AP512A - Derivatives of 1-aminocarbonylmethyl-3-amino-2,4-dioxo-1-5 benzodiazepines having CCKA agonist activity. - Google Patents
Derivatives of 1-aminocarbonylmethyl-3-amino-2,4-dioxo-1-5 benzodiazepines having CCKA agonist activity. Download PDFInfo
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- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
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- C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
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Abstract
Novel benzodiazepine compounds of formualr
Description
1,5-Benzodiazepine Derivatives
This invention relates to novel 1,5-benzodiazepine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. More particularly, it relates to compounds which exhibit agonist activity for CCK-A receptors thereby enabling them to modulate the hormones gastrin and cholecystokinin (CCK) in mammals.
Cholecystokinins (CCK) and gastrin are structurally related peptides which 10 exist in gastrointestinal tissue and in the central nervous system.
Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form, its carboxyl terminal octapeptide, CCK-8 (also a naturally occurring neuropeptide), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14- amino acid forms, with the minimum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH2 (CCK-4) which is the common structural element shared by both CCK and gastrin.
CCK and gastrin are gastrointestinal hormones and neurotransmitters in the neural and peripheral systems and perform their respective biological roles by binding to particular receptors located at various sites throughout the body. There are at least two subtypes of cholecystokinin receptors termed CCK-A and CCK-B and both are found in the periphery and in the central nervous system.
The CCK-A receptor, commonly referred to as the “peripheral-type” receptor, is primarily found in the pancreas, gallbladder, ileum, pyloric sphincter and on vagal afferent nerve fibers. Type-A CCK receptors are also found in the brain in discrete regions and serve to provide a number of CNS effects. Due to the ability of CCK-8 and Type-A CCK-selective agonists to suppress food intake in several animal species, considerable interest has been generated toward the development of new substances which function as Type-A receptorselective CCK agonists in order to serve as anorectic agents.
The CCK-B or gastrin receptors are found in peripheral neurons, gastrointestinal smooth muscle and gastrointestinal mucosa, most notably in parietal cells, ECL cells, D cells and chief cells. CCK-B receptors also predominate in the brain and have been implicated in the regulation of anxiety, arousal and the action of neuroleptic agents.
? 9 0 0 / Ί 6 /J/dV
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U.S. Patent No. 4,988,692, to Gasc, et al. describes a group of 3-acylamino 1-alkyl-5-phenyl 1,5-benzodiazepine derivatives which behave as cholecystokinin antagonists to reverse or block the effects of the endogenous hormone at its receptors.
US Patent No. 4,490,304 and PTC applications No's W090/06937 and WO91 /19733 describe peptide derivatives that exhibit CCK-A agonist activity. Such compounds have been disclosed for appetite regulation as well as the treatment and/or prevention of gastrointestinal disorders or disorders of the central nervous in animals and, more particularly, humans.
We have now discovered a novel group of 3-amino 1,5-benzodiazepine compounds which exhibit a agonist activity for the CCK-A receptor thereby enabling them to modulate the hormones gastrin and cholecystokinin (CCK) in mammals. Certain of these compounds also exhibit antagonist activity at CCK-B receptors.
The present invention thus provides compounds of the general Formula (I)
(I)
AP/P/ 9 4/ 0 0 6 3 5 and physiologically salts and solvate thereof wherein:
X is either hydrogen, trifluoromethyl, alkyl, Ci ^alkylthio, -O(Ci -4alkyl) or halogen;
R1 is either Formula II or -NR4R3·;
CD
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AF «> ο 0 5 12
R2 is either:
(1) a heterocycle linked at its 2- position and selected from pyrrole, tetrahydropyrrole, indole, benzofuran, thiophene, benzothiophene, indoline, quinoline or 4-oxobenzopyran and wherein said pyrrole, tetrahydropyrrole, indole or indoline may optionally be substituted on the ring nitrogen thereof by the group R® as defined hereunder and said indole, indoline, quinoline, benzofuran, benzothiophene or 4-oxo-benzopyran may optionally be substituted in the benzo ring thereof by the group R® as defined hereunder or r
(2) phenyl or phenyl mono- or disubstituted independently with halogen, hydroxy, cyano, carboxy, -O(Ci-4alkyl), -O(CH2C6H5), -COO(Ci4alkyl), amino, dimethylamino, -NHR13, 1-pyrrolidinyl or tetrazolyl; or (3) pyridine or pyridinyl mono- or disubstituted independently with halogen, methyl, hydroxy, nitro, cyano, carboxy, -O(Ci-4 alkyl),
-O(CH2C6H5), -COO(Ci-4alkyl), amino or dimethylamino; or (4) -NHR11 where R11 is defined hereinunder or R11 is 7-indazolyl containing a group R16 at the N-1 position;
( R3 is hydrogen, Ci-6alkyl, C3-6cycloalkyl, phenyl or phenyl mono- or disubstituted independently with halogen;
R4 is independently C3-6alkyl, C3-6cycloalkyl, C3-6alkenyl, phenyl,
-(CH2)pCN or -(CH2)pCOO(Ci-4alkyl) and R5 is independently C3-6alkyl, C3-6cycloalkyl, C3-6 alkenyl, benzyl, phenyl or phenyl mono- or disubstituted independently with Ci-3alkyl, cyano, hydroxy, dimethylamino, -O(Ci-4alkyl), -O(CH2C6H5), -NH(Ci-4alkyl), -COO(Ci-4alkyl), -N(C1-4alkyl)2 pyrrolidino, morpholino or halogen or R4 is Ci-2alkyl and R5 is phenyl substituted at the
2- or 4- position with chloro, methyl, methoxy or methoxycarbonyl;
AP/P/ 9 4/00635
R6 is hydrogen or methyl;
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R7 is hydrogen, hydroxy, fluoro, dimethylamino, -O(Ci-4alkyl) or -O(CH2C6H5);
R6 is -(CH2)bCOOH;
R9 is methyl, chloro, nitro, hydroxy, methoxy or -NHR10;
R10 is hydrogen, acetyl, Ci-4alkyl, -SO3H, -SO2CH3, -SO2CF3 or -SO2C6H5, C-|_4alkoxycarbonyl;
R11 is phenyl or phenyl mono- or disubstituted independently with fluorine, trifluoromethoxy, Ci _4alkylthio, -(CH2)cCOOH, -(CH2)cCOO(Ci-4alkyl), -(CH2)cSCH3, -(CH2)cSOCH3, -(CH2)cSO2CH3, -(CH2)cCONH2, -SCH2COOH, -CONH(SO2CH3), -CONH(SO2CF3), -(CH2)cN(Ci-4alkyl)2, 15 (CH2)cNH(SO2CF3),-(CH2)cN(SO2CF3)(Ci-4alkyl), -(CH2)cSO2NHCO(Ci4alkyl), -(CH2)cSO2N(Ci-4alkyl)CO(Ci-4alkyl), -(CH2)cCONHSO2(Ci4alkyl), -(CH2)eCON(Ci-4alkyl)SO2(Ci-4alkyl), -(CH2)cOR12
-(CH2)cNHR19 or phenyl monosubstituted with -(CH2)c(tetrazolyl), -(CH2)c (carboxamidotetrazolyl) or -(CH2)c(pyrrolidinyl) or R11 is selected from pyridine or pyridinyl mono- or disubstituted independently with halogen, methyl, hydroxy, nitro, cyano, carboxy, -O(Ci-4 alkyl), amino, dimethylamino, -NHR10;
R12 is hydrogen, C-|^alkyl, C3^cycloalkyl, -CH2C6H5, -CH2COOH,
-CH2CONH2, -CH2CONH(Ci_4alkyl), -CH2CON(Ci_4alkyl)2 or
-(CHj)cCO-N\_ Ο or -(CH2)cC0-N _^N-R10 z is 1 or 2;
n is 1 or 2;
p is an integer from 1-4;
b is an integer from 0-3; and
AF;K 9 4 / ύ U 6 3 5 c is 0 or 1.
