iii) above, 1,3-dibronio propane (8.6 ml, 10 eq, 84.9 mmol) and anhydrous sodium carbonate (2.7 g, 3 eq, 25.4 mmol) in dry DMF (85 ml) was heated at 70 0 C for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound 1 g, yield 47%) as viscous oil.
'H NMR (200 MHz, CDCI 3 6: 2.10-2.28 (in, 211), 3.30 J=4.4Hz, 2H), 3.38 (t, J=6.7Hz, 211), 3.49 J =6.2Hz, 2H), 4.24 J=4.4Hz, 211), 6.50 6.70 (aromatics, 3H1).
Mass ni/z 274 [M( 7 9 276 Preparation 11 N-{(3,4-Dihyclro-2H-benzo [bi oxazin-4-yl)propyllbenzylamiiie N H Cesium hydroxide monohydrate (28 8 mg, 1. 1 eq, 1.72 mmol), and grinded molecular sieves 4A (500 mg) was stirred at RT in diy DMF (7 ml) for 15 min. To this benzylamine (510 tl, 3 eq,.4.68 nurmol), was added, followed by stirring for another min. Finally 3 ,4-dihydro-2H-benzo [1 ,4]oxazin.-4-yl)propyl bromide- (400 mng, 1 eq, 1.50 mmol) obtained in preparation 2, in DMF (3 ml) was added. After stirring for 16 h at RT, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was condensed and WO 03/033481 PCT/IB02/04275 71 chromatographed using chloroform methanol to obtain the title compound as viscous liquid (307 mg, yield 'H NMR (200 MHz, CDC13) 8: 1.77 J=6.8Hz, 2H), 2.00 (bs, 1H), 2.67 J 7.3Hz, 2H), 3.20 3.28 4H), 3.76 2H), 4.16 J=4.4Hz, 2H), 6.50 6.82 (aromatics, 4H), 7.18 7.38 (aromatics, IR (neat) 3311 2931, 1669.
Mass m/z 283 Preparation 12 Methyl 2-ethoxy-3-{4-(4-hydroxybenzyl)aminophenyl}propanoate
CO
2 Me SN P OEt HO H H00 Methyl 2-ethoxy-3-(4-aminophenyl)propanoate (500 mg, 1 eq, 2.24 mmol) obtained in preparation 7, 4-hydroxybenzaldehyde (273 mg, 1 eq, 2.24 mmol), and catalytic amount of p-TsOH were taken in DCM (5 ml) along with few pieces of molecular sieves The reaction mixture was stirred at RT for 24 h, diluted with excess amount of ethyl acetate and washed with aqueous sodium bicarbonate. The EtOAc layer was dried over anhydrous sodium sulfate and then condensed on rotary evaporator. The crude was dissolved in methanol (10 ml) and treated with Na(CN)BH3 (166 mg, 1.2 eq, 2.64 mmol) in presence of cone. HC1 (220 mL) at 0 °C and stirred for 2 h. The reaction mixture was diluted with excess amount of ethyl acetate, washed with water and brine. The EtOAc layer was dried over anhydrous sodium sulfate and then condensed on rotary evaporator. The residue was chromatographed using EtOAc hexane to obtain the title compound as solid mass (405 mg, yield 55%, mp 109-110 1H NMR (200 MHz, CDC13) 8: 1.17 J=6.9Hz, 311), 2.89 J=6.4 Hz, 2H), 3.22- 3.42 1H), 3.50-3.65 1H), 3.70 (bs, 5H, COzMe, -OH, 3.98 (t, J=6.8Hz, 1H), 4.20 2H), 6.56 J=8.3 Hz, 2H), 6.78 J=8.3 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 7.21 J=8.3 Hz, 2H).
IR (KBr) cm- 1 3369, 1680.
WO 03/033481 PCT/IB02/04275 72 Mass m/z 330 Preparation 13 Methyl 2 -ethoxy-3-{3-(4-hyhroxybenzyl)aminophenyl}propanoate HO
H
S- N CO 2 Me 1 OEt Methyl 2-ethoxy-3-(3-aminophenyl)propanoate (1.0 mg, 1 eq., 4.4 mmol), obtained in preparation 9, 4-hydroxybenzaldehyde (547 mg, 1 eq, 4.4 mmol), and cat. amount of p-TsOH was taken in CH 2 C12 (25 ml) along with few pieces of activated molecular sieves The reaction mixture was stirred at RT for 24 h, which was then diluted with excess amount of ethyl acetate and washed with aqueous sodium bicarbonate. The EtOAc layer was dried over anhydrous sodium sulfate and then condensed on rotary evaporator. The crude was dissolved in MeOH (20 ml), and treated with Na(CN)BH 3 (415 mg, 1.5 eq, 6.6 mmol) in presence of cone. HC1 (528 mL) at 0 After 2 h of stirring, the reaction mixture was again diluted with excess amount of ethyl acetate and washed with water and brine. The EtOAc layer was dried over anhydrous sodium sulfate and then condensed on rotary evaporator. The residue was chromatographed using EtOAc/Hexanes to afford the title compound (450 mg, yield) as viscous liquid.
'H NMR (200 MHz, CDC13) 8: 1.19 J=7.0Hz, 3H), 1.29 1H, 2.96 (d, J=6.3 IIz, 3.30-3.50 1H), 3.50-3.70 1H), 3.73 (bs, 3H), 4.07 (t, J=6.6Hz, 1H), 4.21 2H), 6.50-6.70 3H), 6.81 J=8.3 Hz, 2H), 7.11 J=7.8, 1H), 7.22 J=8.3 Hz, 2H), 7.39 1H, -OH).
IR (neat) cm-: 3391, 1738, 1607.
Mass m/z 330 Preparation 14 3-(3,4-Dihydro-2H-benzo [1,4]thiazin-4-yl)propylbromide.
WO 03/033481 PCT/IB02/04275 73
N
v Br A mixture of 3,4-dihydro-2H-benzo[b][1,4]thiazine (2.0 g, 1.0 eq, 13.24 mmol), 1,3dibromopropane (14 ml, 10 eq, 132.4 mmol) and anhydrous Na 2
CO
3 (4.21 g, 3.0 eq, 39.7 mmol) in dry DMF (130 ml) was heated at 70 °C for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water and brine. The organic layer was dried (Na 2 SO4), condensed, and the residue was chromatographed using ethyl acetate and hexanes to obtain the title compound as yellow oil (2.13g, 59% yield).
1 H NMR (200 MHz, CDC13) 5: 2.11-2.25 2H), 3.02 J=4.4 Hz, 2H), 3.20-3.28 4H), 3.62 J=4.4 Hz, 2H), 6.60-6.72 (aromatics, 2H), 6.90-7.20 (aromatics, 2H).
Mass m/z 271 [M 7 9 272 [M (7Br) 273 [M 271 [M ("Br) Preparation 2-(3,4-Dihydro-2H-benzo [1,4]oxazin-4-yl)ethylbromide
CYO
.Br A mixture of 3,4-dihydro-2H-benzo[b][l,4]oxazine (1.5 g, 1.0 eq, 11.12 mmol), 1,3dibromoethanc (10 ml, 10 eq, 111.2 mmol) and anhydrous K 2 CO3 (4.6 g, 3.0 eq, 33.36 mmol) in dry DMF (110 ml) was heated at 70 oC for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water and brine. The organic layer was dried (Na 2
SO
4 condensed, and the residue was chromatographed using ethyl acetate and hexane to obtain the title compound as yellow oil (940 g, 34%).
iH NMR (200 MHz, CDC13) 5: 3.45 J=4.4 Hz, 2H), 3.50-3.72 4H), 4.24 (t, J=4.4 Hz, 2H), 6.65 J= 7.8 Hz, 2H), 6.78- 6.90 (aromatics, 2H).
WO 03/033481 WO 03/33481PCT/lB02104275 74 Mass m/z 241 LM 242 [M ('9B 243 EM (8 1 Br)1, 244 LM 81 Br) Preparation 16 4.-{2-(3,4-Dihydro-2H-b enzo 11,41 oxazin-4-yl)etlioxyl aniline
NH
2 0 Step (i) A mixture of 2-(3,4-dihydro-2H-benzoibllil,4]oxazin-4-yl)ethyl bromide (500 mg, eq, 2.07 immol) obtained in preparation 15, 4-nitrophenol (288 mg, 1 eq, 2.07 mmiol) and anhydrous K 2 C0 3 (857 mg, 3.0 eq, 6.21 mmol) in dry acetone (12 mul) was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water and brine. The organic layer was dried (Na2SO 4 condensed.
The crude mass was used for the step (ii).
Step (ii) A inethanolic solution (10 ml) of the crude product (600 mg, .1 eq. 2.0 mmol), obtained in step was hydrogenated at RT under atmospheric pressure using ammonium formate (Z.6g, 20 eq., 40 mmol) and 10 Pd/C as catalyst (500 mg).
After 6 h of stirring TLC -indicated absence of starting material. The reaction mixture was filtered through celite and condensed. The residue was cliromnato graphed using ethyl acetate and hexane to obtain the title compound as viscous liquid (355 mg, 66%).
I H NMR (200 MHz, CDCl 3 6: 3.40 (bs, -NH 2 3.51 J=4.4 Hz, 2H), 3.6 5 J= 5.8 Hz, 2H), 4. 10 J=5.6 Hz, 2H), 4.23 J= 4.4 Hz, 2H1), 6.5 0- 6.90 (aromatics, 4H).
Mass m/z 270 271 Preparation 17 3-(2-methyl-7-Fluoro-3,4-dihydro-2H-belzo [bI I1,4]oxazin-4-yl)propylbroflide WO 03/033481 PCT/IB02/04275 F-aO Br Step (i) To a solution of 2-nitro-5-fluorophenol (1.0 g, 1 eq, 6.36 mmol) and ethyl 2bromopropionate (0.91 ml, 1.1 eq, 6.99 mmol) in dry acetone (32 ml) was added anhydrous potassium carbonate (2.63 g, 3 eq, 19.08 mmol) and the reaction mixture was refluxed for 16 h. The reaction mixture was filtered through celite and then condensed on rotavapour. The residue was diluted with ethyl acetate and washed with water and brine to yield ethyl 2-(2-nitro-5-fluorophenoxy)propanoate as crude compound (1.6 g, yield which was used in step (ii).
Step (ii) The crude compound obtained in step (1.6 g, 1 eq, 6.22 mmol) was taken in dry methanol (150 ml). To this iron powder (5.23 g, 15 eq, 93.37 mmol) and glacial acetic acid (5.6 ml, 15 eq, 93.37 mmol) was added and heated at 110 oC for 4 h. The solvents were removed from the reaction mixture and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous ammonium chloride, water and brine.
The residue was chromatographed to yield 2-methyl-3-oxo-7-fluoro-3,4-dihydro-2Hbenzo[b][l,4]oxazine as solid (1.0 g, yield 88 Mp: 166-168 °C 'H NMR (200 MHz, CDC13) 8: 1.59 J 6.9 Hz, 4.67 J 6.9 Hz, 1H), 6.60 6.80 (aromatics, 3H), 8.61 (bs, 1H).
IR (KBr) cm-: 1677, 1610.
Mass m/z 182 Step (iii) 2-Methyl-3-oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.8 g, 1 eq, 26.5 mmol) obtained in step (ii) in dry THF (60 ml) was added drop wise to a refluxing THF (200 ml) containing LAH (6.05 g, 6 eq, 159.1 mmol). It was further refluxed for 3 h and quenched with ethyl acetate, and hydrolyzed with saturated aq. sodium WO 03/033481 PCT/IB02/04275 76 sulfate. Once AI(OH) 3
.H
2 0 precipitated out, it was filtered though celite. The filtrate was condensed on rotavapour and chromatographed (ethyl acetate and hexane) to yield 2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.3 g, yield 97 as yellow oil.The crude product was used for the next reaction.
'H NMR (200 MHz, CDC13) 1.36 J 6.5 Hz, 3H); 3.05 (dd, J 11.3, 8.0 Hz, 1H); 3.32 J 11.8 Hz, 1H); 3.60 (bs, 1H, 4.18-4.30 1H), 6.40 6.60 (aromatics, 3H).
IR (KBr) cm- 1 3387, 2977, 2933, 1605, 1510.
Mass m/z 168 Step (iv) A mixture of 2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.3 g, 1 eq, 25.74 mmol) obtained in step (iii) above, 1,3-dibromo propane (26.1 ml, 10 eq, 257 mmol) and anhydrous sodium carbonate (8.2 g, 3 eq, 77.2 mmol) in dry DMF (260 ml) was heated at 70 oC for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound (3.5 g, yield 48%) as viscous oil.
'H NMR (200 MHz, CDC13) 6: 1.35 J 6.7 Hz, 3H); 2.02-2.22 2H); 3.01 (dd, J= 11.3, 8.3 Hz, 1H); 3.32 (dd, J= 11.6, 2.3 Hz, 1H); 3.22-3.58 4H); 4.18-4.35 1H), 6.42 6.62 (aromatics, 3H).
Mass m/z 288 [M( 79 290 Preparation 18 3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylbromide Br Step (i) Starting from 2-nitrophenol (10 g, 1 eq, 71.9 mmol) and ethyl 2-bromopropionate (10.2 ml, 1.1 eq, 79.09 mmol) the procedure of Step preparation 17 was followed WO 03/033481 WO 03/33481PCT/lB02104275 77 to obtain ethyl 2-(2-nitrophenoxy)propanoate in crude form (16 g) which was used for step (ii).
Step (Ri) The crude compound obtained in step (16 g, 1 eq, 62.2 mmol) was converted to 2methyl-3-oxo-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazine as solid (10.0 g, yield 98 following the procedure of step preparation 17.
Mp: 164-166' 0
C
'H NMR (200 MI-z, CDCl 3 6: 1.59 J =6.7 Hz, 3H); 4.67 J 6.7 H-z, 1H), 6.80 7.00 (aromatics, 4H), 9.45 (bs, lH).
IR (KBr) cm-1: 3500, 3198, 2917, 1675, 1608, 1501.
Mass m/z 164 Step (ift) 2-Methyl-3-oxo-3,4-dihydro-2H--benzo[b][1,4]oxazine (5.0 g, 1 eq, 30.6 mmol) obtained in step (ii) was reduced to 2-methyl-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazine (4.3 g, yield 90 as yellow oil following the procedure of step (iii), preparation 17.
1H NMR (200 MHz, CDC1 3 6: 1.37 J 6.1 Hz, 3H); 3.10 (dd, J1 11.3, 8.1 Hz, 1H); 3.34 J 11.6, 2.5 Hz, 1H); 3.60 (bs, 1H1, 4.18-4.30 (in, 1I), 6.50 6.80 (aromatics, 4H).
IR (KBr) cm-1: 3389, 2977, 2976, 1608, 1503.
Mass m/z 150 Step (iv) From 2-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.5 g, I eq, 30.2 mmol) obtained in step (iii) above, and 1,3-dibromo propane (30 ml, 10 eq, 300 rumol) and following the procedure of step preparation 17 title compound (3.5 g, yield 48%) was obtained as viscous oil.
1H NMR (200 MHz, CDCl 3 5: 1.29 J 6.4 HzT7, 3H); 2.05-2.25 (in, 211); 3.07 (dd, J 11.3, 8.3 Hz, l1H); 3.24 (dd, J 11.6, 2.3 Hz, IH); 3.30-3.58 (in, 4H); 4.18-4.35 (mn, 111), 6.50 6.82 (aromnatics, 4H).
Mass mn/z 270 [M( 7 9 272 [M(s 1 Br)+1].
WO 03/033481 WO 03/33481PCT/lB02104275 78 Preparation 19 3-(2-propyl-3,4-dihydro-2H-benzo[bI 11,4] oxazin-4-yl)propylbromide Br Step (i) Starting from 2-nitrophenol (1.0 g, 1 eq, 7.19 mmol) and ethyl 2-bromopentanoate (2.97 ml, 3.0 eq, 21.54 mmol) the procedure of step preparation 17 was followed to obtain ethyl 2-(2-nitrophenoxy)pentanoate (2.0 g) as crude which was used for step (ii), Step (Hi) The crude compound obtained in step (1.7 g, -1 eq; 6.36 mmol) was converted to 2-propy1-3-oxo-3,4-dihydro-2H-benzo[bIi1,4]oxazine as solid (1.2 g, yield 87 over 2 steps) following the procedure of step preparation 17.
Mp: 172-174 0
C
'H NMVR (200 MI-z, CDCI 3 6: 0.98 J 7.0 Hz, 3H); 1.40-1.70 (in, 211); 1.70- 1.98 (in, 2H); 4.59 J =6.4 Hz, 1H); 6.84-7.00 (aromatics, 4H), 9.00 (bs, 1H).
JR (KBr) cm-1: 3198, 2917, 1677, 1611, 1502.
Mass m/z 192 Step ORi) 2-Propy1-3-oxo-3,4-dihydro-2H-benzoj~b][1,4]oxazile (2.0 g, 1 eq, 10.4 minol) obtained in step (ii) was reduced to 2-propyl-3,4-di.Lhydro-2H-benzo[b][1 ,4]oxazi.ne (1.65 g, yield 90 as crude following the procedure of step (iii), preparation 17 and preceded for the next reaction.
Mass in/z 178 WO 03/033481 PCT/IB02/04275 79 Step (iv) From 2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.65 g, 1 eq, 9.3 mmol) obtained in step (iii) above, and 1,3-dibromo propane (9.4 ml, 10 eq, 93 mmol) and following the procedure of step preparation 17 title compound (915 mg, yield 33 was obtained as viscous oil.
'H NMR (200 MHz, CDC13) 6: 0.97 J 7.0 Hz, 3H); 1.40-1.80 4H); 2.00-2.25 2H); 3.10 (dd, J 11.6, 8.0 Hz, 1H); 3.27 (dd, J 11.6, 2.4 Hz, 1H); 3.35-3.58 4H); 4.00-4.18 1H), 6.50 6.90 (aromatics, 4H).
Mass m/z 298 300 [M( 1 Br)+1].
Preparation (S)-Ethyl 2-ethoxy-3-(4-aminophenyl)propionate COEt H2N IOEt H 2
N
Step (i) To a solution of (S)-(4-nitrophenyl) alanine (10g, 47.6 mmol) in a mixture of water mL), H 2 S0 4 (1M, 60 mL) and acetone (150 mL) at -5 was added under stirring, a solution of sodium nitrite (9.85g, 142.8 mmol) in water (40 mL) drop wise over a period of 30 min. The reaction mixture was stirred at -5 to 0 OC for another h, followed by stirring at room temperature for 16 h. Acetone was removed and then the reaction mixture was diluted with 500 mL ethyl acetate. Organic layer was washed with brine, dried over anhydrous Na 2
SO
4 and concentrated. The crude mass was purified by crystallization from isopropyl acetate (9.0 g, 96 Mp: 134-136°C -250 (c 1.0, MeOH) 'H NMR (CDC1 3 5: 3.04 (dd, J 14, 7.8 Hz, 1H), 3.24 (dd, J 14, 4, Hz, 1H), 4.39 (dd, J 7.3, 4.1 Hz, 1H), 7.42 J 8.7 Hz, 2H), 8.16 J 8.7 Hz, 2H).
IR (neat) cm1: 3485, 3180, 2927, 1715, 1515, 1343.
Mass m/7 212 WO 03/033481 PCT/IB02/04275 Step (ii) (S)-2-Hydroxy-3-(4-nitrophenyl)propionic acid (9.0 g, 42.6 mmol), obtained from step above, was dissolved in dry EtOH (300 mL). To this solution was added cone. H 2 S0 4 (326 mL, 5.9 mmol), and refluxed for 5 to 6 h. The reaction mixture was neutralized with aqueous sodium bicarbonate. Ethanol was condensed on rotavapor, and the residue was dissolved in ethyl acetate. Organic layer was washed with aqueous sodium bicarbonate, water, brine, and then dried over anhydrous Na 2
SO
4 and concentrated. Desired product was obtained from the crude mass by crystallizing from diisopropylether (8.0 g, 78.5 Mp: 74-76 oC.