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AF C h 0 5 12
When R1 represents the group of Formula (II), examples of such a group include those wherein R6 is hydrogen or more particularly methyl, R7 is hydrogen, hydroxyl, methoxy, or fluorine, and n is 1.
When R1 represents the group NR4R5 , examples of suitable groups include those wherein R4 represent C3-6 alkyl, such as propyl or isopropyl, cyclohexyl or phenyl and R5 represents C3-6 alkyl, benzyl or phenyl optionally substituted in the para- position by hydroxy, dimethylamino methoxy, fluorine, pyrrolidino or morpholino. Within this group, particularly useful R1 groups include those wherein R4 is propyl and, more particularly, isopropyl and R5 represents phenyl or phenyl substituted in the para-position by groups selected from hydroxy, methoxy dimethylamino, fluorine, or morpholino.
Examples of particularly suitable R^ groups include those wherein R1 is the group of Formula (II) wherein R6 is methyl, n is 1 and R7 is hydrogen, hydroxy, fluorine or methoxy or R^ is the group NR4R5 wherein R4 is propyl or isopropyl and R$ is phenyl optionally substituted in the para position by a group selected from hydroxy, methoxy, fluoro, dimethylamino, pyrrolidino or morpholino.
When R2 represents a group selected from indole, indoline, benzofuran, benzothiophene, quinoline or 4-oxobenzopyran, the optional substituent R9 is conveniently a group selected from hydrogen, methyl, methoxy, hydroxy, nitro or amino and, where appropriate, the optional substituent on nitrogen, (R® ), is -CH2CO2H.
When R2 is an optionally substituted phenyl group, this is conveniently phenyl or phenyl substituted by one or two groups, which may be the same or different and selected from chlorine, fluorine, amino, hydroxy or carboxyl.
When R2 represents the group NHR11, R11 is conveniently phenyl (optionally substituted by fluoro, hydroxy, amino, dimethylamino, trifluoromethylsulphonylamino, C1-4 alkoxycarbonyl, carboxy, 1 H-tetrazol-5-yl, acetylamino or OR12 wherein R^2 represents hydrogen, methyl, benzyl, CH2CO2H, CH2CONK2, CH2CONHCH3, CH2CON(CH3)2
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CHjCON^_ O ’ CH,CON_^NH or CH,CON NCO;C(CH,), ) or a 7-indazolyl group wherein the N-1 substituent, (R10 ), is hydrogen.
When R11 is a mono substituted phenyl group, the substituted is conveniently 5 in the meta- position.
Examples of particularly suitable R2 groups includes indole, benzofuran, thiophene, benzothiophene, indoline, quinoline, 4-oxobenzopyran, an optionally substituted phenyl group or the group NHR11. Conveniently, R2 is selected from the group indole, indoline or benzofuran, an optionally substituted phenyl group or the group NHR11. More particularly, R2 represents an indole, an optionally substituted phenyl or NHR11.
When R3 represents C1-6 alkyl, examples of suitable groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl or isoamyl.
When R3 represents C3-6 cycloalkyl, examples of suitable groups include cyclopropyl, cyclopentyl or cyclohexyl.
When R3 represents phenyl, mono or disubstituted by independently with halogen, examples of suitable groups include those wherein the halogen substituent is fluorine e.g., 2-fluorophenyl or 4 fluorophenyl.
Examples of particularly suitable R3 groups include hydrogen, methyl, cyclohexyl, 2-fluorophenyl or phenyl, and more particularly, phenyl.
A particularly useful group of compounds according to the invention include those wherein R1 represents the group of Formula (II) wherein R6 is methyl, n is 1 and R7 is hydrogen, fluorine, hydroxy or methoxy, or more particularly
NR4R5 wherein R4 is propyl or isopropyl and R5 is phenyl optionally substituted in the para position by a group selected from hydroxy, methoxy, fluoro, dimethylamino or monopholino; R2 represents phenyl (optionally substituted independently by one or two groups selected from chlorine, fluorine, hydroxy, amine or carboxy), NHR11 wherein R11 represents phenyl (optionally substituted by amino, dimethylamino, trifluoromethylsulphonylamino, carboxy, 1 H-tetrazol-5-yl, acetylamino or OR12 wherein
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R12 represents hydrogen, methyl, benzyl, CH2CO2H, CH2CONH2, CH2CONHCH3, CH2CON(CH3)2.
CH;CON\_ O ’ CH:CON NH or CH,CON NCO;C(CH,), and wherein the substituent is preferably in the meta- position) or an indole wherein the nitrogen atom is optionally subtituted by the group -CH2CO2H and the benzo ring is optionally substituted by chlorine, methyl, methoxy, nitro, hydroxy or amino, R3 represents hydrogen, methyl, cyclohexyl, 2fluorophenyl or phenyl or, more particularly, 2 fluorophenyl or phenyl; and X represents fluorine and z is 1 or, more particularly, X is hydrogen;
A particularly interesting class of compounds of the present invention which exhibits a very high and selective affinity for the CCK-A receptor as well as exceptional efficacy occurs wherein R2 is an indole group. A preferred group of compounds within this class are those wherein the indole group is substituted on the nitrogen atom by the group -CH2CO2H or, more preferably, the nitrogen atom is unsubstituted, and benzo ring of the indole group is optionally substituted by a group selected from chlorine, methyl, methoxy, nitro, hydroxy or amino.
A particularly preferred compound of the invention is:
H-lndole-2-carboxylic acid {1-[lsopropyl-(4-methoxyphenyl)carbamoylmethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}amide and enantiomers thereof.
As provided herein, the term alkyl is generally intended to mean both straight chain and branched chain aliphatic isomers of the corresponding alkyl. For example, C-j-ealkyl is intended to include methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, tertbutyl, n-pentyl, etc.
The term cycloalkyl, as provided herein, is intended to mean all alicyclic isomers of the corresponding alkyl. For example, the term C3-6 alkyl, as provided herein, is intended to include such groups as cyclopropyl, cyclopentyl and cyclohexyl.
The term halogen is intended to mean F, Cl, Br or I.
c 9 0 0 / 4 6 ,'d'dV
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The term tetrazole as a group or part of a group refers to the (1 H)-tetrazol5-yl grouping and tautomers thereof.
Those skilled in the art will recognize that stereocenters exist in compounds 5 of Formula (I). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of Formula (I) and includes not only racemic compounds but also the optically active isomers as well. When a compound of Formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. Additionally, in situations where tautomers of the compounds of Formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds.
It will also be appreciated by those skilled in the art that the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of Formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids as well as quaternary ammonium acid addition salts. More specific examples of suitable salts . » include hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulphonic, methanesulphonic, naphthalene-2sulphonic, benzenesulphonic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. References hereinafter to a compound according to the invention include both compounds of Formula (I) and their pharmaceutically acceptable salts and solvates.
AP/P/ 9 4/ 0 0 6 3 5
The compounds of the present invention exhibit CCK-A agonist activity and can be considered full or partial cholecystokinin agonists in that they bind to
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ST ' : M2
CCK-A receptors and either fully or partially stimulate gallbladder contraction and/or reduce feeding in animal paradigms.
As agonists of CCK-A receptors, the compounds of the present invention are 5 useful anorectic agents advantageous in the treatment of obesity as well as related pathologies, such as diabetes or hypertension. Moreover, the compounds disclosed herein provide for new approaches for inducing satiety, providing for appetite regulation and modifying food intake in mammals, especially humans, to regulate appetite, treat obesity and maintain weight loss.
Additionally, certain compounds of the present invention may also exhibit some antagonist activity at particular site-specific CCK-B and gastrin receptors as demonstrated by their inhibition of CCK-4 stimulated contraction of isolated guinea-pig ileum longitudinal muscle-myenteric plexus and pentagastrin-stimulated acid secretion in rat isolated gastric mucosa using the procedures described by M. Patel and C. F. Spraggs in Br. J. Pharmac., (1992), 106, 275-282 and by J. J. Reeves and R. Stables in Br. J. Pharmac., (1985), 86, 677-684.
The relavtive affinities of compounds of the invention for the CCK-A and CCK-B receptors may be determined using known conventional procedures such as described by Fornos et al J. Pharmacol Exp. Then, 1992 261, 10561063.
The ability of compouds of the invention to inhibit gastric acid secretion, such as pentagastrin stimulated acid secretion may be determined in the conscrious gastric fistula rat using methods described by Hedges and Parsons Journal of Physiology 1977, 267 191 -194.
In particular, the invention provides a compound of Formula (i) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, and in particular, in human medicine.
According to another aspect, the present invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of conditions
AP/P/ 9 4/ 0 0 6 3 5
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According to a further aspect of the present invention, there is provided 5 herein a method for the treatment of a mammal, including man, in particular in the treatment conditions where modification of the effects of CCK and/or gastrin is of therapeutic benefit, the method comprising administering to the patient an therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02 - 5000 mg per day, e.g., 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. Accordingly, the present invention further provides for a pharmaceutical formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Formulations of the present invention include those especially formulated for oral, buccal, parenteral, implant, or rectal administration, however, oral administration is preferred. For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner. Tablets and capsules for oral administration may contain conventional
AP/r- 9 4/00635
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Λ Ρ Γ· Α η 5 1 I excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulphate. The tablets may be coated according to methods well-known in the art.
Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia, nonaqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
Additionally, compositions the present invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.
The composition according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (as an emulsion
AP/P/ 9 4/ 0 0 6 3 5
G1055 in an acceptable oil, for example), ion exchange resins or as sparingly soluble derivatives as a sparingly soluble salt, for example.
The compositions according to the invention may contain between 0.1 - 99% 5 of the active ingredient, conveniently from 30 - 95% for tablets and capsules and 3 - 50% for liquid preparations.
Compounds of general Formula (I) may be prepared by the general methods outlined hereinafter. In the following description, the groups X and R1’12 are as defined for the compounds of Formula (I) unless stated otherwise.
Compounds of general formula (I) and salts thereof may be prepared by the general methods outlined hereinafter. In the following description, the groups RrR12 and X are as defined for the compounds of formula (I) unless otherwise stated.
According to a first general process A, compounds of formula (I) may be prepared by the reaction of an amine of formula (III) wherein R1, R2, R3, X and z have the meanings defined in formula (I)
NH, (HI) to co o
o •-T
X with a compound R11Y (IV) wherein Y is the group -NCO, HNCOCI or NHCORa where Ra is nitro substituted phenoxy group or a 1-imidazole group.
The reaction conveniently takes place in the presence of a suitable solvent such as a halohydrocarbon (e.g. dichloromethane), an ether (e.g. tetrahydrofuran) or nitrile (e.g. acetronitrile) or a mixture thereof at a temperature in the range of 0°-80°C.
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Compounds of formula (IV) wherein Y is -NCO) may be purchased or prepared by the reaction of amines H2N-R11 with phosgene or triphosgene in a suitable solvent such as methylene chloride. Compounds of formula (IV) wherein Yis NHCOCI are also prepared by the reaction of amines H2NR11 with phosgene or triphosgene in a suitable solvent such as methylene chloride. Compounds of formula (IV) wherein Y is NHCORa and Ra is a 1imidazole group are prepared by treatment of amines H2N-R11 with carbonyl diimidazole in a suitable solvent (dichloromethane, ether, tetrahydrofuran) at a temperature ranging from 0-80° C (conveniently at room temperature).
Compounds of formula (IV) wherein Y is HNCORa and Ra is a nitro substitued phenxoy group are prepared by the reaction of amines H2N-R11 with the appropriate chloroformate RaCOCI in the presence of a base (pyridine, triethylamine) in a suitable solvent (dichloromethane) and at a temperature of 0 - 50° C.
According to a further general process B, compounds of formula (I) may be prepared by reaction of an intermediate of formula (V).
R
C 9 0 0 / V 6 /d/dV wherein Y is the group -NCO, -NHCOCI or NHCORa wherein Ra is a nitro substituted phenoxy group or a 1-imidazole group with an amine (VI)
H2N-R11 (VI) and optionally in the the presence of a base such as a tertiary amine (e.g. triethylamine).
The reaction conveniently takes place in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or an ether (eg.
tetrahydrofuran) or an amide (e g. Ν,Ν-dimethyl formamide) optionally at a temperature ranging from room temperature to the reflux temperature of the solvent.
G1055
Conveniently the compounds of formula (V) are prepared in situ from the amine (III).
In a particular aspect of the process (B) when Y is the group NHCORa and 5 Ra is a 1-imidazole group, the imidazolide (V) may be formed in situ in which case the amine of formula (VI) will be mixed with the compound of formula (HI)
in the presence of carbonyldiimidazole under the aforementioned conditions.
o
For process B when Y is the group NHCORa and Ra is a nitro substituted phenoxy group the reaction with the primary amine (VI) is preferably carried τ out in the presence of a base such as a tertiary amine e.g. triethylamine. Λ
For process B when Y is the isocyanate group -N=C=O the reaction with the primary amine (VI) is preferably carried out in an aprotic solvent such as a halohydrocarbon e.g. methylene chloride. Conveniently the isocyanate is generated in situ prior to the addition of the primary amine (VI).