-13° (c 1.0, MeOH) 'H NMR (CDC13) 8: 1.30 J 7 Hz, 3H), 3.06 (dd, J 14, 7, Hz, 1H), 3.25 (dd, J 14, 4.3, Hz, 1H), 4.25 J 7 Hz, 2H), 4.25 (dd, J 7, 4.3 Hz, 1H), 7.42 J 8.7 Hz, 2H), 8.16 J 8.7 Hz, 2H).
IR (neat) cm' 1 3432, 2924, 1736, 1518, 1347.
Mass m/z 240 Step (iii) To a mixture of (S)-Ethyl 2-Hydroxy-3-(4-nitrophenyl)propionate (4.77g, 19.95 mmol), obtained in step ii above, molecular sieves (4 A) (5.0 g) and powdered Ag 2 0 (13.8g, 59.8 mmol) in dry acetonitrile (100 mL), was added ethyl iodide (6.4 mL, 79.8 mmol) at room temperature. The reaction mixture was heated at 60 °C for 16h.
The reaction mixture was filtered through celite, and concentrated. The crude mass was chromatographed using ethyl acetate and hexanes to obtain the desired product as viscous liquid (3.5g, 67% isolated yield). Unreacted starting material was recovered (900 mg) which could be reused.
-260 (c 1.0, MeOH) 'H NMR (CDC13) 8: 1.15 J 7 Hz, 3H); 1.26 J 7.1 Hz, 3H); 3.10 J 3.8 Hz, 1H); 3.13 1H); 3.16-3.35 1H); 3.45-3.65 1H); 4.03 (dd, J 7.5, 5.4 Hz, 1H); 4.21 J 7.2 Hz, 2H); 7.43 J 8.6 Hz, 21); 8.15 J 8.6 Hz, 2H).
IR (neat) cm- 2980, 1747, 1604, 1521, 1347.
WO 03/033481 PCT/IB02/04275 81 Mass m/z 268 Step (iv) (S)-Ethyl 2-ethoxy-3-(4-nitrophenyl)propionate 25.3 mmol), obtained in step (iii) above, was dissolved in dry methanol (100 mL). To this solution was added Pd/C (2.0 and was hydrogenated using hydrogen gas (20 psi) for 3-4 h. The reaction mixture was filtered through celite, and the filtrate was concentrated to provide a syrupy mass. The product was obtained in quantitative yield.
-14.20 (c 1.0, MeOH).
Chiral HPLC: >98 ee.
'H NMR (CDC1 3 6: 1.16 J 7.0Hz, 3H), 1.22 J 7.0Hz, 3H), 2.90 J 6.3Hz, 2H), 3.30 (bs, 2H, NH 2 3.24-3.42(m, 1H), 3.50-3.70 1H), 3.94 J 6.3Hz, 1H), 4.15 J 7.0Hz, 2H), 6.62 J 8.3Hz, 2H), 7.03 J 8.0Hz, 2H).
IR (neat) 3372, 1738.
Mass m/z 238 192 (M OC 2
H
5 Prreparation 21 (S)-Ethyl 2-methoxy-3-(4-aminophenyl)propionate
CO
2 Et
H
2 N HiOMe 2
N
Step (i) To a mixture of (S)-Ethyl 2-Hydroxy-3-(4-nitrophenyl)propionate (12.5 g, .52.3 mmol), obtained in step (ii) of preparation 20, and powdered Ag2O (36.3 g, 157 mmol) in dry acetonitrile (260 mL) was added methyl iodide (13 mL, 209.2 mmol) at room temperature. Activated molecular sieves (4 A) (12.5 g) were added and then the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered through celite, and concentrated. The crude mass was chromatographed using ethyl acetate and hexanes to obtain the desired product as viscous liquid (10.0 g, [ca]D: -30.10 (c 1.0, MeOH) WO 03/033481 WO 03/33481PCT/lB02104275 1 HNMR (CDC1 3 6: 1.24 J =7.1 Hz, 311); 3.09 J 5.4 Hz, 111); 3.12 J 2.7 Hz, 11H); 3.35 3H); 3.96 (dd, J 7.5, 5.1 Hz, 111); 4.19 J 7.1 Hz, 211); 7.39 J 8.6 Hz, 2H); 8.13 J 8.6 Hz, 2H).
JR (neat) cnf': 2995, 1747, 1604, 1521, 1343.
Mass m/z 254 Step (Hi) (8)-Ethyl 2-rnethoxy-3-(4-nitrophenyl)propionate 31.6 mmol), obtained in step above, was dissolved in dry methanol (200 mL). To this solution was added Pd/C (2.5 and hydrogenated using hydrogen gas (20 psi) for 3-4 li. The reaction mixture was filtered through celite, and concentrated to a syrupy mass. After column chromatography using ethyl acetate hexanes the desired product was isolated as thick liquid (7.0 g, quantitative).
[MD: -14.1' (c 1.0, MeOH).
Chiral HPLC: >98 ee.
'H NMR (CDCl 3 6: 1.23 J =7.2H-z, 3H1), 2.91 J 6.11Hz, 211), 3.30 (bs, 2H1,
NH
2 3.34 3H1), 3.88 J 6.2Hz, 111), 4.17 J 7.21-z, 211), 6.62 j 8.3H1z, 2H1), 7.01 J 8.1Hz, 2H).
JR (neat) cuf': 3372, 2985, 2932, 1739, 1627, 1519.
Mass m/z 223 234 192 (M OMe).
Preparation 22 Ethyl 2-isopropoxy-3-(4-aminophenyl)propioflate
CO
2 Et
H
2
N
WO 03/033481 PCT/IB02/04275 83 Step 4-nitrophenylalanine (5 g, 1 eq, mmol) was added in portions to a solution of dry ethanol (mL) and thionylchloride (mL) at -5 OC. It was stirred at that temperature for another one hour, followed by stirring at RT for 16h. The reaction mixture was condensed on rotavapour, azeotroped with toluene, and then dried over high vaccum pump to obtain 4-nitrophenylalanine ethyl ester hydrochloride as white solid (quantitative yield).
Step (ii): 4-nitrophenylalanine ethyl ester hydrochloride (2 g, 1.0 eq, 7.28 mmol) obtained in step(i) was dissolved in ethyl acetate (150 mL). To that Na 2
CO
3 (386 mg, 0.5 eq, 3.64 mmol) was added and was stirred for 15 min. The reaction mixture was washed with aq. NaHCO 3 The organic layer was dried (Na2SO 4 and condensed to obtain 4nitrophenylalanine ethyl ester as thick oil (1.55 g, 89%).
Step (iii): 4-nitrophenylalanine ethyl ester (1.55 g, 1.0 eq, 6.51 mmol), obtained in step(ii) above was dissolved in chloroform (33 mL). To that glacial acetic acid (20 pL, 0.05 eq, 0.33 mmol), and isoamylnitrite (958 pL, 1.1 eq, 7.16 mmol) were added and the reaction mixture was heated at reflux for 30 min. The reaction mixture was diluted with chloroform, and was washed with aq. NaHCO 3 The organic layer was dried (Na 2
SO
4 and condensed (caution!) to a yellowish liquid.
Step (iv): The liquid (1.54 g, 1.0 eq, 6.18 mmol) thus obtained in step (iii), was dissolved in dry isopropanol (31 mL), and to that catalytic amount of Rh 2 (OAc) 4 .2H 2 0 (38 mg, 0.02 eq, 0.12 mmol) was added and the reaction mixture was stirred at room temperature for 16h. Isopropanol was condensed, and the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, dried (Na 2
SO
4 and concentrated. Column chromatography, using ethyl acetate and hexanes, provided the desired compond ethyl 2-isopropoxy-3-(4nitrophenyl)propionate (1.25 g, 61% overall).
WO 03/033481 WO 03/33481PCT/lB02104275 84 'H NMR (200 MHz, CDC1 3 6: 0.92 J =5.8 Hz, 3H1), 1.16 J =5.8 Hz, 3H), 1.27 J =7.4 Hz, 3H), 3.00-3.10 (in, 211), 3.52 (quintet, 1H); 4.08 (dcl, J =8.7 and 4.8 Hz, 1H), 4.21 J 7.4 Hz, 2H), 7.43 J 8.7 Hz, 2H), 8.16 J 8.7 Hz, 2H).
JR (neat) cm 1 l: 2975, 1747, 1602, 1522, 1347.
Mass m/z 282 [M+11 Step Ethyl 2-isopropoxy-3 -(4-nitropheniyl)propionate (1.52 g, 5.4 inmol) obtained in step was hydrogenated under 10 psi pressure of molecular hydrogen using 10% Pd/C (700 mng) as catalyst in ethyl acetate (200 mL) at room temperature for 3-4 h. The desired product was isolated after filtering the reaction -mixture and concentrating the filterate under reduced pressure. Column chromatography of the crude mass using ethyl acetate and hexanes provided the desired compound ethyl 2-isopropoxy-3-(4aminophenyl)propionate 16 g, 86% overall).
11H NMR (200 MHz, CDCl 3 5: 0.97 J 5.8 Hz, 3H), 1.15 J1 5.8 Hz, 3H), 1.23 J1 7.0 Hz, 3H), 2.80-2.95 (irn, 2H), 3.49 (quintet, 111); 3.98 (dd, J 8.1 and 5.7 Hz, 1H), 4.16 J 7.0 Hz, 2H), 6.61 J 8.3 Hz, 2H), 7.03 J =8.3 Hz, 2H).
IR (neat) cnf 1 3455, 3371, 2975, 2929, 1737, 1626, 1519.
Mass m/z 252 [M+I1] Example 1 Ethyl 3- [4-{3-(3,4-dihydro-2H-beuzo I i1,4loxazin-4-yl)propylamilo} phenyl]-2-ethoxypropaloate
CO
2 Et N QEt
H
Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (2 g, 1 eq, 8.4 minol) obtained in preparation 1, 3 -(3,4-dihydro-2H-benzo[b][1 ,4]oxazin-4-yl)propyl bromide (2.36 g, WO 03/033481 WO 03/33481PCT/lB02104275 1.1 eq, 9.3 mmol), obtained in preparation 2, and anhydrous K 2 C0) 3 (3.5 g, 3 eq, mmcol), were heated at 70 'C in DMF (40 ml) for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The residue was chromnatographed using a mixture of ethyl acetate and hexane as eluent to afford the title compound as a 'iscous liquid (1.04 g, yield 'H NMIR (200 MHz, CDCl 3 1.17 J=7.Oflz, 3H), 1.23 J=7.0Hz, 3H), 1.92 (q, J=7.OHz, 2H), 2.90 J=6.8Hz, 2H), 3.20 J=7.OHz, 2H), 3.22 3.41 (in, 5H), 3.45 3.62 (in, 111), 3.95 J=6.4Hz, 1H1), 4.05 4.37 (in, 4H), 6.65 J=8.3Hz, 2H), 6.61 6.85 (in, 4H), 7.05 J=8.3Tlz, 2H).
JR (neat) cm-13396 1740.
Mass mIz 413 Example 2 3-[4-{3-(3,4-Dihydro-2H-beuzo [hI [1,4loxazin-4-yl)propylaminolphenyll-2ethoxypropanoic acid HN O Et
H
Ethyl 3-114- {3-(3,4-diliydro-2H-benzolb] [1 ,4]oxazin-4-yl)propylaminolphenyl]-2ethoxypropanoate (700 mg, 0.98 mmol) obtained in example 1, was hydrolyzed using lithium hydroxide monohydrate (123 mng, 2.9 mmnol), in methanol-water at RT till all the starting material was consumed (4 to 5 The reaction mixture was diluted with water, acidified with dil. HCl to adjust the pH1 to 4-5 and then extracted with ethyl acetate. The ethyl acetate layer was dried over NazSO 4 and concentrated on rotavapour. The residue was chromatographed using methanol and chloroform. to yield the title compound as viscous liquid (256 mg, yield 68%).
'H NMIR (200 MHz, CDCI 3 8: 1.19 J=7.4Hz, 3H), 1.94 J=7.4Hz, 2H), 2.90 (dd, J=14.0 and 7.0 Hz, 1H), 3.05 (dd, J=14.0 and 4.9Hz, lH), 3.21 J=6.8Hz, 2H), 3.25-3.40 (in, 511), 3.40-3.62 (in, 111), 4.00-4.17 (in, 1H), 4.18-4.22 (in, 2ff), 6.59 (d, J=8.3Hz, 211), 6.65-6.85 (in, 411), 7.06 J=8.3H~z, 211).
IR (neat) cmn 1 :3 500, 1725.
WO 03/033481 WO 03/33481PCT/lB02104275 86 Mass m/z 385 Example 3 3-[4-{3-(3,4-Dihydro-2H-benzolbl [1,4joxazin-4-yl)propylamino}phenyl -2ethoxypropanoic acid arginine salt ~I yC0 2 H NH 2 -f NH H N 1) GEt C0 2 H NH
H
To a solution of 3-194- ,4-diliydro-2H-benzo[b][1 ,4]oxazin-4yl)propylaminolphenyl]-2-ethoxypropanoic acid (200 mng, 1 eq, 0.52 umni) obtained in example 2, in dry methanol: dichioroethane (10 (5 ml), L-arginine (90.5 mng, 1 eq, 0.52 mmol) was added and allowed to stir for 3-4 h. The solvent was removed on rotavapour followed by benzene azeotrope. The residue was dried under high vacuum pump to yield the title compound as a free flowing solid (yield 100%), mp: 92-94 0
C
DSC: endotherm (weak and broad): 66.6 'C XRD: Amorphous.
Example 4 Ethyl 3-[4-N-hepty1-N-{2-(3-oxo-3,4-dihydro-2H-belzo [1,41 oxazin-4yl)ethylamino}phenyl-2-ethoxypropaloate L' 0 N O Et 3-Oxo-3,4-dihydro-2-H-beinzo[b][jl,4]oxazine (1.85 mg, 1.24 mmol), ethyl 2-ethoxy- 3 {N-heptyl-N-(2'-bromoethyl)} aminophenyl]propanoate (500 mg, 1 eq, 1.13 mmol) obtained in preparation 3, and anhydrous K 2 C0 3 (468 mg, 3 eq, 3.39 mrnol), were heated at 70 'C in DMIF (6 ml) for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The fesidue was chromatographed using WO 03/033481 WO 03/33481PCT/lB02104275 87 a mixture of ethyl acetate and hexanes as diluent to afford the title compound as thick liquid (363 mg, yield 63%).
'H1 NMR (200 MHz, CDCl 3 6: 0.88 (bt, 1=6.3Hz, 3H), 1.05-1.42 (in, 14H), 1.42- 1.68 (in, 211), 2.92 J=6. IHz, 2H), 3.25 1=7.3Hz, 2141), 3.30-3.45 (in, 11H), 3.50- 3.70 (mn, 311), 3.97 J=6.6Hz, 111), 4.08 1=7.3Hz, 211), 4.17 1=7.01hz, 2H), 4.57 2H), 6.57 1=8.3Hz, 2H1), 6.99 411), 7. 10 1=8.0Hz, 2H-).
IR (neat) cm- 1 1747.
Mass mj'z 511 Example 3-14-N-Heptyl-N-{2-(3-oxo-3,4-dihydro-211-benzolb] [1,4loxazin-4yl)ethylaminolphenyll-2-ethoxypropanoic acid N
OE
3-[4-N-Heptyl-N- -oxo-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) ethylanifinolphenyl]-2-ethoxypropanoate (350 mg, 1 eq, 0.68 iniol) obtained in example 4, was hydrolyzed using lithium hydroxide monohydrate (86 mg, 3 eq, 2.04 minol) in methanol -water at RT till all the starting material was consumed (4 to hi). The reaction mixture was diluted with water, acidified with dii. HCl to pH 2-3 and then extracted with ethyl acetate. The ethyl acetate layer was dried over Na 2
SO
4 and concentrated on rotavapour. The residue was chromatographed using methanol and chloroform to yield the title compound as a gummy mass (197 ing, yield 1 H NMR (200 MHz, CDCl 3 8: 0.88 (bt, 1=6.3Hz, 3H), 1.05-1.42 (in, 11ff), 1.42- 1.68 (in, 2H1), 2.82-3.10 (in, 211), 3.25 1=7.3Hz, 2H1), 3.40-3.70 (in, 4H), 3.98-4.15 (mn, 311), 4.56 2H), 6.67 1=8.3Hz, 2H1), 6.98 4H1), 7.10 1=8.0Hz, 2H).
JR (neat) cm- 1 3 500 1687.
M ass in/z 483 WO 03/033481 WO 03/33481PCT/lB02104275 88 Example 6 3-t4-N-Heptyl-N-{ZkA3-oxo-3,4-dihydro-2H-benzo I1,4loxaziu-4yl)ethylaminolphenyl]-2-ethoxypropanoic acid arginine salt
NN
3 [4-N-Heptyl-N- -oxo-3 ,4-dihydro-2H1-benzo 1,4] oxazin-4-yl) ethylaniinolphenyl]-2-ethoxypropanoic acid (150 mg, 1 eq, 0.31 mmol) obtained in example 5, and L-arginine (54 mg, I eq, 0.31 mmol) were taken in dry methanol (2 ml), and'stirred at RT for 2-3 h. The solvent was removed on rotavapour followed by benzene azeotrope. The residue was dried under high vacuum pump to yield the title compound as a free flowing solid (yield 100%), mp: 118-120 'C.
Example 7 Methyl 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-belzo [bi oxazin-4-yl)-2oxoethyl)aminomethyllphenyllpropaloate C N
CO
2 Me 0 ~K~N K QEt 2-(3,4-Dihydro-2H-benzojb]oxazin-4-y)carboxymethyI chloride (208 mg, 1 eq, 0.98 mmol) obtained in preparation 4, and methyl 2-ethoxy-3-[4-(Nheptylaminomethyl)phenyl]propanoate (300 mg, 1 eq, 0.89 mmol) obtained in preparation 6, in acetonitrile (5 ml), was treated with anhydrous sodium carbonate (285 mg, 3 eq, 2.68 mmol). The reaction mixture was stirred at 80 'C for 4 h. TLC indicated absence of starting materials. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was WO 03/033481 WO 03/33481PCT/lB02104275 89 chromatographed using ethyl acetate and hexane to afford the title compound (250 mg, yield 55%) as viscous liquid.
'H1 NMR (200 MHz, CDCl 3 6: 0.86 (bt, J=6.3Hz, 311), 1.14 J=6.8Hz, 3H), 1.20- 811), 1.50-1.70 (in, 21H), 2.57 J"7.OHz, 211), 2.99 J=6Hz, 211), 3.22- 4.40 l11H), 3.67 311), 6.80-7.26 (aromatics, 811).
JR (neat) cm- 1 1752, 1683.
Mass m/z 511 Example 8 2-Ethoxy-3- [4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[Ll oxazin-4-yl)-2oxoethyl)aminomethyllphenyllpropanoic acid N
CO
2
H
N QEt Methyl 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-211-benzo[b]oxazinI-4-yl)-2oxoethyl)aminomethyl}phenyllpropano ate (240 mg, 1 eq, 0.47 mmol) obtained in example 7, was hydrolyzed using lithium hydroxide monohydrate (99 mng, 5 eq, 2.35 mmol) in methanol-water at RT (takes 4-5 The reaction mixture was acidified with aqueous HCl and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue'was chromatographed (ethyl acetate and hexane methanol clloroform) to afford the title compound (13 0 mng, yield 5 as viscous liquid.
'H NMIR (200 MHz, CDCI1 3 8: 0.86 (ht, J=6.3Hz, 311), 1.10-1.40 (in, 1111), 1.40- 1.60 (in, 211), 2.79 J=7.5Hz, 211), 2.90-4.22 (in, 1311), 6.80-7.26 (aromnatics, 81-1).
Mass m/z 497 WO 03/033481 WO 03/33481PCT/lB02104275 Example 9 2-Ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo [bloxazin-4-yl)-2oxoethyl)aminomethyllphenyllpropanoic acid arginine salt 0> ~C0 2 H NH 2 NH ~NH 2 N~ OEt N C HNH 2-Ethoxy-3-[4- {N-heptyl-N-(2-(3,4-dihydro-2H-benzo[bjoxazin-4-yl)-2oxoethyl)aminomethyllpheny1propanoic acid (90 mg, 0.18 mmol) obtained in example 8, and L-arginine (32 mg, 0. 18 mmol) were taken in dry methanol (2 ml), and stirred at RT for 2-3 h. The solvent was removed on rotavapour followed by benzene azeotrope. The residue was dried under high vacuum pump to yield the title compound as a free flowing solid (yield 100%), mp: 118-120 'C.