Γ 20
The compounds of formula (V) wherein Ra is an optionally substituted phenoxy group may be prepared from the primary amine (III) by reaction with the corresponding nitro substituted phenyl chloroformate in the presence of a base such as pyridine. The reaction may be carried out in a solvent such as a halohydrocabon e.g. dichloromethane and at a temperature from 0-50°.
Compounds of formula (V) wherein Ra is a 1-imidazole group may be prepared by reacting a compound of formula (III) with carbonyldiimidazole in the presence of a suitable solvent such as a halogenated hydrocarbon (e.g.
dichloromethane) or an ether (e.g. tetrahydrofuran) at a temperature ranging from 0θ to 80θ (conveniently at room temperature).
G1055
Compounds of formula (V) wherein Y is the isocyanate grouping -N=C=O or carbamoyl chloride -NHCOCI may be prepared from the primary amine (III) by reaction with phosgene (COCI2) or triphosgene in a suitable solvent such as methylene chloride.
According to a further general process C compounds of formula (I) may also be prepared by a reaction of the compound of formula (VII)
R
(VII) with an acetylbromide or chloride having the formula (VIII)
R1COCH2hal (VIII) wherein hal = Cl or Br.
The reaction is conveniently carried out by treating the compound of formula (VII) with a strong base such as sodium hydride in a polar aprotic solvent such as Ν,Ν-dimethylformamide followed by reaction with the acetyl halide (VIII).
The acetyl halide (VIII) is prepared by the reaction of the amine R1-H with corresponding haloacetyl bromide in dichloromethane at 0°C, with a suitable base, such as triethylamine.
The amines R1-H wherein R1 is the group -NR4R5, may be prepared by the reductive alkylation of the amine H2N-R5 with an appropriate aldehyde or ketone.
IT.
ΚΊ <r c
ex
CL <
According to general process D, compounds of general Formula (I) may also be prepared by the reaction of the intermediate of Formula (III) with acids of Formula (IX), as set forth below.
HOOC-R2 (IX)
G1055 * Γ r : γ. 5 < 2
Thus reaction of the intermediates of formula (III) with the acid of formula (IX) may be carried out in the presence of a suitable dehydrating agent such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylammopropyl)-3ethylcarbodiimide hydrochloride (EDC) or bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP).
Alternatively, compounds of general Formula (I) may be obtained by reaction of the intermediates of Formula (III) with an activated derivative of the acid (IX) such as an acid chloride or anhydride thereof, including mixed anhydrides.
Preferred solvents for general process D include Ν,Ν-dimethylformamide or dichloromethane. Preferred temperatures are between 0-60°C. Preferred bases for this reaction include triethylamine or N,N-dimethylaminopyride
C 15 (DAMP).
According to a further general process (E) compounds of the invention may be converted into other compounds of the invention. Thus for example compounds of formula (I) wherein R8 is the group (CH2)bCO2H may be preapred by reaction of a compound of formula (I) wherein R8 is hydrogen with compound Br(CH2)bCOOR* wherein R’ is Chalky I in the presence of a strong base such as sodium hydride followed by removal of the carboxy protecting group by conventional procedures e.g. acidic or basic hydrolysis ro
X>
o o
r
3)
Compounds of formula (III) may be prepared by reduction of compounds of formula (X)
COR*
C I
wherein W is CH-N3 or C=N-NHPh.
Compounds of formula (X) wherein W is CH-N3 may be reduced to a compound of formula (III) by hydrogenation in the presence of a suitable catalyst such as 5-10% palladium on a support such as carbon or calcium
G1055
4Γ ο '' 1 ?
carbonate, or platinum (IV) oxide. The reaction conveniently takes place in the presence of a solvent such as an alkanol (e.g. ethanol) an ester (e.g. ethyl acetate) or acetic acid.
Compounds of formula (X) wherein W is C=N-NHPh may be reduced to a compound of formula (III) by reaction with zinc and acetic acid. This reaction may be carried out a temperature with the range 0-50θ.
Compounds of formula (X) wherein W is CHN3 may be prepared from a 10 compound of formula (X) wherein W is CH2 by treatment with a strong base such as sodium hydride or potassium tert-butoxide followed by tri-isopropyl benzenesulphonyl azide or di-tertbutoxyazidodicarboxylate. The reaction conveniently takes place in a solvent such as an ether (e.g. tetrahydrofuran) at a temperature in the range of -78θ to 20θ.
Compounds of formula (X) in which W is C=NNHPh or CH2 may be prepared by reaction of the ortho-phenylenediamine (XI) with the diacid chloride (XII) wherein Q is CH2 or C=NNHPh, in a suitable solvent such as an ether e.g. tetrahydrofuran cor1
(xi)
AP/P/ 9 4/ 0 0 6 3 5
CICO\
C1CO (XII)
The compound of formula (XII) wherein Q is C = NNHPh may be prepared by reaction of ketomalonic acid with phenyl hydrazone followed by reaction with phosphorus pentachloride.
Compounds of formula (XI) are either known compounds or may be prepared by analogous methods. Thus for example a compound of formula (XI) may be prepared by alkylation of the amine (XIII).
G1055
R3
Thus the amine (XIII) may be reacted with the compound R1COCH2hal wherein hal is chlorine or bromine, optionally in the presence of sodium iodide in a solvent such as N.N-dimethylformamide.
An alternative preparation of the intermediate of Formla (III) as set forth below, involves treatment of the intermediate of Formula (XIV) with sodium hydride followed by addition of an acetyl halide (VIII) in a suitable solvent, such as Ν,Ν-dimethyl formamide, at o°C to provide the protected intermediate of Formual (XV)
900/76 idciV (XV)
Intermediate (XV) is converted to the required amine (III) by catalytic 15 hydrogenation (40 - 60 psi) using a suitable catalyst, such as 5-10% pd/C, in a suitable solvent, such as methanol, ethanol, ethyl acetate, chloroform or acetic acid, at room temperature. Alternatively, intermediate (XVI) may be
G1055
Intermediate (XIV) is obtained from the intermediate of Formula (XVI) by reaction with benzyloxychloroformate in dichloromethane, using triethylamine as base. This reaction is run conveniently at room temperature.
Intermediate (XVI) is prepared from phenylene diamine (XIII) by the following process.
Reaction of the diamine (XIII) with p-methyoxylbenzoylochloride followed by reduction of the amide thus formed with lithium aluminum hydride yields the N-protected diamine (XVII)
(XVII)
AP/P/ 94/00635
Reaction of compound (XVII) with the diacid chloride (XII; Q = C=NNHPh) followed by reduction with zinc and acetic acid yields the amine (XVIII)
The compound of formula (XVIII) may be converted into the required compound (XVI) by rection with Ce(NO2)6NH4 (ceric ammonium nitrate).