Example Methyl 3-14-15-(3,4-dihydro-2H-benzolb] [1,41 phenyll-2-ethoxypropanoatc N
C
2 Me 0 N Et
H
A solution of methyl 2-ethoxy-3-(4-aminophenyl)propanoate (337 mg, 1 eq, 1.51 mmol) obtained in preparation 7, 5-(3,4-dihydro-2H-benzo[b][l ,4]oxazin-4-yl)-5oxopentyl bromide (450 mg, 1 eq, 1.51 mmol) obtained in preparation 8, in DMF (6 ml) was treated with anhydrous potassium carbonate (627 mg, 3 eq, 4.54 mmol) and the reaction mixture was stirred at 70 'C for 6 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatographed using ethyl acetate and hexane to afford the title compound as a viscous liquid (179 mg, yield 27%).
WO 03/033481 WO 03/33481PCT/lB02104275 91 1 H NMR (200 MHz, CDCl 3 6:1.16 J=7.OHz, 3H), 1.50-1.70 (in, 2H), 1.70-1.90 (in, 2H), 2.64 J=7.OHz, 2H), 2.89 J=6.9Hz, 2H), 3.08 J=6.7Hz, 2H), 3.22- 3.42 (in, 1H), 3.42-3.62 (in, 2H), 3.68 3141), 3.88-4.00 (111, 3H), 4.26 J=4.8, 21), 6.50 J=7.8Hz, 2H, aromatics), 6.82-7.10 (aromatics, 4H), 7.04 J=7.8Hz, 2H, aromatics).
IR (KBr) cm- 1 3408, 1739, 1683.
Mass m/z 441 Example 11 1o 3-[4-{5-(3,4-Dihydro-2H-benzo j1,4]oxazin-4-yl)-5-oxopentylaminoI phenyll 2-ethoxypropanoic acid N C0 2
H
0 N Et
H
Methyl 3 {5-(3,4-dihydro-2H-benzo jb] [1,4]oxazin-4-yl)-S-oxopentylamino phenyl]-2-ethoxypropanoate (211 mg, 1 eq, 0.48 inmol) obtained in example 10, was hydrolyzed using lithium hydioxide monohydrate (60 mg, 3 cq, 1.44 inmol) in methanol water at RT (takes 4-5 hi). The reaction mixture was diluted with water, acidified (pH 3-4) with aqueous HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatographed (ethyl acetate and hexane methanol chlorofonn) to afford the title compound (139 ing, yield as viscous liquid.
'H NMR (200 MHz, CDCl 3 5: 1.14 J=7.OHz, 314), 1.50-1.90 (im, 2H1), 2.62 (t, J=6.8Hz, 2.80-3.15 (mn, 4H), 3.22-3.42 (in, 111), 3.42-3.62 (in, 1H1), 3.82-4.00 (in, 311), 4.25 J=4.9, 214), 6.40-7.30 (hr shoulder, N-H, COzH), 6.55 J=7.8Hz, 2H1, aroinatics), 6,82-7.10 (aromatics, 4H1), 7.04 J=7.gI-Iz, 2H, aromatics).
IR (KBr) cnf 1 3408, 1719, 1680.
Mass m/z 427 WO 03/033481 WO 0/03481PCT/11B02/04275 92 Example 12 3-[4-{5-(3,4-Diliydro-2H-benzo[b] I1,4]oxazin-4-yl)-5-oxopentylamino} phenyll 2-ethoxypropanoic acid arginine salt NC0 2 H NH 2 NH -TNH 2 0 N Et C0 2 H NH
H
,4-Dihydro-2H-benzo[b][1 ,4]oxazin-4-yl)-5-oxopentylaminolphenyl]-2ethoxypropanoic acid (120 mng, 1 eq, 0.28 minol) obtained in example 11, and Larginine (49 mg, 1 eq, 0.28 mmol) were taken in dry methanol (3 ml), and stirred at RT for 2-3 h. The solvent was removed on rotavapour followed by benzene azeotrope. The residue was dried under high vacuum pump to yield the title compound as a free flowing solid (yield 100%), mp: 137-139 TC.
Example 13 Methyl 3-13-{3-(3,4-dihydro-211-beuzotbl li,4]oxazin-4-yl)propylamino} phenyl]- 2-ethioxypropanoate
H
N C 2 Me 0 IC Methyl 2-ethoxy-3-(3-aminophenyl)propaloate (200 mg, 1 eq, 0.89 mmol) obtained in preparation 9, 3-(3 ,4-dihydro-2H-benzojb] [1 ,4]oxazin-4-yl)propylbromide (253 mg, 1.1 eq, 0.98 mmcl) obtained in preparation 2, and anhydrous Na 2
CO
3 (285 mg, 3 eq, 2.68 mmol) were heated at 70 'C in DMF (5 ml), for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound (304 mg, yield 86%) as viscous liquid.
1 H NMR (200 MI-z, CDC1 3 6: 1.17 J=7 Hz, 3H1), 1. 98 J=7 Hz, 2H), 2.92 (d, J'=6.8 Hz, 2H), 3.19 J=~7 Hz, 211), 3.22-3.41 (in, 51H), 3.45-3.62 (in, 111), 3.70 (s, 3H), 4.02 J=6.4 Hz, 111), 4.22 J=4.3 Hz, 211), 6.40-6.82 (mn, aromatics, 6H1), 6.75 J=7.8Hz, 111), 7.08 J=7.8 Hz, 1H1).
WO 03/033481 WO 03/33481PCT/lB02104275 93 IR (neat) cm- 1 3380 1743, 1680.
Mass mn/z 399 Example 14 3-[3-{3-(3,4-Dihydro-2H-henzolbl 11,4loxazin-4-yl)propylaminolpheuyll-2ethoxypropanoic acid 0
H
N N C0 2
H
Et Methyl {3-(3,4-dihydro-2H-benzo jb][Li,4]oxazin-4-yl)propylamino~phenyl]-2ethoxypropanoate (350 mg, 1 eq, 0.87 mmol) obtained in example 13, was hydrolyzed using lithium hydroxide monohydrate (110 mg, 3 eq, 2.64 mrnol), in methanol-water at RT till all the starting material is consumed (4 to 5 hi). The reaction mixture was diluted with water, acidified (pH with dii HCI and then extracted with ethyl acetate. The ethyl acetate layer was dried over anihydrous sodium sulfate and concentrated on rotary evaporator. The residue' was chromalographed using methanol and chloroform to afford the title compound (203 mg, yield 6 as viscous oil.
1H NMR (200 MHz, CDC1 3 8: 1.19 J=7.4Hz, 3H1), 1.94 J=7.411z, 211), 2.85- 3.60 (in, 10H1), 4.00-4.17 (in, 111), 4.23 J=4.4 Hz, 211), 4.95 (bs, NiH, C0 2 6.42- 7.20 (aromatics, 8H-).
JR (neat) cm 4 1 3500 1727.
Mass mn/z 385 Example 3-[3-{3-(3,4-Dihydro-2H-benzo tbI [1,4]oxazin-4-yl)propylamfiflolphelylI-2ethoxypropaloiC acid arginine salt 0
H
N N-N C0 2 H NH 2 y -NHrN H, -O x E Qt C0 2 H NH WO 03/033481 WO 03/33481PCT/lB02104275 94 ,4-Diliydro-2H-benzolb]El,4]oxazin-4-yl)propylaminolphenyl]-2ethoxypropanoic acid (90 mg, 1 eq, 0.23 mmol) obtained in example 14, and Larginine (40.8 mg, 1 eq, 0.23 mmol) were taken in dry methanol (5 ml), and stirred at RT for 2-3 h. The solvent was removed on rotavapour followed by benzene azeotrope. The residue was dried under high vacuum pump to yield the title compound as a free flowing solid (yield 100%), mp: 178-180 'C Example 16 Methyl 3- [4-{3-(7-fluoro-3,4-dihydro-2H-benizo[b] oxazin-4-yl) propylaminolphenyl]-2-ethoxypropanoate Fjl NOj N
CO
2 Me N i OEt
H
Methyl 2-ethoxy-3-(4-aminophenyl)propanoate (405.8 mg, 1 eq, 1.82 mmol) obtained in preparation 7, 3-(7-fluoro-3,4-dihydro-2H-benzo[b][Li,4]oxazin-4yl)propylbromide (500 mg, 1 eq, 1.82 mmol) obtained in preparation 10, and anhydrous Na 2
CO
3 (572 mg, 3 eq, 5.4 mmol), were heated at 70 'C in acetonitrile for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The residue was chromatographed using ethyl- acetate and hexane to afford the title compound (333 mg, yield 44%) as viscous liquid.
1H NMR (200 MiHz, CDCl 3 8: 1.17 J=7 Hz, 3H), 1.88 J=7 Hz, 2H1), 2.91 (d, J=6.8 Hz, 2H), 3.10-3.42 (in, 7H1), 3.45-3.65 (in, 11H), 3.69 311), 3.98 J'=6.3 Hz, 1H), 4.22 .J=3.9 Hz, 2H1), 6.40-6.70 (m1, aromatics, 5H), 7.04 J=8.3 Hz, 2H).
JR (neat) cm- 1 3382 1746, 1616.
Mass nilz CCI): 417 FExample 17 3-[4-{3-(7-Fhioro-3,4-dihydro-2H-benzo [hi [1,4loxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid WO 03/033481 WO 03/33481PCT/lB02104275 N J: ORt
H
Methyl {3-(7-fluoro-3,4-dihydro-2H-benzo[b] [1,4loxazin-4yl)propylaminolphenylJ-2-ethoxypropanoate (180 mng, 1 eq, 0.43 mnmol) obtained in example 1.6, was hydrolyzed using lithium hydroxide monohydrate (55 mg, 3 eq, 1.2 mmol), in methanol-water at RT till all the starting material is consumed (4 to 5 h).
The reaction mixture was diluted with water, acidified (pH with dil. HCI 1.1d then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatographed using ethyl acetate and hexanes methanol and chloroform to afford the title compound (121 mg, yield 70%) as viscous liquid.
'H NMR (200 MHz, CDGI 3 8: 1.19 J=7.4Hz, 3H), 1..94 (quintet, J=7.4Hz, 2H), 2.85-3.10 (mn, 2H), 3.10-3.20 (in, 6H), 3-40-3.70 (in, 2H), 3.90-4.10 (mn, 1H), 4.107 4.30 (in, 2H1), 6.20 (bs, CO 2 6.42-6.70 (in, aromatics, 511), 7.07 J=8.3 Hz, 211).
IR (KBr) cmnf 1 3394, 1725, 1619.
Mass mniz 403 (M-Il).
Example 18 3-14-{3-(7-Fluoro-3,4-dilydro-21-beUzo~b] [1,4J oxazin-4-yl)propylamino} phenylJ-2-ethoxypropanoic acid arginine salt F 0~jj NCOH NH 2 N H..TNH 2 N Ot C0 2 H N H
H
3 {3-(7-Fluoro-3 ,4-dihydro-2H-benzo jb] Ill,4]oxazin-4-yl)propylamino phenyl].- 2-ethoxypropanoic acid (120 mg, 1 eq, 0.298 nurol) obtained in example 17, and Larginine (52 mg, 1 eq, 0.298 minol) were taken in dry methanol (2 ml), and stirred at RT for 2-3 h. The solvent was removed on rotavapour followed by benzene azeotrope. The residue was dried under high vacuum pump to yield the title compound as a free flowing solid (yield 100%), inp: 158-160 OC.
WO 03/033481 WO 03/33481PCT/lB02104275 96 Example 19 Methyl 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo 11,41 oxazin-4yl)propyloxy)benzyl}aminophenyllpropanoate N
CO
2 Me A mixture of methyl 2-ethoxy-3- {4-(4-hydroxybenzyl)aminophenyl}propanoate (600 mg, 1 eq, 1.82 mmol) obtained in preparation 12, 3-(3,4-dihydro-2benzo[b][l,4]oxazin-4-yl)propylbromide (467 mg, 1 eq, 1.82 mmol) obtained in preparation 2, and anhydrous'K 2 C0 3 (75 5 mg, 3 eq, 5.46 mmol) in DMFT (10 ml) was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and was concentrated on rotary evaporator. The residue was chromatograplied using EtOAc hexanes to afford the title compound (520 mg, 56% yield) as thick liquid.
'H NMR (CDCl 3 200 MHz) fr 1. 19 J=7.OHz, 311), 2.00-2.20 (mn, 2H), 2.90 (d, 1.J=6.3 Hz, 211), 3.3 0-3.60 (in, 6H), 3.70 (bs. 3H), 3.80-4. 10 (in, 3H 4.10-4.25 (in, 4H), 6.57 J=8.3 Hz, 2H), 6.60-6.90 (mn, 6H), 7.04 J=8.3 Hz, 2H1), 7.28 (d, J=8.3 Hz, 2H).
IR (neat) cm-' 3401 1742, 1614.
Mass in/z 504 505 [M~l1.
Example Methyl 2-ethoxy-3-13-{4-(3-(3,4-dihydro-2-belzo bI [1,41 oxazin-4yl)propyloxy)benzyl} aminiophenyl] propanoate 0~.
N OEt C 0 WO 03/033481 WO 03/33481PCT/lB02104275 97 The title compound was prepared (340 mg, yield 90%) as viscous liquid from a mixture of methyl 2-ethoxy-3- {3 -(4-hydroxybenzyl)aminophenyllpropanoate (250 mg, 1 eq, 0.75 inmol) obtained in preparation 13, and 3-(3,4-dihydro-2Hbenzo[b][1,4]oxazin-4-yI)propylbromide (192 mng, 1 eq, 0.75 minol) obtained in preparation 2, by following the similar procedure as described for example 19.
'H1 NMR (200 MHz, CDC1 3 8: 1.19 J=7.011z, 311), 1.95-2.18 (in, 211), 2.90 (d, J=6.3 Hz, 211), 3.22-3.60 (in, 611), 3.70 (bs, 311), 3.90-4.10 (in, 4.10-4.25 (mn, 4H), 6.42-6.90 (aromnatics, 811), 7.05 111), 7.20-7.30 aromatics, 311).
JR (neat) cm-1: 3 407 1742, 1607.
Mass in/z 504 505 Example 21 2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b] [1,4loxazin-4-yl)propyloxy) benzyllaminophenylj propanoic acid 0 0 N C0 2
H
N Et
H
Methyl 2-ethoxy-3-[4- -(3,4-dihydro-2H-benzoib] [1 ,4]oxazin-4-yl)propyloxy) benzyl} aminophenyl]propanoate (5 10 ing, 1 eq, 1.0 1 minol) obtained in example 19, was hydrolyzed using lithium hydroxide monohydrate (127 ing, 3 eq, 3.03 minol) in methanol-water at RT till all the starting material was consumed (4 to 5 The reaction mixture was diluted with water, acidified (pH with dil. HCI and then extracted with EtOAc. The residue was chromatographed. using ethyl acetate/ hexanes to yield the title compound as sticky liquid (250 mng, 5 1H1 NMR (200 MHz, CDCI 3 6: 1. 18 J=6.9Hz, 3H), 1.26 J=7.3Hz, 111, N-H), 1.98-2.18S (mn, 211), 2.90 (dd, J14.1, 7.4 Hz, 111), 3.04 (dd,J=14.1, 4.4 Hz, 111), 3.35 J=4.2 Hz, 211), 3.40-3.64 (in, 411), 3.95-4.10 (mn, 311); 4.10-4.25 (in, 4H1), 6.57 (d, J=8.3 Hz, 211), 6.60-6.82 (in, 411), 6.88 J=8.3 Hz, 211), 7.05 J=8.3 Hz, 2H1), 7.28 J=r8.3 Hz, 211).
JR (neat) cm- 3407, 1723, 1610.
WO 03/033481 WO 03/33481PCT/lB02104275 98 Mass m/z 490 491 Example 22 2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H9-benzo [bi [1,4]oxazin-4-yl)propyloxy) benzyllaminophenylJpropanoic acid N C 2
H
N~ OEt The title compound was prepared (220 mg, yield 53%) as viscous liquid from methyl 2-ethoxy-3-j3 ,4-dihydro-2H-benzo ,4]oxazin-4-yl) to propyloxy)benzyllaminophenyl]propanoate (420 mg, 0.83 mmol) obtained in example 20, by following the similar procedure as described for example 2 1.
I H NMR (200 MIz, CDC1 3 8: 1.15 .1=6.9Hz, 3H1), 1.26 J=7.3Hz, 1H1, N-H), 1.98-2.18 (in, 2H1), 2.90 (dd, J=14.1, 7.8 Hz, 111), 3.05 (dd, J1=13.7, 3.9 H-z, 111, 3.30-3.60 (in, 611), 3.70 (bs, 31H), 4.00-4.10 (in, 311), 4.10-4.25 (in, 4H), 6.42-6.90 (in, aromnatics, 811), 7.09 J=7.8, 1M1, 7.20-7.30 (in, aromatics, 3H1).
IR (neat) cin': 3407 1725, 1606.
Mass ni/z 491 Example 23 2-Ethoxy-3-[4-{4-(3-(3,4-dihydro-211-benzo [bIl 1,41 oxazin-4-yl)propyloxy) benzyllarninophenyl] propanoic acid arginine salt NC0 2 H NH 2 NH-rNH 2 N Et C0 2 H N
K~H
2-Ethoxy-3-14- ,4-dihydro-2H-benizo Ib][l ,4]oxazin-4-yl)propyloxy) benzyl}aminophenylpropafloic acid (250 ing, 1 eq, 0.5 minol) obtained in example 21, and L-arginine (88.7 mg, I eq, 0.5 1 inmol) was stirred in dry methanol (3 ml) for WO 03/033481 WO 03/33481PCT/lB02104275 1 99 3-4 h at RT. The solvent was condensed on rotavapour, followed by benzene azeotrope. The residue was dried under high vacuum pump to yield the title compound as a solid (yield 100%), mnp: 141 142 'C.
Example 24 2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-211-benzo [bI oxazin-4-yl)propyloxy) benzyl}aminophenyllpropanoic acid arginine salt 0 OE N0 C 2 H NH 2 NH-r~NH 2 K~fl) Q~tC 2 H NH 2-Ethoxy.-3-[3- ,4-dihydro-2H-benzorb] rI,4]oxazin-4-yl)propyloxy) benzyl}I aminophenyl]propanoic acid (140 mg, 1 eq, 0.28 mmol) obtained in example 22, and L-arginine (50 mg, 1 eq, 0.28 nimol) was stirred in dry methanol (3 ml) for 3-4 h at RT. The solvent was condensed on rotavapour and followed by benzene azeotrope. The residue was dried under high vacu-um pump to yield the title compound as a solid (yield 100%), mp: 152-154 'C.
Example Ethyl 2-etlioxy-3-1,4-{3-(3,4-dihydro-2H-benzo tl,4lthiazin-4yl)propylaminolphenyllpropanoate HN CO 2 Et 11 N QEt A mixture of 3-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl)propybromlide (1.76 g, 1.1 eq, 6.5 minol), obtained in preparation 14, ethyl 2-ethoxy-3-(4ainiophenyl)propanoate (1.4 g, 1.0 eq, 5.9 mmol), obtained in preparation 1, and anhydrous K 2 C0 3 (2.45 g, 3.0 eq, 17.7 mmol) in dry DMF (30 ml) was stirred at RT WO 03/033481 WO 03/33481PCT/lB02104275 100 for 2 days. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water and brine. The organic layer was dried (Na 2
SO
4 condensed, and the residue was chrornatographed using ethyl acetate and hexane to obtain the title compound as viscous liquid (500 mg, 20% yield).
1 NMR (200 MHz, CDCI 3 8: 1.17 J=6.8 Hz, 3H), 1.23 J 6-6 Hz, 3H), 1.27 (bs, 11H, 1.94 (quintet, 6.8 Hz, 2.90 J=6.9 Hz, 2H), 3.03 J=-4.8,Hz, 211), 3.20 J=6.9 Hz, 211), 3.20-3.45 (in, 311), 3.45-3.64 (mn, 311), 3.95 J=6.4 Hz, 1H), 4.16 J=6.9 Hz, 211), 6.50-6.72 (aromatics, 411), 6.90-7.10 (aromatics, 4H).
IR (neat) cm- 1 3398, 2926, 1742, 1616.
Mass inlz 428 429 [M 1].
Example 26 2-Ethoxy-3-[4-{3-(3,4-dihydro-211-benzo [hi [1,4Jthiazin-4-yl)propylamin9} phenyllpropanoic acid N C0 2
H
N QEt
H
Ethyl 2-ethoxy-3-[4- {3-(3,4-dihydro-2H-benzo[bl r1 ,4]thiazin-4-yl)propylaminoI phenyllpropanoate (250 mng, 1.0 eq, 0.58 minol), obtained in example 25, was hydrolyzed by treating with LiOH.11 2 0 (74 mg, 3 eq, 1.75 minol) in MeOH-THFwater solvent mixture at RT for 3-4h. The reaction mixture was condensed, diluted with water and acidified (pH at 4) with aq. HCl. Finally the crude acid was extracted with ethyl acetate. The ethyl acetate layer was dried (Na 2
SO
4 condensed, and chrornatographed using MeGH and CHC1 3 as eluent to obtain the title compound as thick liquid (152 mg, 68% yield).
I H NMR (200 MHz, CDCl 3 3: 1.17 J=6.9 Hz, 311), 1.26 (bs, 111, 1.93 (quintet, 6.9 Hz, 2H), 2.85-3.10 (mn, 4H), 3.02 J=5.1 Hz, 211), 3.19 J=6.9 Hz, 3.20-3.65 (mn, 4H), 4.02 (dd, J=6.9, 4.4 Hz, 1H1), 4.70 (bs, 1H1, CO 2 6.50-6.72 (aromatics, 411), 6.90-7.10 (aroinatics, 4H).
IR (neat) cm-' 3411, 2929, 1726, 1616.
Mass m/z 400 401 [M 1].
WO 03/033481 WO 03/33481PCT/lB02104275 101 Example 27 2-Ethoxy-3-[4-{3-(3,4-dihydro-21-benzo[b] [1,4lthiazin-4-yl)propylamino} phenyllpropanoic acid arginine salt NN C H NH 2 C H N H H Kz( N 2H N Et 0HN
H
A mixture of 2-ethoxy-3-L4- ,4-dihydro-2H-be'nzo [b][1,4]thiazin-4yl)propylaminolpheny]propaloic acid 110 mg, 1 eq, 0.27 mmol), obtained in example 26, and L-aiginine (47.9 mg, 1 eq, 0.27 mmiol) was taken in dry MeOH ml) was stirred at RT for 2 h to get a clear solution. The solvent was condensed, the residue was azeotroped with dry benzene and dried over vacuum pump to obtain the title compound as a solid mass (100% yield), mp: 142-144 'C.
Example 28 Ethyl 2-ethoxy-3-[4-{2-(3,4-dihydro-2ll-belzo [hi [1,4]oxazin-4-yl) ethylarninolphenyllpropalo ate N" O Et NH O~ A mixture of 2-(3 ,4-dihiydro-2H-b enzo [1 ,4]oxazin-4-yl)ethiylbromide (940 mg, 1 eq, 3.8 minol), obtained in preparation 15, ethyl 2-ethoxy-3-{4aminophenyl)propanoate (1.0 g, 1.1 eq, 4.2 mmol), obtained in preparation 1, anhydrous IK 2 C0 3 (1.6 g, 3eq, 10.8 minol) and tetrabutylammonium. bromide (265 mg, 0.2 eq, 0.8 mmol) in dry toluene (20 ml) was heated at 90 'C for 24 h. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water, brine, then dried (Na 2
SO
4 and condensed. The residue was chromatographed with ethyl acetate and hexanes as eluents to obtain the desired product as thick liquid (960 mng, WO 03/033481 WO 03/33481PCT/lB02104275 102 'H NMR (200 MHz, CDC1 3 5: 1.17 J=6.9 Hz, 3H), 1.23 J=6.6 Hz, 3H), 1.27 (bs, 1H, 2.90 J=6.4 Hz, 2H), 3.20-3.65 (in, 8H), 3.95 J=6.4 Hz, 1H), 4.05-4.25 (in, 4H), 6.56 J=8.3 Hz, 2H), 6.60-6.85 (aromatics, 4H), 7.06 J=8.3 Hz, 211).
IR (neat) cm-' 3395, 2977, 1740, 1616.
Mass miz 398 399 [M 1].
Example 29 2-Ethoxy-3- [4-{2-(3,4-dihyclro-2H-benzo I] fl,4Joxazin-4-yl)ethylamino} io plienyllpropanoic acid 0O 2
H
NHO"O~
Ethyl 2-ethoxy-3-[4- {2-(3,4-dihydro-2H-benzo[b] 1 ,4loxazin-4-yl)ethylaminoI phenyl]propanoate (960 mg, 1.0 eq, 2.41 minol), obtained in example 28, was hydrolyzed by treating with LiOH.H 2 0 (350 ing, 3 eq, 7.2 inmol) in MeOH-THFwater solvent mixture at RI for 3-4 1. The reaction mixture was condensed, diluted with water and acidified (pH at 4-5) with aq. HC1. Finally t1he crude acid was extracted with ethyl acetate. The ethyl acetate layer was dried (Na 2 SO4, condensed, and. chromatographed using MeGH and CHC1 3 as eluents to obtain the desired compound as thick liquid (370 mng, 42%).
1 H NMR (200 MHz, CDCl 3 5: 1.17 J=6. 8 Hz, 311), 1.21 (bs, 11H, 2.90 (dd, J=14, 8 Hz, lH), 3.03 (dd, J=14, 4.3 Hz, 111), 3.20-3.65 (mn, SH), 4.02 (dd, J=6.49, 4.4 Hz, 1H1), 4.21 J=4.4 Hz, 2H), 5.00 (bs, CO 2 6.58 J=8.3 Hz, 2H), 6.60- 6.85 (aromnatics, 4H), 7.06 J=83 Hz, 2H).
IR (neat) cm-' 3383 2927, 1727, 1607.
Mass mn/z 3 71 [M 1]J.
WO 03/033481 WO 03/33481PCT/lB02104275 103 Example 2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo [bI [1,41 oxazin-4-yl)ethylaniino} phenyllpropanoic acid arginine salt
NHH
The title compound was prepared as a free flowing solid (mp :142 144 from. 2ethoxy-3 {2-(3,4-dihydro-2H-benzo Fb] 1,4] oxazin-4-yl) ethylamino, }phenyl] propanoic acid, obtained in example 29 and L-arginine, by following the similar procedure as described for example 27.
Example 31 Methyl 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo oxaziu-4-yl)ethoxy} phenylaminomethylJ phenylipropanoate 0 CO 2 Me N NH ONt A mixture of 4- ,4-dihydro-2u-benzo[b] [1 ,4]oxazin.-4-yl)ethoxylanilinie (305 mg, 1 eq, 1.13 mmol) obtained in preparation 16, methyl 2-ethoxy-3-(4formylpbenyl)propanoate (267 mg, 1 eq, 1.13 mmol), obtained in preparation activated molecular sieves (4 and p-TsOH (21 mg, 0. 1 eq, 0.11 mrmol) in diy DCM (4 ml) were stirred at RI for 16 h. The reaction mixture was diluted with ethylacetate (100 ml), washed with aq. sodium bicarbonate, dried (Na 2 SO4), and condensed. The crude mass was dissolved in dry methanol (6 ml) and cone HC1 (125 L)was added at 0 followed by NaB(CN)H 3 (118 mng, 1.5 eq, 1.87 mmol) in portions. The reaction mixture was stirred at 0 'C for 3 h, after that it was diluted with ethyl acetate (100 ml). The organic layer was washed with aq. sodium bicarbonate, dried (Na 2
SO
4 and condensed. The residue was chromatographed using ethyl acetate and hexanes to obtain the title compound as thick oil (525 mg, WO 03/033481 WO 03/33481PCT/lB02104275 104 IH NMR (200 MHz, CDC1 3 3: 1.16 J=6.9 Hz, 311), 1.25 (bs, 3.00 (d, J=6.8, 211), 3.22-3.42 (in, 111), 3.49 J=4.4 Hz, 2H), 3.55-3.75 (in, 3H1), 3.71 (s, 3.99-4.12 (mn, 311), 4.15-4.24 (mn, 41-1), 6.50- 6.90 (aromatics. 8H), 7.19 (d" J=7.8, 2H), 7.28 J=8.0, 211).
JR (neat) cm-' 3405 2927, 1746, 1606.
Mass rn/z 490 491 Example 32 2-Ethoxy-3-14-[4-{2-(3,4-dihydro-2H-benzo [hi[1,4]oxazin-4-yl)ethoxy} phenylaminomethyll plenyllpropauoic acid 0 NH C0 2
H
NH OEt Methyl 2-etlioxy-3-[4-[4- {2-(3,4-dihydro-2H-benzojb] [1,4]oxazin-4-yl)ethoxy} phenylaminomethyl]phenyl]propanoate (520 mng, 1.0 eq, 1.06 mmcl), obtained in example 3 1, was hydrolyzed by treating with LiOH.11 2 0 (134 mg, 3 eq, 3.18 mol) in MeOH-THF-water solvent mixture at RT for 3-4 h. The reaction mixture was condensed, diluted with water and acidified (pH at 4) with aq. HC1. Finally the crude acid was extracted out by ethyl acetate. The ethyl acetate layer was dried (Na 2
SO
4 condensed, and chromatographed using MeGH and CHC1 3 as eluents to obtain the desired compound as thick liquid (150 mng, '11NMR (200 MHz, CDCl 3 8: 1.18 J=6.9 Hz, 3H1), 1.29 (bs, 2.90-3.20 (mn; 21H), 3.22-3.75 (mn, 61-1), 4.00-4.18 (in, 311, 4.20-4.25 (mn, 411), 6.00 (bs, C0 2 1-1), 6.60- 6.90 (aromatics, 8H), 7.24 J=8.3, 211), 7.29 211).
JR (neat) cin1: 3390 2927, 1725, 1605.
Mass m/z 476 477 [MH-1].
WO 03/033481 WO 03/33481PCT/lB02104275 105 Example 33 2-Etlioxy-3-14-14-{2-(3,4-dihydro-211-benzo [l,4]oxaziu-4-yl)ethoxy} plienylaminomethyl] plenyllpropanoic acid arginine salt 0 ;1-1 C0 2
H
NH
00. NH 2 -O 11 NH Y NH -r J~NH 2 C0 2 H NH A mixture of 2-ethoxy-3-[4-[4- ,4-dihydro-2H-benzo~b] [1,4]oxazin-4yl)ethoxy~phienylaminomethyl]phenyl]pr'opanoic acid (110 mg, 1 eq, 0.23 mmol), obtained in example 32, and L-arginine (40 mg, 1 eq, 0.23 mmol) taken in dry MeOH (2 ml) was stirred at RT for 2 h to get a clear solution. The solvent was condensed, the residue was azeotroped with dry benzene and dried over vacuum pump to obtain a solid mass (100% yield), mp: 154-156 0
C.
Example 34 [2S,N(1R)J-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-14-{3-(3,4-dihydro-2benzo [hi 11,4]oxazin-4-yl)propylaminolphenylpropanamide 0 0 'z
OH
11I OEt
H
N J
I
H
To a solution of racemic 2-ethoxy-3-[4- {3-(3,4-dihydro-2H-benzo[b] [1 ,4loxazin-4yl)propylaminolphenyl]propanoic acid (2.0 g, 1.0 eq, 5.20 rnmol) obtained in example 2, in DCM (26 ml) and triethylamine (3.61 ml, 5 eq, 26 mrnol), isobutyichioroformate (1.35 ml, 2 ecj, 10.4 mmol) was added dropwise at 0 The reaction mixture was stirred at RT for 30 min followed by addition of phenylglycinol (1 .42g, 2 eq, 10.4 mmol). The reaction mixture was further stirred at WO 03/033481 WO 03/33481PCT/lB02104275 106 RT for 16 h, which was then diluted with DCM, washed with water and brine, dried (Na 2 S 04), and condensed. The residue was chromatographed using ethyl acetate and hexane to obtain the title compound as faster moving R)-diastereomer (620 mg, 23.7% yield), followed by relatively slower moving R)-diastereomer, (630 mg, 24% yield), both as viscous liquid. Characterization of R)-diastereomer is described in example 1 H NMR (200 MHz, CDCl 3 6: 1.14 3=6.8 Hz, 3H), 1.24 lH), 1.91 (quintet, J=6.8 Hz, 2H1), 2.90 (dd, J=12 and 5.8 Hz, lH), 3.06 (dd, J=12 and 3.9 Hz, 111), 3.19 J=6.8 Hz, 211), 3.25-3.60 (in, 6H), 3.60-3.70 (in, 2H), 3.97 (dd, J= 5.8 and 3.9 Hz, 1H), 4.22 J= 4.4 Hz, 2H), 4.88-5.00 (mn, 1H1), 6.50-7.40 (aromatic and amide-NH, 14H1).
JR (neat) cm'1 3393 2927, 1660.
Mass m/z 503 504 Example [2R,N(1R)I-N-(2-hydroxy-1-phenylethy1)-2-ethoxy-3-[4-{3-(3,4-dihydro-2IIbeuzo jb] [1,4]oxazin-4-yl)propylaminolpbenyljpropanamide
K
0 0
OH
QEt
H
The title compound is obtained by following the similar procedure described in example 34.
1H NMR (200 MHz, CDCl 3 6: 1.16 J=6.8 Hz, 3H), 1.24 111), 1.91 (quintet, J=6.8 Hz, 211), 2.80 (dd, J=14, 7.5 Hz, lH), 3.06 (dd, J=14, 3.9 Hz, 111), 3.17 (t, J=6.8 H-z, 211), 3.25-3.60 (mn, 6H1), 3.78-3.90 (in, 211), 3.89 (dd, J= 7.5, 3.9 H-z, IH), 4.22 J= 4.4 Hz, 211), 4.88-5.00 (mn, 1H1), 6.45-7.35 (aromatics and ainide-INII, 1411).
WO 03/033481 WO 03/33481PCT/lB02104275 107 JR (neat) cm- 1 3399 2927, 1660.
Mass miz 503 504 [M+1.
Example 36 12SN(1R)J-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-14-{3-(3,4-dihydro-211benzo[bI [1,4]oxazin-4-yl)propylaminolphenyll propananhide hydrochloride salt N(S) OH CI To a dry methanolic HC1 solution (2 ml) [2SN(1R)]-N-(2-hydroxy-1 -phenylethyl)-2ethoxy-3-[4- {3-(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propylamino~phenyljpropanamide (95 mg, 0.19 mmol) obtained in example 34, was added and the mixture was stirred at RT for 5 min. Then the reaction mixture was condensed and azofroped using dry benzene on rotary evaporator. The residue was dried on high-vacuum to obtain the title compound as a brown solid mass (100% yield, mp: 74-75 Example 37 [2R,N(IR)J-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-diiydro-21beuzo [hi [1,4]oxazin-4-yI)propylaminolphenyllpropanamide hydrochloride salt N NN(R) QEtH
N
H
To a dry methanolic HCJ solution (2 ml) [2R,N(1R)]-N-(2-bydroxy-1 -phenylethyl)-2etlioxy-3-[4-{3 ,4-dihydro-2H-benzo~b][1 ,4]oxazin-4yl)propylaminolphenyl]propaniamiide (95 mg, 0.19 mmol) obtained in example was added and the mixture was stirred at RT for 5 min. Then the reaction mixture was condensed and azeotroped using dry benzene on rotary evaporator. The residue WO 03/033481 WO 03/33481PCT/lB02104275 108 was dried on high-vacuum to obtain the title compound as a brown solid mass (100% yield, mp: 69-70 Example 38 2-Ethoxy-3-14-t3-(3,4-dihydro-2H-henzo [hi [1,41 oxazin-4-yl)propylamino} phenyllpropanoic acid magnesium salt NC00O Mg 2 QEt
H
A mixture of methanolic solution (2 ml) of 2-ethoxy-3-L4- {3-(3,4-dihydro-2Hbenzo[b] [1 ,4]oxazin-4-yl)propylaminolphenyl]propanoic acid (75 mg, 1 eq, 0.19 mmol) obtained in example 2 and magnesium hydroxide (5.6 mg, 0.5 eq, 0.095 mmol) was heated at 50 'C for 5 h. The resulting solution was condensed, azeotroped with benzene and then finally dried on high vacuum pump to obtain the title compound as free flowing solid (100% yield, mp: 132-134 Example 39 2H-benzo [hi 1,4Joxazin-4-y)propylaminolpheflyllpropaflamide
O
N
H
To a solution of racemnic 2-ethoxy-3-[4- {3-(7-fluoro-3,4-dihydro-2Hbenzo~~b][1,4]oxazin-4-yl)propylaminolphenyl]propaloic acid (1.8 g, 1.0 eq, 4.48 mmol) obtained in example 17, in DCM (25 ml) and triethylamine (2.49 ml, 4 eq, 17.92 mmol), isobutyichioroformate (875 ViL, 1.5 eq, 6.72 mmol) was added WO 03/033481 WO 03/33481PCT/lB02104275 109 dropwise at 0 The reaction mixture was stirred at RT for 30 min followed by addition of (R)-phenylglycinol (1.23 g, 2 eq, 8.96 mmol). The reaction mixture was further stirred at RT for 16 h, which was then diluted with DCM, washed with water and brine, dried (Na 2
SO
4 and condensed. The residue was chromatographed using ethyl acetate and hexane to obtain the title compound as faster moving R)diastereomer (370 mg, 32 yield), followed by relatively slower moving R)diastereomer, (370 mg, 32 yield), both as viscous liquid. Characterization of (R, -R)-diastereonier is described in example 40 (next example).
IH NMR (200 MHz, CDCI 3 6: 1.16 J=6.8 Hz, 3H), 1.92"(quintet, J=6.8 Hz, 2H), 2.92 (dd, J=14, 5.6 Hz, 1K), 3.08 3.5 Hz, 1H), 3.22 J=6.4 Hz, 2H), 3.20-3.40 (in, 4H), 3.40-3.80 (mn, 4H), 3.99 J= 5.2 Hz, 1H), 4.23 J= 4.4 l-Iz, 2H), 4.88-5.02 (mn, 111), 6.40-6.60 and 6.90-7.40 (aromatics and amide-NH, 13H).
IR (neat) cm-l: 3405 2933, 1660, 1615, 1514.
Mass m/z 521 522 [M+l1].
Example -N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro- H-b enzo [1,41 oxazin-4-yl)propylaminolphenyljpropanamide )00) 02 N NR '(HR N OEt
H
H
The title compound is obtained during syntheis of example 39 as another diastereomer R).
[cc]D: 17.4' 1.0 CHC1 3 WO 03/033481 WO 03/33481PCT/lB02104275 110 1 H NMR (200 M~lz, CDC1 3 8: 1.18 J=6.8 Hz, 3H), 1.91 (quintet, J=6.8 Hz, 2H1), 2.51 (bs, NH, OH); 2.82 (dd, JA14.2 and 7.3 Hz, 111), 3.04 (dd, J=14.2 and 3.4 Hz, 1H), 3.20 J=6.4 Hz, 2H1), 3.25-3.40 4H1), 3.42-3.70 211), 3.80-3.90 (in, 2H1); 3.98 (dd, J= 7.3 and 4.0 Hz, 111), 4.24 J= 4.8 Hz, 2H1), 4.88-5.2 (in, I11, 6.4- 6.60 and 7.00-7.40 (aromatic and amide-N-H, 13H).
IR (neat) cn-f 1 3398 2929, 1660, 1616, 1513.
Mass m/z 521 522 [M+1.