G1055
AP Ο 3 Ο 5 1 2
Compounds of formula (I) contain at least one asymmetric carbon atom, namely the carbon atom of the diazepine ring to which the substituted urea grouping is attached. Specific enantiomers of the compounds of formula (I) may be obtained by resolution of the racemic compound using conventional procedures such as chiral HPLC. Alternatively the required enantiomer may be prepared from the corresponding enantiomeric amine of formula (III) using any of the processes described above for preparing compounds of formula (I) from the amine (111). The enantiomers of the amine (III) may be prepared from the racemic amine (II) using conventional procedures such as salt formation with a suitably optically active acid or by preparative chiral HPLC.
EXAMPLES
The following examples are set forth to illustrate the synthesis of some particular compounds of the present invention and to further exemplify particular applications of general process ΑΈ. Accordingly, the following Example section is in no way intended to limit the scope of the invention contemplated herein.
GENERAL PROCEDURES
Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. The following solvents and reagents have been described by acronyms: tetrahydrofuran (THF), dimethylsulfoxide (DMSO)/ dichloromethane (DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), 1, 1-carbonyldiimidazole (CDI), isobutylchloroformate (iBuCF) N-hydroxysuccinimide (HOSu), N30 hydroxybenztriazole (HOBT), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), bis(2-oxo-3-oxazolidinyl) phosphinic chloride (SOP), tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz).
The THNMR spectra were recorded on either a Varian VXR-300 or a Varian
Unity-300 instrument. Chemical shifts are expressed in parts per million (ppm, d units). Coupling constants are in units of hertz (Hz). Splitting patterns are designated as s. singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad.
AP/P/ 94/00635
G1055
Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA, JOEL SX-102 or a SClEX-APliii spectrometers. All mass spectra were taken in the positive ion mode under electrospray ionization (ESI), chemical ionization (Cl), electron impact (El) or by fast atom bombardment (FAB) methods. Infrared (IR) spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1-mm NaCl cell. Rotations were recorded on a PerkinElmer 241 polarimeter. All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 7% ethanolic phosphomolybdic acid or p-anisldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, Merck).
Products were purified by preparative reversed phase high pressure liquid chromatography (RP-HPLC) using a Waters Model 3000 Delta Prep equipped with a Delta-pak radial compression cartridge (Cie, 300 A, 15m, 47 mm X 300 mm). Linear gradients were used in all cases and the flow rate was 100 ml/minute (to = 5.0 min.). All solvents contained 0.1% trifluoroacetic acid (TFA). Analytical purity was assessed by RP-HPLC using a Waters
600E system equipped with a Waters 990 diode array spectrometer (t range
200-400 nM). The stationary phase was a Vydac Cie column (5m, 4.6 mm X 250 mm). The flow rate was 1.0 to 1.5 ml/min. (to = 2.8 or 3.0 min.) and the solvent systems were as described above. Data reported as tr, retention time in minutes (% acetonitrile over time).
C Using the general processes A-E outlined above, the following compounds of the invention have been made.
Example 1
2-Γ2, 4-Dioxo-5-phenyl-3-(3-phenvl-ureido)-2· 3, 4, 5-tetrahvdrobenzofbl [1, 41 diazepin-1-vn-N-isopropvl-N-phenyl-acetamide
To a solution of 1-(2, 4-dioxo-1-phenyl-2, 3, 4, 5-tetrahydro-1 H-benzo [b] [1, 4]-diazepin-3-yl)-3-phenyl urea (0.100 g.) in Ν,Ν-dimethylformamide (2 ml) cooled to 3°C, was added sodium hydride (0.0104 g, 60% suspension in mineral oil) with stirring. The mixture was stirred 20 minutes, then 2-bromoN-isopropyl-N-phenyl acetamide (0.0656 g) was added in one portion. The resultant mixture was stirred at ambient temperature overnight. The crude
AP/P/ 9 4/ 0 0 6 3 5
G1055
AF Ο Ο C 5 1 2 reaction mixture was purified by preparative RP-HPLC with a gradient elution of 60-72% acetonitrile in water with 0.1% trifluoroacetic acid buffer over a 30 minute period at a rate of 100 ml/min. Fractions containing the desired material were combined, frozen and lyophilized to provide the title compound (0.0653 g) as a white powder. 1H NMR (300MHz, DMSO-d6): d 0.95 (d, J=
7.3Hz, 3H), 0.98 (d, J= 7.3Hz, 3H), 4.19 (d, J= 16.6Hz, 1H), 4.48 (d, J= 16.9Hz, 1H), 4.79 (m, 1H), 5.04 (d, J= 7.8Hz, 1H), 6.87-6.92(m, 1H), 6.95(d, J= 7.6Hz, 1H), 7.18-7.57 (m, 17H), 9.14 (s, 1H); MS (FAB): m/z= 562 (MH+);TLC (CH2CI2/CH3OH, 19:1): Rf= 0.19; RP-HPLC (Vydac C-18, 25cm x 4.6mm; 60-72% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 ml/min): tr= 17.5min (t0= 2.5min); m.p.: 230-235°C
Enantiomers of the title compound (0.014 g) were separated on a Pirkle covalent (L)-Phenylglycine column, 25cm x 10.0mm, with an isocratic eluant of methanol/water (80:20) at a rate of 5 ml/min. Fractions from the four injections corresponding to the first eluted enantiopode were combined and evaporated under reduced pressure to give enantiomer 1 as a white powder. Likewise, fractions corresponding to the second eluted enantiopode were combined and evaporated under reduced pressure to give entantiomer 2 as a white powder.
Enantiomer 1: Chiral HPLC (Pirkle covalent (L)-Phenylglycine, 25cm x 4.6mm; CH3OH/H2O (78:22) isocratic; 1.5 ml/min): tr= 14.5min (t0= 2min); MS (FAB): m/z= 562.1 (MH+)
Enantiomer 2: Chiral HPLC (Pirkle covalent (L)-Phenylglycine, 25cm x 4.6mm; CH3OH/H2O (78:22) isocratic; 1.5 ml/min): tr= 18min (t0= 2min); MS (FAB): m/z= 562.0 (MH+)
Example 2
1 H-lndole-2-carboxvlic acid i1-(lsopropyl-phenvl-carbamovlmethvl)-2.4-dioxo5-phenyl-2,3,4,5-tetrahydro-1H-benzofb1f1,41diazepin-3-vn-amide
To a vigorously stirred solution of 2-(3-Amino-2, 4-dioxo-5-phenyl-2, 3, 4, 5tetrahydro-benzo [b] [1, 4] diazepine-1-yl)-N-isopropyl-N-phenyl acetamide (0.116 g) in Ν,Ν-dimethylformamide (5 ml) at ambient temperature was added indole-2-carboxylic acid (0.0423 g, 0.262 mmol), Nhydroxybenzotriazole (0.0354 g), and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (0.0503 g) successively. Triethylamine (8
AP/P/ 94/00635
G1055 drops) was added dropwise to maintain the basicity (pH = 9) of the solution was reached. The resultant mixture was stirred at ambient temperature for five hours. The solvent was evaporated in vacuo to give a yellow oil which was purified by flash chromatography on silica gel (9 g) with an eluant of a mixture of ethyl acetate and hexane (2.3, 200 ml). Fractions containing the desired product were combined and evaporated in vacuo to give the title compound (0.141 g) as a white foam. NMR (300MHz, CDCI3): d 1.06 (d, J= 7.3Hz, 3H), 1.09 (d, J= 7.3Hz, 3H), 4.22 (d, J= 16.6Hz, 1H), 4.40(d, J= 16.4Hz, 1H), 5.02(m, 1H), 5.50(d, J= 7.1Hz, 1H), 7.02(d, J= 8.1Hz, 1H), 7.107.47 (m, 16H), 7.57 (d, J= 6.8Hz, 1H), 7.67 (d, J= 7.8Hz, 1H), 9.29 (br s, 1H);
MS (FAB): m/z= 586.0 (MH+); TLC (EtOAc/Hexane (2:3)): Rf= 0.16; RPHPLC (Vydac C-18, 25cm x 4.6mm; 51-60% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 ml/min): tr= 19.5min (t0= 3min)
Example 3
H-lndole-2-carboxylic acid (1 -flsopropyl-(4-methoxyphenyl)carbamoylmethyl1-2.4-dioxo-5-phenyl-2.3.4.5-tetrahydro-1H-benzofblf1,41diazepin-3-vl)amide
To a solution of 2-(3-Amino-2, 4-dioxo-5-phenyl-2, 3, 4, 5-tetrahydro-benzo [b] [1, 4] diazepine-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (500mg) in Ν,Ν-dimethylformamide (15mL) were added indole-2-carboxylic acid (174mg), N-hydroxybenzotriazole (143mg), and 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 203g) successively with stirring at ambient temperature. The resultant mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated under reduced pressure to give a yellow oil which was taken into ethyl acetate(75mL), washed with water (2 x 30mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to a give a tan foam. The crude product was purified via preparative HPLC chromatography on a DeltaPak C-18 column eluted with a linear gradient from 50% to 60% acetonitrile in water with 0.1% trifluoroacetic acid buffer over a 30 minute period at a rate of 100mL/min. Appropriate fractions were combined, frozen and lyophilized to give the TFA salt of the title compound (,550q) as a white powder.
1H NMR (300MHz, CDCI3): d 1.06(m, 6H), 3.85(s, 3H), 4.27(d, J= 16.6Hz, 1H), 4.34(d, J= 16.6Hz, 1H), 4.99(m, 1H), 5.51 (d, J= 7.4Hz, 1H), 6.967.42(m, 17H), 7.66(m, 2H), 9.54(brs, 1H)
TLC (dichloromethane/methanol(9:1)): Rf= 0.64
AP'P/ 94/00635
APO 0 0 5 1 2
G1055
MS (FAB): m/z= 616.2 (MH+) (calcd. for ¢^33^05= 615.2484)
Example 4
2-ri-(lsopropvl-phenyl-carbamoylmethvl)-2,4-dioxo-5-phenvl-2.3,4,55 tetrahydro-1 H-benzofblH .4ldiazepin-3-ylcarbamovll-indol-1-yl-acetic acid.
To a vigorously stirred solution of 1 H-indole-2-carboxylic acid [1-(lsopropylphenyl-carbamoylmethyl)-2, 4-dioxo-5-phenyl-2, 3, 4, 5-tetrahydro-1 Hbenzo[b][1, 4]diazepin-3-yl]-amide (0.101 g) in Ν,Ν-dimethylforrnamide (3 ml) cooled to 3°C was added sodium hydride (0.0083 g) (60% suspension in mineral oil). After 20 minutes, t-butylbromoacetate (0.0336 g) was added. The resultant mixture was stirred with cooling in an ice bath for 90 minutes followed by slow warming to ambient temperature and stirring overnight. The solvent was evaporated under reduced pressure to give a brown oil which was dissolved in dichloromethane (30 ml) and washed successively with saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml). The resultant solution was dried over sodium sulfate, filtered and evaporated under reduced pressure to give a yellow oil (0.142 g) which was purified by flash chromatography on silica gel (9 g) with an eluant of a mixture of ethyl acetate and hexane (1:2, 200 ml). Fractions containing the desired product were combined and evaporated to give 2-[1-(lsopropyl-phenylcarbamoylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1Hbenzo[b][1,4]diazepin-3-ylcarbamoyl]-indol-1-yl}-acetic acid tert-butyl ester (.092 g) as a white foam. 1H NMR (300MHz, CDCI3): d 1.07 (d, J= 4.9Hz,
3H), 1.09 (d, J= 4.6Hz, 3H), 1.37 (s, 9H), 4.17 (d, J= 16.6Hz, 1H), 4.44 (d, J=
16.9Hz, 1H), 5.01 (m, 1H), 5.18 (d, J= 17.1Hz, 1H), 5.24 (d, J= 18Hz, 1H),
5.47 (d, J= 7.6Hz, 1H), 7.01 (dd, J= 1.2, 8.3Hz, 1H), 7.13-7.51 (m, 17H), 7.57 (d, J= 7.3Hz, 1H), 7.67 (d, J= 7.8Hz, 1H); MS (FAB): m/z= 700.2 (MH+); TLC (EtOAc/Hexane, 2:3): Rf= 0.35; RP-HPLC (Vydac C-18, 25cm x
4.6mm; 60-70% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 ml/min);
tr= 17.5min (t0= 3min)
To a solution of {2-[1-(lsopropyl-phenyl-carbamoylmethyl)-2,4-dioxo-5phenyl-2,3,4,5-tetrahydro-1 H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-indol-1 35 yl}-acetic acid tert-butyl ester (0.072 g) in dichloromethane (4 ml) at ambient temperature was added trifluoroacetic acid (1.5 ml) gradually with stirring. After the reaction was stirred 30 minutes, the dichloromethane and trifluoroacetic acid were evaporated under reduced pressure to afford a clear
AP/P/ 9 4 / 0 0 6 3 5
G1055 /94/00635 glass. The glass was purified by preparative RP-HPLC on a C-18 column with a gradient elution of 45-55% acetonitrile in water with 0.1% trifluoroacetic acid buffer over a 30 minute period at a rate of 100 ml/min. Fractions containing the desired material were combined, frozen and lyophilized to afford the title compound (0.050 g) as a white powder. 1H NMR (300MHz,
CDCI3): d 1.07 (d, J= 4.4Hz, 3H), 1.10 (d, J= 4.4Hz, 3H), 4.23 (d, J=
16.6Hz, 1H), 4.40 (d, J= 16.6Hz, 1H), 5.01 (m, 1H), 5.06 (s, 2H), 5.44 (d, J=
7.1Hz, 1H), 7.03 (dd, J= 1.2, 8.1Hz, 1H), 7.17-7.52 (m, 17H), 7.67 (d, J=
8.1Hz, 1H), 7.74 (d, J= 7.1Hz, 1H); MS (ES): m/z= 644.2 (MH+); TLC (CH2Cl2/CH3OH(19:1)): Rf= 0.15; RP-HPLC (Vydac C-18, 25cm x 4.6mm;
45-55% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 ml/min): tr=
22min (t0= 3min).