Example 41 l 2 SN(lR)I-N(2hydroxy-1phenylethyl)2ethoxy-3[413(3, 4 -dihydro- 2
H-
benzolbl [1,4Ioxazin-4-yl~propylamiflphellpropafamide hydrochloride salt O Et
H
N
H
To a dry methanolic H-CI solution (2 ml) [2SN(1RI-N-(2-hydroxy--phelylethyl)- 2 ethioxy-3 -[4-{3-(3,4-dihydro-2H-benzo~b] [1 ,4]oxazin-4yl)propylamiiiolphenyllpropaflaiide (95 mg, 0.19 inmol) obtained in example 34, was added and the mixture was stirred at RT for 5 mmi. Then the reaction mixture was condensed and azeotroped using dry benzene on rotary evaporator. The residue was dried on high-vacuum to obtain the title compound as a brown solid mass (100% yield, inp: 74-75 Examplc 42 [2,~RIN(-yrx--hnltyl--toy3[-3(,-iyr-H benzo~bl 1 1,4]oxazin-4-yl~propyllmilphelIpropanamide hydrochloride salt k o HCI
NNR
HH
WO 03/033481 WO 03/33481PCT/lB02104275
III
To a dry methanolic HCI solution (2 ml) [2R,N(1R)]-N-(2-hydroxy-1-phenylethyl)-2ethoxy-3-[4- ,4-dihydro-2H-benzo:b] [1 ,4loxazin-4-yl)propylaminolphenyl] propanamide (95 mg, 0.19 mmol) obtained in example 35, was added and the mixture was stirred at RT for 5 min. Then the reaction mixture was condensed and azeotroped using dry benzene on rotary evaporator. The residue was dried on highvacuum to obtain the title compound as a brown solid mass (100% yield, mp: 69-70 0
C).
Example 43 (-)-(S)-3-t4-{3-(3,4-Dihydro-211-benzo [bI tl,4loxazin-4-yI)propylaminolphenyil- 2-ethoxypropanoic acid NZZ 0 C
CO
2
H
H
[cc]D: -17' 1.0 MeOH).
1H NM (200 MIHz, CDCI 3 8: 1.19 J=7.4Hz, 3H), 1.94 J=7.4Hz, 2H), 2.90 (dd, J=14.0 and 7.0 Hz, 1H), 3.05 (dd, J=14.0 and 4.9Hz, 1H), 3.21 J=6.gHz, 2H1), 3.25-3.40 (in, 5HI), 3.40-3.62 (mn, 111), 4.00-4.17 (in, 4.18-4.22 (in, 2H1), 6.59 (d, J=8.3Hz, 211), 6.65-6.85 (in, 4H1), 7.06 J=8.3Hz, 2H).
IR (neat) cm- 1 3 500, 172 Mass m/z 385 1).
Example 44 (+)-(R)-3-[4-{3-(3,4-Dihydro-2H-benzo [bi 11,41 oxazin-4-yI)propylamino}phenyl]- 2-ethoxypropanoic acid N C02O~' H
H
Lcaio: 16.8' 1.0 MeOll).
WO 03/033481 WO 03/33481PCT/lB02104275 112 IH NMIR (200 MHz, CDCI 3 5: 1 .19 J=7.4Hz, 3H), 1.94 J=7.4H-z, 211), 2.90 (dd, J=14.0 and 7.0 Hz, 1H1), 3.05 (dd, J=14.0 and 4.9Hz, 111), 3.21 J=6.8Hz, 2H), 3.25-3.40 (in, 5H), 3.40-3.62 (in, 111), 4.00-4.17 (in, 1H), 4.18-4.22 (in, 2H), 6.59 (d, J=8.3Hz, 2H), 6.65-6.85 (in, 411), 7.06 J=8.3Hz, 211).
IR (neat) cm-1:3 500, 1725.
Mass m/z 385 Example Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo [bI [1,4loxazin-4-yl) propylamino}phenyl]-2-ethoxypropanoate NNO
CO
2 Et I b Ot
N
H
(S)-Ethyl 2-ethoxy-3-(4-aminophenyl)propano ate (2.20 g, 1 eq, 9.28 minol) obtained in .preparation 20, 3-(7-fluoro-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propylbromidc (3.30 g, 1.3 eq, 12.06 inmol) obtained in preparation 10, and anhydrous K,,C0 3 (3.84 g, 3 eq, 27.84 inmol), and tetrabutyl ammionium bromide (597 mg, 0.2 eq., 1.85 mmol) were heated at 90 'C in'dry toluene (47 mL) for 20 h.
The reaction mixture was diluted with ethyl acetate, washed with water and brine.
The residue was chroinatographed using ethyl acetate and hexane to afford the title compound (1.78 g, yield 44.5%) as viscous liquid.
(c 1.0, MeOR).
'H NMVR (200 MHz, CDC1 3 6: 1.17 J=7 Hz, 3H), 1.23 J=7 H-z, 311), 1.89 J=6.8 Hz, 211), 2.90 J-6.5 Hz, 2H), 3.10-3.42 (in, 7H1), 3.45-3.65 (111, 1H), 3.95 (t, J=6.7 Hz, i1H), 4.10-4.30 (in, 4H1), 6.40-6.70 (mn, aromatics, 5H), 7.05 J==8.4 Hz, 2H1).
JR (neat) cm7' 3394 2978, 1740, 1617.,1514.
Mass mlz 431 1).
WO 03/033481 WO 03/33481PCT/lB02104275 113 Example 46 [4-{3-(7-Fluoro-3,4-dihydro-2H-henazobIj oxazin-4-yl)propylamino} phenyll -2-ethoxypropanoic acid NFII IN: 0 N 02
H
(S)-Ethyl 34[4- {3-(7-fluoro-3 ,4-dilydro-2H-benzo Ill,41oxazirn-4yl)propylaminolphenyl]-2-ethoxypropanoate (1.7 g, 1 eq, 3.95 mmol) obtained in example 45, was hydrolyzed using lithium hydroxide monohydrate (249 mg, 1.5 eq, 5.93 mmol), in mnethaniol-THF-water at RT till all the starting material is consumed (4 to 5 The reaction mixture was diluted with water, acidified (pH with dii.
HCI and then extracted with ethyl acetate. TIhe ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The, residue was chromatographed using ethyl acetate and hexanes -4 methanol and chloroform to afford the title compound (1.5 g, yield 94%) as viscous liquid.
Chiral I-PLC: >98 ee.
'H NMR (200 MHz, CDCl 3 8: 1.19 J=7.4Hz, 3H), 1.94 (quintet, J=7.4Hz, 2H), 2.85-3.10 (in, 211), 3.10-3.20 (in, 6H1), 3.40-3.70 (in, 2H), 3.90-4.10 (in, lH), 4.10- 4.30 (in, 2H), 6.20 (bs, NH, C0 2 11), 6.42-6.70 (in, aromatics, 5H1), 7.07 J=8.3 Hz, 2H).
JR (KL~r) cm-' 3 394, 1725, 1619.
Mass m/z 403 Example 47 (,S)-3-14-{3-(7-Fluoro-3,4-diliydro-2H-benzo [1,4]oxazin-4-yl)propylamino} phenyll-2-ethoxypropanoic acid L-arginine salt F 0 'Ia N Nj CO H NH 2
NH-'
1
.N--NH
2 n -~Et C0 2 H NH
H
WO 03/033481 WO 03/33481PCT/lB02104275 114 -(7-Fluoro-3,4-dihydro-2H.-benzo[bjfl ,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid (300 mg, 1 eq, 0.74 mmol) obtained in example 46, and L-arginine (130 mg, 1 eq, 0.74 mmol) were taken in dry methanol (4 ml), and stirred at RT for 2-3 h. The solvent was removed on rotavapour followed by benzene azeotrope. The residue was dried under high vacuum pump to yield the title compound as a free flowing solid (yield 100%).
Mp: 114-116 'C.
Example 48 (S)-3-[4-{3-(7-Fluoro-3,4-dihydro-211-henzo [hi oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid magnesium salt F 0
CO
2 2+ NN I-OD Mg
H
-2 f{3-(7-Fluoro-3,4-dihydro-2H-benzo[b] [1,4]oxazin-4-yl)propylanmino} phenyl] -2-ethoxypropanoic acid 13 g, 1.0 eq, 2.81 mmol), obtained in example 46, in dry methanol (15 mL) was treated with Mg(O)Me) 2 (121 mg, 0.5 eq, 1.4 mmol).
The resulting mixture was heated at 55-60 'C for 7-8h. The reaction mixture was condensed on rotavapour, azeotroped with benzene, and finally dried on high vacuum pump. The sticky mass was triturated with hexanes to obtain the desired salt as a powdery solid (quantitative yield).
Mp: 240-242' 0 C (dec.).
WO 03/033481 WO 03/33481PCT/lB02104275 115 Example 49 Ethyl 3- [4-{3-(7-fluoro-3,4-dihyclro-2H-benzo thJ oxazin-4-yI) propylaminolphenyl].-2-metlioxypropanoate N,,a
CO
2 Et
N
H
(S)-Ethyl 2-methoxy-3-(4-aminophenyl)propanoate (800 mg, 1.0 eq, 3.58 mmol) obtained in preparation 21, 3 -(7-fluoro-3,4-dihydro-2H-benzo jb] [1 ,4]oxazin-4yl)propylbromide (1.27 g, 1.3 eq, 4.65 mmol) obtained in preparation 10, and anhydrous K 2 C0 3 (1.48 g, 3 eq, 10.79 mmol), and tetrabutyl ammonium bromide (576 mg, 0.5 eq., 1.79 mmol) were heated at 90 'C in dry toluene (20 mL) for 9 h.
The reaction mixture was diluted with ethyl acetate, washed with water and brine.
The residue was chrornatographed using ethyl acetate and hexane to afford the title compound (1.1 g, yield 73 as viscous liquid.
[cx]D: (c 1.0, MeGH).
IH NMR (200 MHz, CDC1 3 8: 1.25 J=7.3 Hz, 3H), 1.89 J=7.0 Hz, 2H), 2.91 J=6.0 Hz, 2H), 3.05-3.42 (in, 6H), 3.36 3.90 J=6.4 Hz, IH), 4.10-4.30 (in, 4H), 6.40-6.70 (in, aromatics, 5H), 7.05 (aromatics, 2H).
JR (neat) cnf 1 3385 2934, 1741, 1617, 1514.
Mass rn/z 417 Example (S)-3-[4-{3-(7-IFluoro-3,4-dihlydro-2H-belzo [bI tl,4loxazin-4-yl)propylaminO} phenyl]-2-methoxypropanoic acid F 0
HO
2 (S)-Ethyl 3 {3 (7-fluoro-3,4-dihydro-2H-benzo~b][l ,4]oxazin-4yl)propylainino}plienyl]-2-inethoxypropaloate (1.0 g, 1 eq, 2.4 mmol) obtained in WO 03/033481 PCT/IB02/04275 116 example 49, was hydrolyzed using lithium hydroxide monohydrate (151 mg, 1.5 eq, 3.6 mmol), in methanol-THF-water at RT till all the starting material is consumed (4 to 5 The reaction mixture was diluted with water, acidified (pH with dil.
HC1 and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatographed using ethyl acetate and hexanes 4 methanol and chloroform to afford the title compound (650 mg, yield 70 as viscous liquid.
[ca]D: -14.20 (c 1.0, MeOH).
Chiral HPLC: >98 ee.
'H NMR (200 MHz, CDC13) 5: 1.9 (quintet, J=7.4Hz, 2H), 2.85-3.10 2H), 3.10- 3.38 6H), 3.40 3H); 3.90-4.05 1H); 4.24 J=4.2 Hz, 2H); 6.42-6.70 (m, aromatics, 5H); 7.05 J=8.0 Hz, 2H).
IR (neat) cm 3396, 2936, 1727, 1614, 1513.
Mass m/z 389 Example 51 {3-(7-Fluoro-3,4-dihydro-2H-benzo [1,4]oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoic acid magnesium salt F O N 0 2 Mg 2 k ,J j N H OMe
H
2 (S)-3-[4-{3-(7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoic acid (400 mg, 1.0 eq, 1.03 mmol), obtained in example in dry methanol (5 mL) was treated with Mg(OMe) 2 (44.3 mg, 0.5 eq, 0.51 mmol). The resulting mixture was heated at 55-60 0 C for 7-8h. The reaction mixture was condensed on rotavapour, azeotroped with benzene, and finally dried on high vacuum pump. The sticky mass was triturated with hexanes to obtain the desired salt as a powdery solid (quantitative yield).
WO 03/033481 WO 03/33481PCT/lB02104275 117 Mp: 210-212'C (dec.).
Example 52 Ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-belzo [bi [1,4]oxazin-4yl) propylaminolphelyll-2-ethoxypropafloate F N N N CO 2 Et N 0[Et
H
Ethyl 2-ethoxy-3-(4-aminophel)propanoate (500 mg, 1 eq, 2.11 mmol) obtained in preparation 1, 3-(2-methyl-7-fluoro-3 ,4-dihydro-2I--benizo~b] Ill,4]oxazin-4yl)propylbromide (670 mg, 1.1 eq, 2.32 mmol) obtained in preparation 17, and anhydrous K 2 C0 3 (875 mng, 3 eq, 6.33 mmol), and tetrabutyl armmonium bromide (340 mg, 0.5 eq., 1.O5 mmol) were heated at 90 'C in dry toluene (11I rnL) for 12 h.
The reaction mixture was diluted with ethyl acetate, washed with water and brine.
The residue was chromatographed using ethyl acetate and hexane to afford the title compound (320 mng, yield 32 in the form of mixture of diastereomners as viscous liquid.
1 1- NMR (200 MHz, CDC1 3 8: 1.10-1.25 (in, 911), 1.80-2.00 (in, 211), 2.82-3.02 (in, 2H), 3.10-3.50 (in, 2H), 3.28-3.44 (in, 311), 3.50-3.65 (mn, 1H1); 3.90-4.00 (in, 1H1), 4.10-4.30 (mn, 3H1), 6.40-6.80 (aromatics, 5H1), 7.00-7.20 (aromnatics, 211).
IR (neat) cm-1 3389 2929, 1740, 1617, 1515.
Mass mlz 445 Example 53 3-41-2mtyl7Fur-,-dhdo2 ez[bI I1,41oxazin-4yl)propylamifl phenyl1-2-ethoxypropale acid F N 0 C0 2
H
N QEt WO 03/033481 WO 03/33481PCT/lB02104275 118 Ethyl 3 {3 -(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propylamninolphenyl]-2-ethoxypropanoate (320 mng, 1 eq, 0.72 mmol) obtained in example 52, was hydrolyzed using lithium hydroxide inonohydrate (46 mg, 1.5 eq, 1.08 mmol), in methanol-THE-water at RI till all the starting material is consumed (4 to 5 hi). The reaction mixture was diluted with water, acidified (PH with dii.
HCI and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chrornatographed using methanol and chloroform to afford the title compound (190 mng, yield 64%) as viscous liquid.
'HNMR (200 MHz, CDC1 3 6: 1.21 (t J =7.1 Hz, 31H), 1.36 J =6.4 Hz, 3H), 1.92 (quintet, J 6.8 Hz, 2H1), 2.90-3.10 (mn, 211), 3.10-3.40 (in, 611), 3.42-3.60 (in, 2H); 4.06 (dd, J 6.8, 3.9 Hz, 111), 4.20-4.35 (in, 111); 6.50-6.62 (aromatics, 511), 7.07 J =8.3 Hz, 2H1).
IR (KBr) cin' 3387,2927, 1726, 1615, 1514.
Mass in/z 417 (MI1).
Example 54 3-[4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzo [1,41oxazin-4yi)propylamino} phenyl]-2-ethoxypropanoic acid magnesium salt F 0 N02 Mg 2 N OEt
H
2 3 {3-(2-methyl-7-Fluoro-3,4-dihydro-2H-benzolb] [1,4]oxazin-4-yl)propylamino phenyl]-2-ethoxypropanoic acid (170 ing, 1.0 eq, 0.41 mmol), obtained in example 53, in dry methanol (5 mE) was treated with Mg(OMe) 2 (17.6 mng, 0.5 eq, 0.21 mmol). The resulting mixture was heated at 55-60 'C for 7-8h. The reaction mixture was condensed on rotavapour, azeotroped with benzene, and finally dried on high WO 03/033481 WO 03/33481PCT/lB02104275 119 vacuum pump. The sticky mass was triturated with hexanes to obtain the desired salt as a powdery solid (quantitative yield).
Mp: 110- 112 T.
Example Ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b] [1,4loxazin-4-yl) propylaminolphenyl]-2-ethoxypropanoate 4- N CO 2 Et N lo CEt
H
Starting fromi ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (438 mg, 1 eq, 1.85 mmol) obtained in preparation 1, and 3-(2-methyl-3,4-dihydro-2Hbenzo[b] [1 ,4]oxazin-4-yl)propylbromide (550 mg, 1.1 eq, 2.32 mmol) obtained in preparation 18, -and following the procedure of example 52 the title compound (300 mg, yield 35 was obtained in the form of mixture of diastereomers as viscous liquid.
1 H NMR (200 MHz, CDCl 3 5: 1.17 J =7.0 Hz, 3H); 1.23 J 7.0 Hz, 3H); 1.35 J 6.4 Hz, 3H); 1.80-2.00 (in, 2H1), 2.91 J 6.7 LHz, 2H); 3.00-3.42 (mn, 7H1); 3.45-3.65 (mn, 1H); 3.95 J 6.7 Hz, 1H), 4.10-4.30 (mn, 3H), 6.53 J 8.3 Hz, 2H1); 6.65 J 7.8 Hz, 2H1); 6.79 J 7.8 Hz, 2H); 7.06(d, J 8.3 Hz, 211).
IR (neat) cm-1 3400 2976, 1741, 1616, 1520.
Mass m/z 427 Example 56 3- [4-13-(2-methyl-3,4-dihydro-211-benzo oxazin-4-yl)propylamiuo} phenyl]-2-ethoxypropauoic acid N C0 2
H
N ~0OEt
H
WO 03/033481 WO 03/33481PCT/lB02104275 120 Ethyl 3 f{3-(2-methyl-3,4-dihlydro-2H-benzo[b][1 ,4jjoxazin-4yl)propylamino}phenyl]-2-ethoxypropanoate (300 mg, 1 eq. 0.72 mmol), obtained in example 55 was hydrolyzed following the procedure of example 53 to obtain the title compound (170 mg, yield 61%) as viscous liquid.
'H NMR (200 MHz, CDCl 3 6: 1.17 J 7.0 Hz, 311); 1.34 J =6.1 Hz, 3H);1.80-2.00 (in, 211), 2.80-3.70 (in, 1011); 4.02 (dd, J= 7.3, 4.5 Hz, 1H), 4.10-4.30 (mn, 1H), 5.6 (bs, 211, CO 2 fl, NHl); 6.55 J =8.3 Hz, 2H); 6.64 J =7.8 Hz, 2H); 6.79 J 7.8 Hz, 2H), 7.06 J 8.3 Hz, 211).
JR (KBr) cm-1: 33 93, 2974, 1726, 1617, 1503.
lo Mass m/z 399 Example 57 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo [hI oxazin-4-yl)propylamino} phenyll -2-ethoxypropanoic acid magnesium salt K 02 Mg 2 N -QEt
H
-2 From 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid (155 mg, 1.0 eq, 0.39 mmol), obtained in example 56 and Mg(OMe) 2 (16.5 mg, 0.5 eq, 0.20 mmol) the desired salt as a powdery solid( quantitative yield) following the procedure of example 54.
Mp: 102-104 0
C.
WO 03/033481 WO 03/33481PCT/lB02104275 121 Example 58 Ethyl (2S)-3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo Ib] [1,4]oxazin-4-yl) propylaminolphenylJ-2-methoxypropanoate (N
CO
2 Et H O e Starting from ethyl (S)-2-methoxy-3-(4-amiinophenlyl)propanoate (500 mg, 1 eq, 2.24 mmol) obtained in preparation 21, and 3-(2-methyl-3 ,4-dihydre-2Hbenzo[b] [1 ,4]oxazini-4-yl)propylbromide (666 mg, 1.1 eq, 2.47 mmol) obtained in preparation 18, and following the procedure of example 52, the title compound (340 mg, yield 38 was obtained in the form of mixture of diastereomers as viscous liquid.