Example 5
2-(2,4-dioxo-5-phenyl-3-(3-f3-(1H-tetrazol-5-vl)-phenvH-ureido)
2,3.4,5-tetrahydro-benzofb1f1,41diazepin-1 -yl)
N-isoproovl-N-phenvIacetamide
To a vigorously stirring solution of 2-(3-amino-2,4-dioxo-5-phenyl-2,3,4,520 tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (.070
g) in tetrahydrofuran (3 ml) at ambient temperature was added 1,1- · * carbonyldiimidazole (.025 g) in one portion. The resulting mixture was stirred for 90 minutes at ambient temperature. 3-(2H-tetrazol-5-yl)phenylamine hydrochloride (31.3 mg), was added in one portion and the reaction mixture was heated to reflux overnight. The reaction mixture was filtered and the filtrate concentrated to a yellow oil. The oil was purified by preparative RP-HPLC on a C-18 column with a gradient elution of 43-53% acetonitrile in water with 0.1% trifluoroacetic acid buffer over a 30 minute period at a rate of 100 ml/min. Fractions containing the desired material were combined, frozen and lyophilized to provide the title compound as a white powder (50 mg).
1H NMR (300MHz, DMSO-d6): d 0.96(d, J= 7.3Hz, 3H), 0.98(d, J= 7.3Hz,
3H), 4.20(d, J= 16,8Hz, 1H), 4.49(d, J= 17.1Hz, 1H), 4.79(m, 1H), 5.06(d, J=
7.3Hz, 1H), 6.98(m, 2H), 7.24-7.55(m, 17H), 8.17(s, 1H), 9.44(s, 1H)
MS (FAB): m/z= 630.2 (MH+) (calcd. for C34H3-1 NgC>4= 629.2502)
TLC (CH2Cl2/CH3OH(9:1)): Rf= 0.24
RP-HPLC (Vydac C-18, 25cm x 4.6mm; 43-53% CH3CN in Η3Ο with 0.1%
G1055
APO Γ, Γ 5 1 2
Example 6
3-<3-f1-(lsopropvl-phenvl-carbamovlmethvl)-2,4-dioxo5-phenvl-2,3.4.5-tetrahvdro-1H-benzofb1f1.41diazepine-3-vn-ureido) benzoic acid ethvl ester
A solution of 3-ethoxycarbonyl phenylisocyanate (124 mg) in dichloromethane (3 ml) was added to a solution of 2-(3-amino-2,4-dioxo-5pheny I-2,3, 4,5-tetrahydrobenzo[b][ 1,4]diazepin-1 -y l-N -isopropyl-N10 phenylacetamide (288 mg), in dichloromethane (3 ml). The reaction was allowed to stir at room temperature for 30 minutes. The dichloromethane was evaporated in vacuo and the residue was suspended in acetonitrile and heated at reflux for 1 hour with stirring. Compound 40 precipitated upon cooling to 0°C. The filtrate was washed with cold acetonitrile to give the title compound as a white solid (312 mg. 76%). 1H-NMR (300 MHz, d6-DMSO): d 9.4 (s, 1H), 8.05 (s, 1H), 7.6 - 6.9 (m, 18H), 5.05 (d, 9 Hz, 1H), 4.8 (m, 1H),
4.48 (d, 16 Hz, 1H), 4.3 (dd, 6.8 Hz, 2H), 4.18 (d, 15.8 Hz, 1H), 1.27 (t, 7.2 Hz, 3H), 0.96 (m, 6H); MS (FAB) = 634 (MH+).
Example 7
3-(3-f1-(Isopropyl-phenyl-ca rbamoylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5tetrahvdro-1 H-benzoib1f1,41diazepine-3-vll-ureido) benzoic acid
A solution of 3-{3-[1-(lsopropyl-phenyl-carbamoylmethyl)-2,4-dioxo-5-phenyl25 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-3-yl]-ureido} benzoic acid ethyl (312 mg, 0.493 mol) in methanol (23 ml) and tetrahydrofuran (10 ml) was heated to reflux. Aqueous 5% potassium carbonate (6.5 ml) is added and the reflux was maintained for 2.5 hours. The reaction mixture was concentrated in vacuo and the residue was neutralized and triturated with 1N HCl and water to give the crude product. The crude product was dissolved in ethyl acetate (20 ml), heated to reflux for 3 hours then cooled. The resulting precipitate was separated by filtration and dried under vacuum to provide the title compound as a white solid (225 mg, 75%). 1H-NMR (300 MHz, d6DMSO): d 9.4 (s, 1H), 8.05 (s, 1H), 7.6 - 6.9 (m, 18H), 5.05 (d, 9 Hz, 1H), 4.8 (m, 1H), 4.48 (d, 16 Hz, 1H), 4.18 (d, 15.8 Hz, 1H), 0.96 (m, 6H); MS (FAB) =
AP/P/ 9 A / 0 0 6 3 5
G1055
ΑΡ'ΌΡ 51 2
The aforementioned Examples are set forth so as to better illustrate synthesis approaches for preparing the compounds of the present invention. Additionally, particular intermediates useful in the general processes set forth herein can be prepared as set forth below.
Intermediate 1
2-(phenylhydrazono)-malonic acid
To a vigorously stirred solution of ketomalonic acid monohydrate (29.33 g) in ethanol (140 ml) and water (300 ml) at ambient temperature was added phenylhydrazine (23.3 g) dropwise over a 40 minute period. The resultant slurry was stirred overnight at ambient temperature. The solid was separated by filtration, washed sucessively with cold water (100 ml) and ethanol (25 ml) and air dried. Subsequent drying was performed at 75°C overnight in a vacuum oven to give the title compound as a yellow solid (42.38 g). 1H (300MHz, DMSO-d6); d 7.12(t, 1H), 7.35-7.48(m, 4H); m.p.; 155-157°C (dec).
Intermediate 2
2-(phenylhydrazono)-propanedioyl dichloride
To a stirred slurry of Intermediate 1 (14.73 g), in chloroform (90mL) at 5°C was added phosphorous pentachloride (36.84 g) portionwise over a 20 minute period. After complete addition, the solution was warmed to room temperature and stirred one hour followed by heating to reflux for three hours. The solution was cooled in an ice bath and the resultant precipitate was separated by filtration, washed with cold hexane (50 ml), and dried under vacuum overnight to give the title compound (13.4 g) as a bright yellow solid. 1H (300MHz, DMSO-de) d 7.12(t, 1H), 7.20-7.56(m, 4H); m.p.: 135-138’C (dec).