111 NMR (200 MHz, CDCl 3 5: 1.25 J 7.2 Hz, 3H); 1.36 J =6.4 Hz, 3a); 1.80-2.00 (in, 2ff), 2.92 J =6.2 Hz, 2H); 3.02-3.50 (in, 9ff); 3.90 f1 6.2 Hz, 1H), 4.10-4.30 (mn, 6.54 J =8.3 Hz, 21H); 6.65 J 7.2 H-z, 2H); 6.80 J =7.2 Hz, 2H); 7.05 J =8.3 Hz, 2H).
JR (neat) cm-1: 3398 2928, 1741, 1613, 1520.
Mass m/z 413 Example 59 14-{3-(2-methyl-3,4-dihydro-2H-benzo [hi [1,4loxazi-4yl)propylamino}phenyl]-2-methoxypropanoic acid KI~IN~C0 2
H
N 1 HO4
H
Ethyl {3 -(2-methyl-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propylaininolphenyl]-2-methoxypropanoate (170 mg, 1 eq. 0.4 13 minol), obtained in example 58, was hydrolyzed following the procedure of example 53, to obtain the title compound (100 mng, yield 63%) as viscous liquid.
WO 03/033481 WO 03/33481PCT/lB02104275 122- 1 H NMR (200 MHz, CDCl 3 6: 1.35 (di, J =6.5 Hz, 3H); 1.80-2.00 (in, 2H), 2.85- 3.60 (in, 1 IH); 3.98 (dci, J 7.0, 4.3 Hz, 1H), 4.15-4.30 (in, 1H), 6.55 (di, J 8.3 Hz, 211); 6.65 J=7.2 Hz, 2H); 6.79 (d,JI= 7.2 Hz,211); 7.05 1 8.3 Hz, 2H).
IR (KBr) cmn': 3391, 2930, 1727, 1608, 1506.
Mass m/z 385 (M4l-1).
Example (2S)-3-[4-{3-(2-methyl-3,4-dihydro-2H-benzolb] oxazin-4-yl)propylamino} phenyll-2-methoxypropanoic acid magnesium salt C N T02 Mg 2
H
-2 From {3-(2-methyl-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4yl)propylamino} phenyl]-2-ethoxypropanoic acid (90 mng, 1.0 eq, 0.23 mmol), obtained in example '59, and Mg(OMe) 2 (10.1 mg, 0.5 eq, 0.12 inmol) the desired salt as a powdery solid quantitative yield) following the procedure of example 54.
Mp: 160-162 "C.
Example 61 Ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2Hf-benzo [1,41 oxazin-4-yl) propylaminolphenyll-2-ethoxypropanoate o N CO 2 Et N QEt
H
Starting from ethyl 2-ethoxy-3-(4-aminoplienyl)propanoate (325 mng, 1 eq, 1.37 mmol) obtained in preparation 1, and 3-(2-propyl-3,4-dihydro-2H- WO 03/033481 WO 03/33481PCT/lB02104275 123 benzo[b] Ill,4]oxazin-4-yl)propylbrom-ide (450 mg, 1.1 eq, 1.5 immol) obtained in preparation 19, and following the procedure of example 52, the title compound (343 mg, yield 69 was obtained in the form of mixture of diastereomers as viscous liquid.
1 HNMR (200 MHz, CDC1 3 8: 0.97 J =7.0 Hz, 3H1); 1.17 J 7.2 Hz, 3H); 1.22 J =7.3 Hz, 3H1); 1.40-1.80 (in, 4H1); 1.91 (quintet, J =6.7 Hz, 2H), 2.90 J =6.4 Hz, 2H1); 3.00-3.42 (in, 7H); 3.45-3.65 (in, Ill); 3.94 J =6.4 Hz, 1H), 4.00-4.22 (in, 311), 6.52 J 8.3 Hz, 2H); 6.64 J =7.0 H~z, 2H1); 6.78 J 7.2 Hz, 211); 7.05 J 8.3 Hz, 2H).
IR (neat) cnf': 3400 2959, 1741, 1616, 1520.
Mass m/z 455 Example 62 3-14-{3-(2-propyl-3,4-dihydro-2H-beizo I [1,4joxazin-4-yl)propylamino} phenyll-2-ethoxypropanoic acid C 0 N C0 2
H
N z GEt
H
Ethyl 3 f{3 -(2-propyl-3 ,4-dihydro-21-benzo [1 oxazin-4yl)propylaininolphenyl]-2-ethoxypropanoate (305 mg, 1 eq, 0.67 minol), obtained in example 61, was hydrolyzed following the procedure of example 53 to obtain the title compound (177 ing, yield 62 as viscous liquid.
'H NMR (200 MHz, CDCl 3 6: 0.97 J 7.0 Hz, 311); 1.18 J =7.2 Hz, 3H1); 1.40-1.80 (in, 411); 1.92 (quintet, J 6.7 Hz, 211), 2.80-3.62 (in, 10 11); 3.95-4.15 (in, 211); 4.60 (bs, 21H); 6.55 J 8.3 Hz, 2H); 6.64 J1 7.0 Hz, 2H1); 6.79 J 7.2 Hz, 211); 7.06 J 8.3 Hz, 2H).
IR (K.Br) cm'1: 3 500, 2931, 1724, 1606, 1504.
Mass nilz 427 853 (M 2 H-1).
WO 03/033481 WO 03/33481PCT/lB02104275 124 Example 63 3-[4-{3-(2-propyl-3,4-dihydro-2H-beuzo [hi [1,4]oxazinI-4-yl)propylamino} phenyl] -2-ethoxypropanoic acid magnesium salt N 02 Mg 2 N 0GEt
H
-2 From 3 -(2-propyl-7-3,4-dihydro-2H-benzolb] [1,4]oxazin-4-yl)propylamino} phenlyl]-2-ethoxypropanoic acid (164 mg, 1.0 eq, 0.39 mmol), obtained in example 62, and Mg(OMe) 2 (16.5 mg, 0.5 eq, 0.20 rnmol) the desired salt as a powdery solid quantitative yield) following the procedure of example 54.
Mp: 104-106'C.
Example 64 Ethyl (2S)-3-[4-{3-(2-propyl-3,4-dihydro-211-benzo 1b] [1,41oxazin-4-yl) propylaininolphenylj-2-methoxypropanoate C N
CO
2 Et
N
H
Starting from ethyl (SJ-2-methoxy-3-(4-aminophenyl)propanoate (312 mg, 1 eq, 1.1.40 mmol) obtained in preparation 21, and 3-(2-propyl-3,4-dihydro-2Hbenzo[b][1,4]oxazini-4-yl)propylbromide (460 mg, 1.1 eq, 1.54 mmol) obtained in preparation 19, and following the procedure of example 52, the title compound (255 mg, yield 69 was obtained in the form of mixture of diastereomers as viscous liquid.
'I-I NMIR (400 MHz, CDCI 3 5: 0.99 J =6.8 Hz, 3H1); 1.26 J 7.2 Hz, 3H1); 1.47-1.61 (in, 3H1); 1.69-1.74 (in, M1); 1.89-1.97 (mn, 2H), 2.92 J =4.0 Hz, 1H1); 2.93 J =2.0 Hz, iH); 3.09 (dd, J 11.2, 7.8 Hz, 1H); 3.18-3.30 (in, 311); 3.36 (s, WO 03/033481 WO 03/33481PCT/lB02104275 125 3H); 3.31-3.48 (in, 211); 3.90 J =6.0 Hz, 1H), 4.06-4. 10 (in, 111), 4.19 J 7.2 Hz, 211); 6.54 J =8.8 Hz, 2H); 6.55-6.65 (aromatics, 2H1); 6.79 J 7.2 Hz, 211); 7.04 J 8.8 Hz, 211).
IR (neat) cm- 1 3396 2930, 1741, 1613, 15 18.
Mass m/z 441 (M±1 Example (2S)-3-[4-{3-(2-propyl-3,4-dihydro-211-benzo [1,4joxazin-4-yl)propylamino} phenyll-2-methoxypropanoic acid c 0 0 :N C0 2
H
W ~Oe
N
H
Ethyl -(2-propyl-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazini-4yl)propylaminiolphenyl]-2-methoxypropanoate (240 mng, I eq, 0.55 mnol), obtained in example 64, was hydrolyzed following the procedure of example 53 to obtain the title compound (164 mg, yield 73 as viscous liquid.
1 H NMR (200 MHz, CDC 3 5: 0.96 J 7.0 Hz, 311); 1.44-1.67 (mn, 4H); 1.91 (quintet, J 7.0 Hz, 2H1), 2.90-3.33 (in, 8 3.38 3H); 3.92-4.06 (mn, 211); 4.60 (lbs, 211); 6.55-6.66 (aromatics, 4H); 6.78 J 7.4 Hz, 211); 7.06 J 8.2 Hz, 2H1).
JR (KBr) cm- 1 3397, 2930, 1727, 1606, 1504.
Mass nl/z 413 825 (M 2 1237 (M 3 Example 66 (S)-3-[4-{3-(2-propyl-3,4-diliydro-2H-benzo [bI [1,4loxazin-4-yl)propylamino} phenyl] -2-methoxypropanoic acid magnesium salt WO 03/033481 WO 03/33481PCT/lB02104275 126 M p 1 7 70C NN Mg2
H
Stati romo ethyl -2-roxyp3-(4aminophenyd (14anoate (0 g, 1.3 eq, obtedlb~ in]xapei ndlMropbome (1 g, .1 eq, .85 mmol) tied inl paaiondr 10,i (antttvyed following the procedure of example 52,tettecopud(0 1.Ethl 2 Hz, oy3);1.-1.8(nor-,4-H); 2.8-29 (n 2 1 4H); Mass~~~ m/ (CI: 45 M+1) WO 03/033481 WO 03/33481PCT/lB02104275 127 Example 68 2-Isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-belzo[bl oxazin-4-yl) propylamino}phenyl]propanoic acid N C0 2
H
NN
Ethyl 2-isopropoxy-3-j4- {3 -(7-fluoro-3 ,4-dihydro-2H-benzorblf I,4]oxazin-4yl)propylaminolphenyl]propanoate (600 mg, 1 eq, 1.35 inmol), obtained in example 67, was hydrolyzed following the procedure of example 53 to obtain the title compound (240 mg, yield 43 as viscouls liquid.
'H NilvR (200 MHz, CDCI 3 8: 1.01 J 6.2 Hz, 3H); 1. 16 J 6.2 Hz, 3H); 1.91(quintet, J =6.7 Hz, 2H1); 2.84 (dd, J =14, 8.1 Hz, lH); 3.00 (dd, J 14, 4.2 Hz, 1H1); 3.16-3.34 (in, 6H); 3.42-3.60 (in, 1H); 4.06 (dd, I 8.1, 4.2 Hz, 111), 4.20-4.25 (in, 211), 6.09 (bs, 211); 6.47-6.58 (aromatics, 511); 7.06 J 8.3 Hz, 2H).
IR (neat) ctrf 1 3388 2932, 1722, 1616, 1513.
Mass m)'z 417 Example 69 2-isopropoxy-3- 14-t3-(7-fluoro-3,4-dihydro-2H-benzolbI [1,4]oxazin-4yi)propylamino} phenylipropanoic acid magnesium salt F 0O N0 C0 2 Mg 2 -2 From 2-isopropoxy-3-14- {3-(7-fluoro-3 ,4-dihydro-2Hf-benzolb] [1 ,4]oxazin-4yl)propylamnino~pheniyl]propa-noic acid (240 mng, 1.0 cq, 0.57 inmol), obtained from example 68, and Mg(OMe)2 (25 mng, 0.5 eq, 0.29 rnmol) the desired salt as a powdery solid quantitative yield) following the procedure of example 54.
WO 03/033481 WO 03/33481PCT/lB02104275 128 Mp: 110 0
C.
Example Ethyl (2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo [hi[1,4] oxazin-4-yl) propylaminolphenyl]-2-methoxypropanoate F 0 105 CO Et
H
Starting from ethyl (S)-2-methoxy-3-(4-aminiophenyl)propano ate (500 mg, 1 eq, 2.24 mmol) obtained in preparation 21 and 3-(2-methyl-7-fluoro-3,4-dihydro-2Hbenzo[b][l,4]oxazin-4-yl)propylbromide (711 mg, 1.1 eq, 2.47 mmol) obtained in preparation 17, and following the procedure of example 52, the title compound (380 mg, yield 40 was obtained in the form of mixture of diastereomers as viscous liquid.
1 HNMR (200 MHz, CDCl 3 6: 1.20-1.40 (in, 611); 1. 80-2.00 (in, 211), 2.90-3.02 (mn, 211); 3.02-3.40 (in, 911); 3.90 J =6.3 lIz, 111), 4.10-4.30 (ti, 3H1), 6.40-6.60 (aromatics, 5H); 7.05 J 8.3 Hz, 2H).
IR (neat) cm'1: 3450 2926, 1740, 1617, 1515.
Mass m~z 431 Example 71 [4-{3-(2-methyI-7-fluoro-3,4-dihydro-2H-belzo oxazin-4yl)propylaminophenyll-2-nthoxypropaloic acid F 0 N0 2
H
HO~
Ethyl {3-(2-inetliyl-7-fluoro-3 ,4-dihydro-2H-benzo[bl [1 ,4]oxazin-4yl)propylaminolphenyl]-2-lethoxypropancoate (380 mg, 1 eq, 0.88 mmol), obtained WO 03/033481 PCT/IB02/04275 129 in example 70, was hydrolyzed following the procedure of example 53, to obtain the title compound (150 mg, yield 43 as viscous liquid.
'H NMR (200 MHz, CDC1 3 5: 1.37 J 6.2 Hz, 3H); 1.80-2.00 2H), 2.90- 3.60 13H); 3.98 (dd, J 7.0, 4.3 Hz, 1H), 4.18-4.35 1H), 6.55-6.70 (aromatics, 5H); 7.10 J= 8.0 Hz, 2H).
IR (KBr) cm- 1 3400 2930, 1729, 1614, 1513.
Mass m/z 403.3 805.5 (M 2 Example 72 (2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo [1,4]oxazin-4yl)propylamino} phenyl]-2-methoxypropanoic acid magnesium salt F O fCO 2 Mg 2 N Mg ,NR Me
H
-2 From {3 -(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b] [1,4]oxazin-4yl)propylamino} phenyl]-2-ethoxypropanoic acid (150 mg, 1.0 eq, 0.37 mmol), obtained in example 71, and Mg(OMe)z (16 mg, 0.5 eq, 0.185 mmol) the desired salt as a powdery solid quantitative yield) following the procedure of example 54.
Mp: 208-210 OC.
The compounds of the present invention lowered random blood sugar level, triglyceride, total cholesterol, LDL, VLDL and increased HDL. This was demonstrated by in vitro as well as in vivi animal experiments.
Demonstration of Efficacy of Compounds A) In vitro: a) Determination of hPPARa activity Ligand binding domain of hPPARa was fused to DNA binding domain of Yeast transcription factor Gal 4 in eucaryotic expression vector. Using superfect WO 03/033481 PCT/IB02/04275 130 (Qiagen, Germany) as transfecting reagent HEK-293 cells are transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter. Compound can be added at different concentrations after 42 hrs of transfection and incubated overnight. Luciferase activity as a function of compound binding/activation capacity of PPARa will be measured using Packard Luclite kit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992. 118: 137 -141; Superfect Transfection Reagent Handbook. February 1997. Qiagen, Germany).
b) Determination of hPPARy activity Ligand binding domain of hPPARyl is fused to DNA binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector. Using lipofectamine (Gibco BRL, USA) as transfecting reagent HEK-293 cells arc transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter. Compound can be added at 1 jLM concentration after 48 hrs of transfection and incubated overnight. Luciferase activity as a function of drug binding/activation capacity of PPARyl will be measured using Packard Luclite kit (Packard, USA) in Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992. 118: 137 -141; Guide to Eukaryotic Transfections with Cationic Lipid Reagents. Life Technologies, GIBCO BRL, USA).
Example No Concentration PPARa Concentration PPARy 3 50 tM 4.7 1 .tM 9 50 pM 4.6 1 l.M 6.2 18 50 gM 4.4 1 .M 1.2 23 50 ptM 4.2 1 tM 4.4 27 50 iM 4.3 1 .tM c) Determination of HMG CoA reductase inhibition activity Liver microsome bound reductase is prepared from 2% cholestyramine fed rats at mid-dark cycle. Spectrophotometric assays are carried out in 100 mM
KH
2
PO
4 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 [tg of liver WO 03/033481 PCT/IB02/04275 131 microsomal enzyme. Total reaction mixture volume was kept as 1 ml. Reaction was started by addition of HMG CoA. Reaction mixture is incubated at 37 °C for 30 min and decrease in absorbance at 340 nm was recorded. Reaction mixture without substrate was used as blank (Goldstein, J. L and Brown, M. S. Progress in understanding the LDL receptor and HMG CoA reductase, two membrane proteins that regulate the plasma cholesterol. J. Lipid Res. 1984, 25: 1450 1461). The test compounds will inhibit the HMG CoA reductase enzyme.
B) In vivo a) Efficacy in genetic models Mutation in colonies of laboratory animals and different sensitivities to dietary regimens have made the development of animal models with non-insulin dependent diabetes and hyperlipidemia associated with obesity and insulin resistance possible. Genetic models such as db/db and ob/ob (Diabetes, (1982) 31(1) 1- 6) mice and zucker fa/fa rats have been developed by the various laboratories for understanding the pathophysiology of disease and testing the efficacy of new antidiabetic compounds (Diabetes, (1983) 32: 830-838; Annu. Rep. Sankyo Res.
Lab. (1994). 46: 1-57). The homozygous animals, C57 BL/KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant Clin. Invest., (1990) 85 962-967), whereas heterozygous are lean and normoglycemic. In db/db model, mouse progressively develops insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled. The state of pancreas and its course vary according to the models. Since this model resembles that of type II diabetes mellitus, the compounds of the present invention will be tested for blood sugar and triglycerides lowering activities.
Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight range of 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animal house, were used in the experiment. The mice are provided with standard feed (National Institute of Nutrition (NIN), Hyderabad, India) and acidified water, ad libitum. The animals having more than 350 mg dl blood sugar will be used for testing. The number of animals in each group was 4.
WO 03/033481 PCT/IB02/04275 132 Test compounds are suspended on 0.25% carboxymethyl cellulose and administered to test group at a dose of 0.1 mg to 30 mg kg through oral gavage daily for 6 days. The control group receives vehicle (dose 10 ml kg). On 6th day the blood samples will be collected one hour after administration of test compounds vehicle for assessing the biological activity.
The random blood sugar and triglyceride levels can be measured by collecting blood (100 gl) through orbital sinus, using heparinised capillary in tubes containing EDTA which was centrifuged to obtain plasma. The plasma glucose and triglyceride levels can be measured spectrometrically, by glucose oxidase and glycerol-3-P04 oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits, Hyderabad, India) methods respectively.
The blood sugar and triglycerides lowering activities of the test compound are calculated according to the formula.
No adverse effects were observed for any of the mentioned compounds of invention in the above test.
Compound Dose (ig kg) Reduction in Blood Triglyceride Glucose Level Lowering 3 3 33 29 18 3 16 The ob/ob mice were obtained at 5 weeks of age from Bomholtgard, Denmark and were used at 8 weeks of age. Zucker fa/fa fatty rats were obtained from IffaCredo, France at 10 weeks of age and were used at 13 weeks of age. The animals were maintained under 12 hour light and dark cycle at 25 1 Animals were given standard laboratory chow (NIN, Hyderabad, India) and water, ad libiturn (Fujiwara, Yoshioka, Yoshioka, Ushiyama, I and Horikoshi, H.
Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes. 1988. 37: 1549 -1558).
The test compounds were administered at 0.1 to 30 mg/kg dose for 9 days.
The control animals received the vehicle (0.25 carboxvmethvlcellulose, dose rnL/kg) through oral gavage.
WO 03/033481 PCT/IB02/04275 133 The blood samples were collected in fed state 1 hour after drug administration on 0 and 9 day of treatment. The blood was collected from the retroorbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for triglyceride, glucose, free fatty acid, total cholesterol and insulin estimations. Measurement of plasma triglyceride, glucose, total cholesterol was done using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India). The plasma free fatty acid was measured using a commercial- kit from Boehringer Mannheim, Germany. The plasma insulin was measured using a RIA kit (BARC, India). The reduction of various parameters examined are calculated according to the formula given below.
In ob/ob mice oral glucose tolerance test was performed after 9 days treatment. Mice were fasted for 5 hrs and challenged with 3 gm/kg of glucose orally.
The blood samples were collected at 0, 15, 30, 60 and 120 min for estimation of plasma glucose levels.
The experimental results from the db/db mice, obiob mice, Zucker falfa rats suggest that the novel compounds of the present invention also possess therapeutic utility as a prophylactic or regular treatment for diabetes, obesity, cardiovascular disorders such as hypertension, hyperlipidaemia and other diseases; as it is known Sfrom the literature that such diseases are interrelated to each other.
Blood glucose level and triglycerides are also lowered at doses greater than mg/kg. Normally, the quantum of reduction is dose dependent and plateaus at certain dose.
b) Plasma triglyceride and Cholesterol lowering activity in hypercholesterolemic rat models Male Sprague Dawley rats (NIN stock) were bred in DRF animal house.
Animals were maintained under 12 hour light and dark cycle at 25 1 OC. Rats of 180 200 gram body weight range were used for the experiment. Animals are made hypercholesterolemic by feeding 2% cholesterol and 1% sodium cholate mixed with standard laboratory chow [National Institute of Nutrition (NIN), Hyderabad, India] for 6 days. Throughout the experimental period the animals were maintained on the WO 03/033481 PCT/IB02/04275 134 same diet (Petit, Bonnefis, M. Rey, C and Infante, R. Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normo- and hyperlipidemic rats.
Atherosclerosis. 1988. 74 215- 225).
The test compounds can be administered orally at a dose 0.1 to 30 mg/kg/day for 3 days. Control group was treated with vehicle alone (0.25% Carboxymethylcellulose; dose 10 ml/kg).
The blood samples were collected in fed state 1 hour after drug administration on 0 and 3 day of compound treatment. The blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for total cholesterol, HDL and triglyceride estimations. Measurement of plasma triglyceride, total cholesterol and HDL are were done using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India). LDL and VLDL cholesterol were calculated from the data obtained for total cholesterol, IHIDL and triglyceride. The reduction of various parameters examined are calculated according to the formula.
Example Dose Triglyceride Total HDL LDL VLDL No. mg/kg Cholesterol 3 10 77 69 254 80 77 18 10 77 64 260 74 77 reduction; t increase c) Plasma triglyceride and total cholesterol lowering activity in Swiss albino mice and Gunie pigs Male Swiss albino mice (SAM) and male Guinea pigswere obtained from NIN and housed in DRF animal house. All these animals are maintained under 12 hour light and dark cycle at 25 1 OC. Animals were given standard laboratory chow (NIN, I-Iyderabad, India) and water, ad libitum. SAM of 20 25 g body weight range and Guinea pigs of 500 700 g body weight range are used (Oliver, Plancke, M.
Marzin, Clavey, Sauzieres, J and Fruchart, J. C. Effects of fenofibrate, WO 03/033481 PCT/IB02/04275 135 gemfibrozil and nicotinic acid on plasma lipoprotein levels in normal and hyperlipidemic mice. Atherosclerosis. 1988. 70 107 114).
The test compounds were administered orally to Swiss albino mice at 0.3 to mg/kg/day dose for 6 days. Control mice are treated with vehicle (0.25% Carboxymethylcellulose; dose 10 ml/kg). The test compounds are administered orally to Guinea pigs at 0.3 to 30 mg/kg/day dose for 6 days. Control animals are treated with vehicle (0.25% Carboxymethylcellulose; dose 5 ml/kg).
The blood samples were collected in fed state 1 hour after drug administration on 0 and 6 day of treatment. The blood was collected from the retroorbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for triglyceride and total cholesterol (Wieland, O. Methods of Enzymatic analysis. Bergenneyer, H. Ed., 1963. 211 214; Trinder, P. Ann. Clin. Biochem. 1969. 6: 24 27). Measurement of plasma triglyceride were done using commercial kits (Dr. Reddy's Diagnostic Division, Hyderabad, India).
Compound Dose (mg kg) Triglyceride Lowering 3 10 6 10 27- 10 43 18 10 61 d) Body weight reducing effect in cholesterol fed hamsters Male Syrian Hamsters were procured from NIN, Hyderabad, India. Animals were housed at DRF animal house under 12 hour light and dark cycle at 25 1 0
C
with free access to food and water. Animals are maintained with 1% cholesterol containing standard laboratory chow (NIN) from the day of treatment.
The test compounds can be administered orally at 1 to 30 mg/kg/day dose for days. Control group animals were treated with vehicle (Mill Q water, dose ml/kg/day). Body weights are measured on every 3 d day.
00 136 Formulae for calculation 1. Percent reduction in Blood sugar triglycerides total cholesterol will be Scalculated according to the formula Percent reduction OT X 100 00
TC/OC
OC Zero day control group value C" OT Zero day treated group value STC Test day control group value TT Test day treated group value 2. LDL and VLDL cholesterol levels will be calculated according to the formula: Triglyceride LDL cholesterol in mg/dl Total cholesterol HDL cholesterol ril mg/dl VLDL cholesterol in mg/dl=[Total cholesterol-HDL cholesterol-LDL cholesterol] mg/dl.
It is to be understood that a reference herein to a prior art document does not constitute an admission that the document forms part of the common general knowledge in the art in Australia.
In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

Claims (16)

  1. 2. A compound according to claim 1, wherein the substituents on R' to Rare selected from halogen, hydroxyl, nitro, thio or unsubstinited or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkoxy, alkoxyalkyl, aryloxyalkyl, arolkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl, alkylamino, alkylthio groups, carboxvlic acid or its derivatives or sulfonic acid or its derivatives; substituents on R 7 are selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives or sulfonic acid or its derivatives. 00 139
  2. 3. A compound according to claim 1, wherein R R 2 and R R 4 when attached n to the carbon atom, are same or different and represent hydrogen, halogen or alkyl; 00 one or both of R 3 and R 4 represent oxo or thioxo group when they are attached to carbon atom; R 3 and R 4 when attached to nitrogen atom represent hydrogen or alkyl; 005 R5 represents hydrogen atom or forms a bond together with the adjacent group R 6; R6 C1 represents hydrogen or forms a bond together with R 5 R 7 represents hydrogen or substituted or unsubstituted alkcyl, aryl or aralkyl; R' represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl or aralkyl; m and n are integers ranging from 0 2.
  3. 4. A compound according to any one of claims 1-3, which is selected from: Ethyl {3 -(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate; ()Ethyl ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propylainino phenyl]-2-ethoxypropanoate Ethyl {3-(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate; ,4-Dihydro-2H-benzo[b] [I ,4]oxazin-4-yl)propylamino~phenyl]-2- ethoxypropanoic acid or its salts; f{3 -(3,4-Dihydro-2H-benzo[b] 1,4]oxazin-4-yl)propyl amino} phenyl]-2- ethoxypropanoic acid or its salts (3 ,4-Dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propylamino~phenyl]-2- ethoxypropanoic acid or its salts; Ethyl 3-[4-N-heptyl-N- {2-(3-oxo-3,4-dihydro-2H-benzo[b] 1,4]oxazin-4- yl)ethylaminolphenyl]-2-ethoxyprbopanoate Ethyl 3-[4-N-heptyl-N- {2-(3-oxo-3 ,4-diydro-2H-benzto[b] [1 ,4]oxazin-4- yl)ethiylaminolphenyl]-2-ethoxypropanoate; Ethyl 3-[4-N-heptyl-N- {2-(3-oxo-3 ,4-dihydro-2H--benzo[b] [1 ,4]oxazin-4- yl)ethyl amino) phenyl]-2-ethoxypropanoate; WO 03/033481 WO 03/33481PCT/lB02104275 140 W± 3-[4-N-Heptyl-N- {2-(3-oxo-3,4-dihydro-2H-benzo[b] [1i,4]oxazin-4- yl)ethylaminolphenyl]-2-ethoxypropanoic acid or its salts H+ 3-[4-N-Heptyl-N- {2-(3-oxo-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4- yl)ethylaminolphenyl]-2-ethoxypropanoic acid or its salts 3-[4--N-Heptyl-N- {2-(3-oxo-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4- yl)ethylaminolphenyl]-2-ethoxypropanoic acid or its salts; Methyl 2-ethoxy-3 {N-heptyl-N-(2-(3 ,4-dih-ydro-2H-benzo[b]oxazin-4-yl)-2- oxoethyl)aniiinomethiyllphenyllpropanoate Methyl 2-ethoxy-3-4- {N-heptyl-N-(2-(3 ,4-dihydro-2H-benzo[b~oxazin-4-yl)-2% oxoethyl)aminomethyllphenyljpropanoate Methyl 2-ethoxy-3 {N-heptyl-N-(2-(3 ,4-dihydro-2H-benzo[b]oxazin-4-yl)-2- oxoethyl)arninorethyllphenyljpropanoate; ()2-Ethoxy-3 {N-heptyl-N-(2-(3 ,4-diliydro-2H-benzo[b]oxazini-4-yl)-2- oxoethyl)aminomethyllphenyllpropanoic acid or its salts; 2-Eth-oxy-3 {N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2- oxoethyl)aminomethyllphenyl]propanoic acid or its salts 2-Ethoxy-3-[4- {N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2- oxoethyl)arninornetlhytlphenyl]propanoic acid or its salts; ()Methyl 3 {5-(3,4-dihydro-2H-benzo[b][l ,4]oxazin-4-yl)-5-oxopentylamino} phenyl]-2-ethioxypropano ate Methyl 34[4- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)-5-oxopeintylamino} phenyl]-2-ethoxypropanoate ()Methyl {5-(3,4-dihydro-2H-benzo[bl [1 ,4]oxazinl-4-yl)-5-oxopentylamino} phenyl]-2-ethoxypropanoate; {5-(3,4-Dihydro-2H-benizo[b] [1 ,4]oxazin-4-yl)-5-oxopcntylamino} phenyl]- 2-ethoxypropanoic acid or its salts;- WO 03/033481 WO 03/33481PCT/lB02104275 141 3-114- ,4-Dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)-5-oxopentylamino} phenyl]- 2-ethoxypropanoic acid or its salts 3 {5-(3,4-Dihydlro-2H-benzo[b][l ,4]oxazin-4-yl)-5-oxopentylaniino} phenyl]- 2-ethoxypropanoic acid or its salts; Methyl 3 {3-(3,4-dihydro-2H-benzorb][l ,4]oxazin-4-yI)propylamino} phenyl]-2-ethoxypropanoate.; Methyl 3 (3 -(3,4-dihydro-2H-benzo[b][l ,4]oxaziin-4-yl)propylarin'O) phenyl]-2-ethoxypropanoate Methyl 3-113- {3-(3,4-dihydro-2H-benzo[bl [1 ,4loxazin-4-yl)propylamino} phenyl]- 2-ethoxypropanoate 3-[3 f 3-(3 ,4-Dihydro-2H-banzo[b] 1,4Joxazin-4-yl)propylaminolphenyl]-2- ethoxypropanloic acid or its salts 3-1[3 ,4-Dihydro-2H-benzo[b] 1,4]oxazin-4-yl)propylamino lphenyl]-2- ethoxypropanoic acid or its salts; 3-113 ,4-Dihydro-2H-benzo[b] 1,4]oxazin-4-yl)propylaminolphenyl]-2- ethoxypropanoic acid or its salts; MethylI 3-[4-{3-(7-fluioro-3,4-dihydro-2H-b-enzo[b][11,4]oxazin-4-yl) propylamino}phenyl]-2-ethioxypropanoate Methyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propylaminolphenyl]-2-ethoxypropanoate Methyl -(7-fluaoro-3,4-dihydro-2H-benzo1b]1 ,4]oxazin-4-yl) propylaminolphenyljj-2-ethoxypropanioate; W± {3-(7-Fluoro-3 ,4-dihydro-2H-benzo[b][ l,4]oxazin-4-yl)propylamino} phenyl] -2-ethoxypropanoic acid or its salts {3-(7-Fluoro-3,4-dihiydro-2IH-benzo[b] [l,4]oxazin-4-yl)propylaminoj phenyl]-2-ethoxypropanoic acid or its salts WO 03/033481 WO 03/33481PCT/lB02104275 142 f 3-(7-Fluoro-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propylamino} phienyl] -2-ethoxypropanoic acid or its salts; M± Methyl 2-ethoxy-3-[4- ,4-dihydro-2H-benzojb] [1 ,4]oxazin-4- yl)propyloxy)belzyl amilophellpropafloate H+ Methyl 2-ethoxy-3-[4- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4- yl)propyloxy)benzylaninophelpropaloate Methyl 2-ethoxy-3-[4- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4- y1)propylo~xy)benzyllamilophelyl]pt~opafoate Methyl 2-ethoxy-3 t4-(3 ,4-dihydro-2-H-benzo[b] 1 ,4oxazin-4- yl)propyloxy)benzyl} aminophenyllipropanoate H+ Methyl 2-ethoxy-3-[3 -(3,4-dihydro-2H-benzo[bl [1 ,4]oxazin-4- yl)propyloxy)benzyl arninophenyllpropano ate Meth-yl 2-eth-oxy-3-[3- ,4-dihydro-2H-benzo [bI]l ,4]oxazin-4- yl)propyloxy)oenzyl} aminophenyllpropanoate; W2-Ethoxy-3-[4- ,4-dihydro-2H-benzo[b][l ,4]oxazin-4-yl)propyloxy) benzyll aminophelyl]popaloic acid or its salts; 2-Ethoxy-3 {4-(3-(3,4-dihydro-2H-belzoIb]1,4]oxazin-4-yl)propyloxy) benzyl} aminophenyl]propanoic acid or its salts 2-Ethoxy-3-14- ,4-dihydro-2H-benzoIbl[1 ,4]oxazin-4-yl)propyloxy) benzyl} aminophenyl]propanoic acid or its salts 2-Ethoxy-3 ,4-dihydro-2H-benzol~bl[1 ,4]oxazin-4-yl)propyloxy) -benzyl} aminophenylipropanoic acid or its salts; 2-Ethoxy-3 ,4-dihydro-2H-benzolb] [t ,4]oxazin-4-yl)propylqxy) benzyl} aminophenyl]propanoic acid or its salts; 2-Ethoxy-3 ,4-dihydro-2J1-benzo[b] 1,4]oxazin-4-yl)propyloxy) benzyl} aminophenyllpropafloic acid or its salts; WO 03/033481 WO 03/33481PCT/lB02104275 143 W± Ethyl 2-ethoxy-3-[4- {3-(3,4-dihydro-2H-benzo Ibl j1 ,4]thiazin-4- yl)propylamnino}phenyljpropanoate; H+ Ethyl 2-ethoxy-3-[4- {3-(3,4-dihydro-2H-benzo [1 ,4]thiazin-4- yl)propylaminolphenyl]propanoate Ethyl 2-ethoxy-3-14-;{3-(3 ,4-dihydro-2H-benzo [l,4]thiazin-4- yl~propylaminolphenyl]propanoate; W± 2-Ethoxy-3 .44- ,4-dihydro-2H-benzofblfl,4]thiazin-4- yl)propylamino lphenyl]propanoic acid or its salts; 2-Ethoxy-3 {3 ,4-dihydro-2H-benzo~Ib[l,4]thiazin-4- yl)propylamino~phenyl]propanoic acid or its salts;- H- 2-Ethoxy-3-[4- {3 ,4-dihydro-2H-benzo [bI [l,4]thiazin-4- yl)propylamino lpenyllpropanoic acid or its salts; Ethyl 2-ethoxy-3-[4- {2-(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) othylaminolphenyllpropanoate Ethyl 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) ethylamninolphenyl]propanoate Ethyl 2-ethoxy-3-[4- {2-(3,4-dihydro-2H-benzo jb] [1 ,4]oxazin-4-yl) ethylaminolphenyl]ptopafloate; W± 2-Ethoxy-3-[4- f{2-(3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)ethylaminoj phenyl]propanoic acid or its salts 2-Ethoxy-3-[4- {2-(3,4-dihydro-2H-benzob] [l 1,4]oxazin-4-yl)ethylamino} phenyl]propanoic acid or its salts 2-Ethoxy-3-[4- {2-(3,4-dihydro-2H-benzolb] 1,4]oxazin-4-yl)ethylamino} phenyl~propanoic acid or its salts; WO 03/033481 WO 03/33481PCT/lB02104275 144 ()Methyl 2-ethoxy-3-[4-[4- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)ethoxy} phenylaminomethyl]phenyllpropano ate Methyl 2-ethoxy-3-[4-[4- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)ethoxy} phienylaminomethyl]phenyl]propano ate; Methyl 2-ethoxy-3-[4-[4- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)ethoxy} phenylaminomethyl]phenyl]propano ate; ()2-Ethoxy-3-[4-[4- ,4-dih-ydro-2H-benoizo[b] [1 ,4]oxazin-4-yl)ethoxC-yj phenylaminomethyl]phenyl]prcopanoic acid or its salts 2-Ethoxy-3-[4-[4- ,4-dihydro-2H-benzo[b] 1,4loxazin-4-yl)ethoxy} phenylaininomethyllphenyllpropanoic acid or its salts; 2-Ethoxy-3-[4-[4- ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)ethoxy} phenylarniinoreth-yl]phenyl]propanoic acid or its salts; Ethyl f 3-(7-fluoro-3 ,4-dihydro-2H-belizo[b] [1 ,4]oxazin-4-yl) propylaminolphenyl]-2-ethoxypropanoate M+ Ethyl 3 {3-(7-fluoro-3 ,4-dihydro-2H-benzo[b][1l,4]oxazin-4-yl) propylaminolphenyl]-2-ethoxypropaaoate Ethyl 3-[14- f{3-(7-fluoro-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propylaminolphenyl]-2-ethoxypropanoate WEthyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][l ,4]oxazini-4-yl) propylaminolpienyl-2-nethoxypropaloate Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2W-benzo~b] [1 ,4]oxazin-4-yl) propylaminolphenyl]-2-meth-oxypropanoate Ethyl -(7-fluoro-3,4-dihydro-2H-benzolb] [1 ,4]oxazin-4-yl) propylaminolphenyl-2-methoxypropaloate {3-(7-Fluoro-3 ,4-dihydro-211-benzo[b 1,4]oxazin-4-yl)propylaminoI phenyl]-2-methoXYPropaloic acid or its salts WO 03/033481 WO 03/33481PCT/lB02104275 145 N+ f{3-(7-Fluoro-3,4-dihydro-2H-benzo jb] [1 ,4]oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoic acid or its salts 3-[4-f 3-(7-Fluoro-3 ,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoic acid or its salts Ethyl 3-[4-f {3-(2-methyl-7-fluoro-3,4-dihiydro-2H-benzo[b] [1 ,4]oxazin-4-yl) propylaminolphenyl]-2-ethoxypropanoate Ethyl 3-[4-f {3-(2-methyl-7-fluoro-3 ,4-dihydro-2H-benzo [bi[1 ,4]oxazin .4-yl) propylaminolphenyll-2-ethoxypropanoate Ethyl 3-114-{3 -(2-methyl-7-fluoro-3 ,4-dihydro-2H-benzolb] [1,4]oxazin-4-yl) propylaminolphenyl]-2-ethoxypropanoate W± 3-[4-f{3-(2-mthyl-7-Fuoro-3 ,4-dihydro-2H-benzo~b] [1 ,4joxazin-4- yl)propylamino} phenyl]-2-ethoxypropanoic acid or its salts 3-[4-f{3-(2-methyl-7-Fluoro-3 ,4-dihydro-2H-benzolb] [1,4]oxazin-4- yl)propylarnino} phenyl]-2-ethoxypropanoic acid or its salts H- 3-4-{3-(2-methyl-7-Fluoro-3,4-dihydro-2H-belzo[b1[1 ,4]oxazin-4- yl)propylamnino} phenyl]-2-ethoxypropanoic acid or its salts Ethyl 34[4- {3-(2-methyl-3,4-dihydro-2H-belzo[b] [1,4]oxazin-4-yl) propylaminolphenyl-2-thoxypropaloate M+ Ethyl 3 -(2-methyl-3,4-dihydro-2H-benzo[b][ 1,4]oxazin-4-yl) propylaminolphenyl-2-ethoxypropaloate Ethyl -(2-methiyl-3,4-dihydro-2H-belzoIb][l ,4]oxazin-4-yl) propylaminopenyl]-2-ethoxypropafloate W± 3-[i4- {3-(2-methyl-3 ,4-dihydro-2H-benzo[b]l[1 ,4]oxazin-4-yl)propylamino} phenyi.]-2-ethoxypropanoic acid or its salts {3-(2-mecthyl-3 ,4-dihydro-2H-benzollbl[l,4]oxazin'-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid or its salts WO 03/033481 WO 03/33481PCT/lB02104275 146 {3-(2-methyl-3 ,4-dihydro-2H-benzo~b] [1 ,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid or its salts Ethyl 3-114- {3-(2-methyl-3 ,4-dihydro-2H-benzolbj [1 ,4]oxazin-4-yl) propylaminolphenyl]-2-methoxypropanoate Ethyl {3-(2-methyl-3 ,4-dihydro-2H-benzo[bl [1 ,4]oxazin-4-yl) propylarninolphenyl]-2-methoxypropanoate Ethyl 3 {3 -(2-methyl-3 ,4-dihydro-2H-benzo[b] [1 ,4joxazin-4-yl) propylaminolphenyl]-2-methoxypropanoate M± 3 3-(2-methyl-3,4-dihydro-2H-benzo[b] [1 ,4]oxazini-4- yl)propylaminolphenyl]-2-methoxypropalnoic acid or its salts N± 3 {3-(2-methyl-3,4-dihydro-2H-benzolb] [1,4]oxazin-4- yl)propylaminolphenyl-2-methoxypropaloic acid or its salts 3-[4-f {3-(2-methyl-3,4-dihydro-2H-benzo[b] [1 ,4loxazin-4- yl)propylaminolphenyl]-2-methoxypropafloic acid or its salts M± Ethyl' {3-(2-propyl-3,4-dihydro-2H-benzo~bj [1 ,4]oxazin-4-yl) propylaminolphenyll-2-ethoxypropanoate Ethyl {3-(2-propyl-3,4-dihydro-21-benzo[b]l[1 ,4]oxazin-4-yl) propylarninlolphenyl]-2-ethoxypropanoate Ethyl 34[4- {3-(2-propyl-3,4-dihydro-211-benzo[b] [1 ,4]oxazin-4-yl) propylaminolphenyl]-2-ethoxypropanoate 3-[4-{3-(2-propyl-3 ,4-dihydro-2H-benzo [bi[1 ,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid or its salts H+ 3-[4-{3-(2-propyl-3 ,4-dihiydro-211-benzollb][l ,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid or its salts 3-[4-f {3-(2-propyl-3,4-dihydro-21I-benzo[bl]l ,4]oxazin-4-yl)propylamino phenyl]-2-ethoxypropanoic acid or its salts WO 03/033481 WO 03/33481PCT/lB02104275 147 Ethyl f{3-(2-propyl-3,4-dihydro-2H-benzolbl [1 ,4]oxazin-4-yl) propylaminolphenyill-2-methoxypropanoate Ethyl {3 -(2-propyl-3,4-dihydro-2H-benzojb] Li ,4]Dxazin-4-yl) propylamino}phenyl]-2-methoxypropanoate Ethyl (2S)-3 f{3-(2-propyl-3 ,4-dihydro-2H-benzolb] [1 ,4]Dxazin-4-yl) propylaminolphenyl]-2-methoxypropanoate 3 {3-(2-propyl-3 ,4-dih-ydro-2H-benzo 1,4]oxazin-4-yl)propylamino I phenlyl-2-methoxypropanoic acid and its salts -(2-propyl-3 ,4-dihydro-2H-benzolbl]l,4]oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoic acid and its salts {3 -(2-propyl- 3 ,4-dihydro-2H-benzo[b][l ,4ljoxazin-4-yl)propylamino} phenyl]-2-rnethoxyprapanoic acid and its salts Ethyl 2-isopropoxy-3-[4- {3-(7-fluoro-3 ,4-dihydro-211-benzolb] [1,4]oxazin-4-yl) propylaminolphenyl] propanoate Ethyl 2-isopropoxy-3-[4- {3-(7-fluoro-3,4-dihydro-2H-benzo~b] [1 ,4]oxazin-4-yl) propylaminolphenyl] propanoate* Ethyl 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-elzo[b] [1 ,4joxazin-4-yl) propylaminolphenyll propanoate 2-Isopropoxy-3-[4- {3 -(7-fluoro-3,4-dihydro-2H-benzo[b][Li,4]oxazin-4-yl) propylaminolphenyl]propaloic acid and its salts 2-Isopropoxy-3-[4- 3 -(7-fluaoro-3,4-dihydro-2H-benzo[bl [1 ,4]oxazin-4-yl) propylaminolphenyl]propanoic acid and its salts 2-Isopropoxy-3-[4- {3-(7-fluoro-3,4-dihydro-2H-benzo~b][Li,4]oxazin-4-yl) propylaminolphenyllpropaloic acid and its salts Ethyl {3-(2-nietlhyl-7-fluoro-J ,4-dihydro-2H-benzo[bl [1 ,4]oxazin-4-yl) propylaminolphenyl]-2-methoxypropalo ate WO 03/033481 WO 03/33481PCT/lB02104275 148 Ethyl {3-(2-methyl-7-fluoro-3 ,4-dihydro-2H-benzo[b][l ,4]oxazin-4-yl) propylamino~phenyl]-2-methoxypropanoate Ethyl 3-[4-1 3 -(2-rnethyl-7-fiuoro-3,4-dihydro-2H-benzo[bl [1 ,4]oxazin-4-yl) propylaminolphenyl]-2-methoxypropanoate M± 3-[4-f{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b] [1 ,4]oxazin-4- yl)propylaminolphenyl]-2-n-ethoxypropaloic acid and its salts N+ 3 {3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo [hi[ l,4]oxazin-4- yl)propylaminolphenyl-2-methoxypropaloic acid anid its salts {3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzotbi [1,4]oxazin-4- yl)propylaminolphenyl-2-methoxypropaloic acid and its salts [2S,N(1R)]-N-(2-hydroxy-l -phenylethyl)-2-ethoxy-3-[4- ,4-dih-ydro-21- benzo[b][ 1,4]oxazin-4-yl)propylamino}phenylpropaflamfide; [2R,N( lR)]-N-(2-hydroxy-l-phenylethyl)-2-ethoxy-3 -(3,4-dihydro-2H- benzo[b] [1 ,4]oxazin-4-yl)propylaminolpheflylipropaflamide; 2S,N(lR)]-N-(2-hydroxy- 1-phenylethiyl)-2-ethoxy-3 f{3-(7-fluoro-3,4-dihydro-2H- benzo[b] [1 ,4]oxazin-4-y1)propylaminolphel]prop aflamide [2R,N(1R)1-N-(2-hydroxy- 1 -phenylethyl)-2-ethoxy-3-[4- {3-(7-fluoro-3 ,4-dihydro-H- benzo[b] [1 ,4]oxazin-4-yl)propylamilpheflylpropaflamide [2S,N( 1R)]-N-(2-hydroxy-l -phenylethyl)-2-othoxy-3-[4- {3 -(3,4-dihydro-2H- benzo[b] [1 ,4]oxazin-4-yl)propylaminolpel1pafamfide hydrochloride salt; [2R,N(lR)]-N-(2-hydroxy-l1-phenylethyl)-2-ethoxy-3-14- {3 -(3,4:-dihydro-2H- beuzo[b] [1 ,4]oxazin-4-yl)propylaminopheyl]propalamide hydrochloride salt; A compound according to claim 1 wherein the pharmaceutically acceptable salt is Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; N,N'-diacetylothylenediamine, betaine, WO 03/033481 PCT/IB02/04275 149 caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, -tromethamine, diethanolamine, meglumine, ethylenediamine, N,N'-diphenylethylenediamine, N,N'- dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine; alkylphenylamine, glycinol, phenyl glycinol; glycine, alanine, valine, leucine, to isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, omrnithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids; D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts; sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates, ammonium or substituted ammnonium salts or aluminium salt.
  4. 6. A process for the preparation of the compound of formula (I) R1 X/ R3 R5 O R2 (CR 1 0 R 1 )n-W-(CRioR11)m -Ar YR N OR 7 H R4 as defined in claim 1 which comprises a. reacting the compound of formula (IIIa) Ri X R 3 R N (CR1o0R II)n-Li (III a) NR1 4 R 2 -N where L 1 is a leaving group and all other symbols are as defined above with a compound of formula (IIIb) 150 SR 5 6° 00 HW-(CR 1 R 1 1 )mAr YR 9 (III b) OR 7 0where W represents NR 1 2 or -O-aryl-(CR'lR' )o-NR 2 and all symbols are as defined 00 C1 above to yield a compound of formula defined above; or C b. Reacting a compound of formula (Ill c) SR X R 3 S(III c) R2 N R 4 where all symbols are as defined above with a compound of formula (Efd) R 5 L'-(CR1R1 -W-(CR 0 R )m-ArR YR9 (III d) OR 7 where L' is a leaving group,W represents NR' 2 or -O-aryl-(CRi'R")o-NR' and all other symbols are as defined above to produce a compound of formula or c. Reacting a compound of formula (Mfle) R 1 X R 3 I -(CRoR1 )n-W-(CRR )m-Ar-CHO (III e) R21/ N .R4 where W represents NR 12 or -O-aryl-(CRlR'l)o-NR 1 2 and all symbols are as defined above with a compound of formula (IIIf) R802C P()(OR3)2 (llf) OR 7 where R 13 represents (CI-C 6 )alkyl and all other symbols are as defined above to yield compound of formula defined above, 00 t51 and optionally, converting the compound of formula obtained in any of the processes described above into a pharmaceutically acceptable salt thereof or 00 O pharmaceutically acceptable solvate thereof; or 00 5 d. Reducing a compound of formula (IVa) SX R3 0 S -(CR R")n-W-(CRoRl )m-Ar (IVa) R 2 N R 7 N 4 OR 7 which represents a compound of formula where R 5 and R 6 together represent a bond and Y represents an oxygen atom and all other symbols are as defined above, to yield a compound of the formula where R 5 and R 6 each represent hydrogen atom and all other symbols are as defined above; or e. Reacting a compound of formula (MIe) R, .X R 3 :-(CROR")n-W-(CRioR")m-Ar-CHO (III e) R NR4 where W represents NR' 2 or -O-aryl-(CR' 0 R'")o-NR 1 2 and all other symbols are as defined above with a compound of formula (IVb) 6 R 5 CO2 R8 (IVb) OR 7 where R 5 represents hydrogen and all other symbols are as defined above to yield compound of formula defined above; or f. Reacting a compound of formula (Ig) WO 03/033481 PCT/IB02/04275 152 R 1 R 3 R1 N (CRoR)n- C-(CRoR)o-L 1 (III g) where L' is a leaving group, n and o are integers ranging from 0-6 and all other symbols are as defined above, with a compound of formula (IIIb) R 5 R O HW-(CR 1 R 1 1 )m-Ar YR 9 (III b) OR 7 where W represents NR 12 and all other symbols are as defined above to yield a compound of formula where W represents -C(=O)-(CRloR 1 )o-NR 1 2 and all other symbols are as defined above; or g. Reacting a compound of formula (IIIi) 1R R 1 R 3 R (CR10 11 )O -(CRoR11),-G 1 (-Gi) H R where n and p are integers ranging from 0-6, G' is CHO or NH 2 and all other symbols are as define above with a compound of formula (IIIh) R 5 O G2 C OR11 R6 (lllh) G -(CRR )q Ar YR OR 7 where q is an integer ranging from 0-6, G 2 is CHO or NH 2 and all other symbols are as defined above to yield a compound of formula where W represents -O-aryl- (CRIOR I )o-NR 1 2 and all other symbols are as defined above; or h. i. Reacting a compound of formula (I) 00 O 153 O 3R X R5 O /R 60 (I) R -(CRR 1 n R-W (CR'OR YR SH R4 OR 7 where all symbols are as defined above and Y represents oxygen or YR 8 represents a 00 halogen atom or COYR 8 represent a mixed anhydride group and all other symbols are as defined above with an amine of formula NHR R 9 where R 8 and R 9 are as defined C 5 above and optionally; ii. Resolving the compound of formula obtained above into stereoisomers; or i. Hydrolysing a compound of formula (I) R R 3 R 5 R6O R -(CR OR11)n-W-(CROR11,---Ar R R N- a 4 o H R 4 OR where R 8 represents unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl group and all other symbols are as defined above to a compound of formula wher R 8 represents hydrogen. optionally coverting the compound of formula obtained in any of the processes described above into a pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate thereof.
  5. 7. An intermediate of formula (Illd) R 5 RO L -(CRoR"),-W-(CROR L (YRd) OR 7 or a tautomeric form thereof, or a stereoisomer thereof, or a polymorph thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein L' is a leaving group; 00 154 O W represents NR' 2 2 -s -O-aryl-(CRR'" ')o-NR2, where R 2 represents hydrogen or 00 substituted or unsubstituted group selected from alkyl, aryl or aralkyl groups; o is an integer ranging from 0-4; R 1 0 and R" are same or different and represent hydrogen or unsubstituted or unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl 00 group; Ar represents substituted or unsubstituted divalent single or fused aromatic or heterocyclic group; R 5 represents hydrogen atom, hydroxy, alkoxy, halogen, alkyl, M n substituted or unsubstituted aralkyl group or forms a bond together with the adjacent group R6; R 6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, C 10 substituted or unsubstituted aralkyl or R 6 forms a bond together with R 5 R 7 represents hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R 8 represents hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NR 9 where R 9 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl, or heteroaralkyl groups; or R 8 and R 9 together form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms, which optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; m and n are integers ranging from 0-6.
  6. 8. An intermediate of formula (IlIg) 1 R 3 I X/ R 0 S C R i O R n- -(CR R)o-L' (lg) H R or a tautomeric form thereof, or a stereoisomer thereof, or a polymorph thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein R 2 and R 3 R 4 when attached to the carbon atom, are same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, 00 155 cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, n heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, 00monoalkylainno, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, 00 aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R3 and R 4 represent oxo or thioxo group when they are attached to carbon atom; R 3 and R 4 when attached to nitrogen atom represent hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, to cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives, or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; R' 0 and R" are same or different and represent hydrogen or substitutcd,.or unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl group; L' is a leaving group; n and o are integer ranging from 0-6.
  7. 9. An intermediate of formula (Illi) 1 R3 R2J (CnoR")n'O- (CRoR")-G1 (Illi) H R or a tautomeric form thereof, or a stereoisomer thereof, or a polymorph thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein R 2 and R 3 R 4 when attached to the carbon atom, are same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, .156 heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, Smonoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, 00 aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its 0 derivatives; one or both of R 3 and R 4 represent oxo or thioxo group when they are attached to carbon atom; R 3 and R 4 when attached to nitrogen atom represent hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, C1 10 acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives, or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; R 0 and R" are same or different and represent hydrogen or substituted or unsubstituted group selected form alkyl, alkoxy, aryl or aralkyl group; G' is CHO or NH 2 n and p are integers ranging from 0-6. A pharmaceutical composition which comprises a compound according to any one of claims 1-5 and a pharmaceutically acceptable carrier, diluent, excipient or solvate. I 1. A pharmaceutical composition which comprises a compound according to any one of claims 1-5 and a HMG CoA reductase inhibitor; fibrate; nicotinic acid; cholestyramine; cholestipol; probucol or their combination and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
  8. 12. A pharmaceutical composition as claimed in claim 10 or 11 in the form of a tablet, capsule, powder, syrup, solution or suspension.
  9. 13. A method of preventing or treating hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases in which insulin resistance is the underlying pathophysiological mechanism comprising administering a compound 00 O O according to any one of claims 1-5 or a pharmaceutical composition according to claim 10 or 11 to a patient in need thereof.
  10. 14. A method according to claim 13, wherein the disease is type II diabetes, Simpaired glucose tolerance, dyslipidemia, disorders related to Syndrome X including hypertension, obesity, insulin resistance, coronary artery disease and other cardiovascular disorders; renal diseases including glomerulonephritis, 00 1 glomeruloscierosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy; retinopathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), dementia, diabetic complications, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer, osteoporosis or inflammation. A method for the treatment and/or prophylaxis of disorders related to Syndrome X, which comprises administering a compound according to any one of claims 1-5 or a pharmaceutical composition according to claim 10 or 11 to a patient in need thereof.
  11. 16. A method of reducing total cholesterol, body weight, blood plasma glucose, triglycerides, LDL, VLDL or free fatty acids or increasing HDL in the plasma comprising administering a compound according to any one of claims or a pharmaceutical composition according to claim 10 or 11 to a patient in need thereof.
  12. 17. The use of a compound according to any one of claims 1-5 in the preparation of a medicament for the prevention or treatment of hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases in which insulin resistance is the underlying pathophysiological mechanism.
  13. 18. The use according to claim 17, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidemia, disorders related to Syndrome X including hypertension, obesity, insulin resistance, coronary artery disease and other cardiovascular disorders; renal diseases including glomerulonephritis, glomeruloscierosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy; retinopathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), dementia, diabetic 00 O O complications, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer, osteoporosis or i inflammation. 00
  14. 19. The use of a compound according to any one of claims 1-5 in the preparation of a medicament for the treatment and/or prophylaxis of disorders C related to Syndrome X. 00 The use of a compound according to any one of claims 1-5 in the preparation of a medicament for reducing total cholesterol, body weight, blood plasma glucose, triglycerides, LDL, VLDL or free fatty acids or increasing HDL in the plasma.
  15. 21. The intermediate according to claim 7 or 8, wherein the leaving group L' is halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate or hydroxy.
  16. 22. A compound according to claim 1, a process according to claim 6, an intermediate according to any one of claims 7 to 9, a pharmaceutical composition according to claim 10 or 11, a method according to any one of claims 13 to 16, or the use according to any one of claims 17 to 20, substantially as herein described with reference to any one of the Examples.
AU2002341289A 2001-10-16 2002-10-15 Benzoxazine and benzothiazine derivatives and pharmaceutical compositions containing them Expired - Fee Related AU2002341289B2 (en)

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IN848MA2001 2001-10-16
IN848/MAS/01 2001-10-16
PCT/IB2002/004275 WO2003033481A1 (en) 2001-10-16 2002-10-15 Benzoxazine and benzothiazine derivatives and parmaceutical compositions containing them

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CN (1) CN1982299A (en)
AU (1) AU2002341289B2 (en)
CO (2) CO5580819A2 (en)
MX (2) MXPA04003628A (en)
NZ (1) NZ532284A (en)
RS (2) RS32404A (en)
RU (2) RU2004111786A (en)
UA (1) UA78522C2 (en)

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RS32304A (en) 2006-12-15
KR20040052242A (en) 2004-06-22
CN1982299A (en) 2007-06-20
RS32404A (en) 2007-02-05
MXPA04003629A (en) 2004-07-30
CO5580781A2 (en) 2005-11-30
UA78522C2 (en) 2007-04-10
RU2004111792A (en) 2005-05-27
NZ532284A (en) 2006-02-24
KR20040048960A (en) 2004-06-10
CO5580819A2 (en) 2005-11-30
MXPA04003628A (en) 2004-07-30
RU2004111786A (en) 2005-10-20

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Legal Events

Date Code Title Description
DA3 Amendments made section 104

Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE INVENTION TITLE TO READ BENZOXAZINE AND BENZOTHIAZINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

MK4 Application lapsed section 142(2)(d) - no continuation fee paid for the application