Intermediate 3
4-methoxv-N-(2-phenylaminophenyl)benzamide
A vigorously stirring solution of N-phenyl-1,2-phenylenediamine (20.15g) in dichloromethane (325 ml) and triethylamine (11.07 g) was cooled in an ice/acetone bath under nitrogen. p-Anisoyl chloride (18.66 g) dissolved in dichloromethane (100 ml) was added dropwise over a 20 minute period while '94/00635
G1055
APO oo5 1 2 maintaining a temperature of <5°C. The reaction mixture was allowed to warm to ambient temperature and stirred for two hours. The organic solution was washed successively with water (200 ml), 2N aqueous HCl (80 ml), and saturated brine solution (160 ml), then dried over sodium sulfate and passed through a pad of silica (150 g). The silica was eluted with ethyl acetate (1L) and the eluent was evaporated in vacuo to a pink solid. The solid was triturated overnight with ethyl ether (350 ml), cooled in an ice bath, filtered, and dried in vacuo to give the title compound as a light pink solid (21.67 g). 1H (300MHz, CDCI3): d 3.82 (s, 3H), 5.75 (br s, 1H), 6.80-6.91 (m, 5H),
7.12-7.29 (m, 5H), 7.62 (d, J= 8.8Hz, 2H), 8.15 (dd, J= 1.7, 7.8Hz, 1H), 8.36 (s, 1H), TLC (EtOAc/Hex, 1:4). Rf=0.24; m.p.: 148-150°C
Intermediate 4
N-(4-Methoxvbenzvl)-Nl-phenvl-benzene-1,2-diamine.
To a stirred solution of lithium aluminum hydride (1.0 g) in THF (40 ml) cooled to 5°C was added a solution of 4-methoxy-N-(2-phenylamino-phenyl)benzamide (5.0 g) in THF (30 ml) over a 45 minute period. After complete addition, the reaction mixture was heated to reflux for 1.5 hrs. The solution was cooled to room temperature and excess lithium aluminum hydride was quenched with ethanol until hydrogen evolution ceased. Saturated agueous sodium hydrogen carbonate (100 ml) was added and the resultant solution extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried with sodium sulfate and filtered through a pad of silica. The silica pad was washed with ethyl acetate (500 ml) and the organic fractions were combined. The filtrate was concentrated in vacuo to a brown oil which solidified on standing to give the title compound . (4.78 g). 1H (300MHz, CDCI3): d 3.79 (s, 3H), 4.27 (s, 2H), 4.52 (br s, 1H), 5.08 (s, 1H), 6.67-6.74 (m,4H), 6.79-6.86 (m, 3H), 7.04-7.24 (m, 6H); TLC (EtOAc/Hex (1:4)): Rf=
0.57
Intermediate 5
-(4-Methoxvbenzvl)-5-phenvl-3-( phenvlhvdrazono)1, 5-dihvdro-benzo fbl [1, 41 diazepine-2, 4-dione
Solutions of Intermediate 4 (4.86 g) in THF (40 ml) and 2-(phenylhydrazono) propandioyl dichloride (5.58 g) in THF (40 ml) were added concomitantly dropwise with stirring in an ice/methanol bath over a 30 minute period. The r
c
(. 25 r
AF r; r r 1 2
G1055 solution was allowed to warm to room temperature and stirred overnight. A yellow precipitate was separated by filtration, washed with cold THF (40 ml), air dried and dried in vacuo overnight to give the title compound (6.23 g) as a yellow solid. 1H (300MHz, CDCI3): d 3.78 (s, 3H), 4.69 (d, J= 14.7Hz, 1H), 5.76 (d, J= 14.9Hz, 1H), 6.80-6.87 (m, 3H), 7.02-7.12 (m, 4H), 7.19-7.40 (m, 11H), 11.19 (s, 1H); MS (FAB): m/z= 477.0 (MH+), TLC (EtOAc/Hex, 1:4): Rf= 0.18
Intermediate 6
3-Amino-1-(4-methoxvbenzvl)-5-phenvl-1,5-dihvdrobenzofb1l1, 41 diazepine2.4-dione
To a vigorously stirred slurry of zinc dust (6.49 g) in acetic acid (50 ml) cooled to 10°C, was added a slurry of 1-(4-Methoxybenzyl)-5-phenyl-3(phenylhydrazono)-l, 5-dihydrobenzo [b] [1, 4] diazepine-2, 4-dione (5.75 g,12.1 mmol) in acetic acid (30 ml) over a fifteen minute period. After complete addition, the solution was warmed to room temperature and stirred three hours. The zinc was separated by filtration and washed with ethyl acetate (75 ml). The filtrate was concentrated in vacuo and partitioned between H2O (60 ml) and ethyl acetate (100 ml). The pH was adjusted to 9 with saturated aqueous sodium carbonate and the phases separated. The aqueous phase was extracted with ethyl acetate (2 x 75 ml), the organic layers combined, dried with magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil which was dried in vacuo to give the title compound (4.79 g) NMR (300 MHz, CDCI3): d 3.05 (s, 2H), 3.75 (s, 3H), 4.35 (s, 1H), 4.64 (d, J= 14.7Hz, 1H), 5.82 (d, J= 14.7Hz, 1H), 6.59-6.85 (m, 6H), 7.067.29 (m, 6H), 7.51 (d, J= 7.4Hz, 1H); MS (FAB): m/z= 388.2 (MH+); TLC (CH2CI2/CH3OH (9:1)): Rf= 0.50
Intermediate 7
3-Amino-1-phenyl-1,5-dihvdrobenzo[bl[1,41 diazepine-2, 4-dione
To a stirred solution of 3-amino-1-(4-methoxybenzyl)-5-phenyl-1,5dihydrobenzo [b] [1, 4] diazepine-2,4-dione (0.50 g) in acetonitrile/H2O (9:1, 12 ml) at ambient temperature was added cerric ammonium nitrate (1.84 g) portionwise over a ten minute period. The solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resultant solid partitioned between saturated aqueous potassium carbonate (40 ml) and ethanol (60 ml). The phases were separated and the aqueous phase
AP/P/ 9 4/ 0 0 6 3 5
G1055 extracted with ethanol (4 x 50 ml). The ethanol portions were combined, dried over sodium sulfate and concentrated in vacuo to a tan solid. This solid was extracted exhaustively with boiling CH2CI2 (10 x 60 ml), the organics combined, dried over sodium sulfate, filtered and concentrated to give the title compound (0.30 g) as a tan solid. 1H (300MHz, DMSO-d6): d 1.98 (br s, 2H), 4.08 (s, 1H), 6.86 (d, J= 8.4Hz, 1H), 7.11-7.46 (m, 8H), 10.78 (br s, 1H); 13C (75.429MHz, DMSO-d6): d 56.98, 123.41, 126.22, 126.51, 127.34, 128.30, 128.89, 130.15, 132.29, 134.42, 142.36, 168.13, 169.39. MS (FAB). m/z= 268.10 (MH+); TLC (CH2Cl2/CH3OH,15:1): Rf= 0.21
Intermediate 8
1-(2, 4-Dioxo-1-phenvl-2, 3, 4, 5-tetrahvdro-1 H-benzo fbl Γ1, 41-diazepin-3-yl)3-phenvl urea
To a slurry of 3-amino-1 -phenyl-1, 5-dihydro-benzo [b] [1,4]-diazepine-2, 4dione (0.398 g) in dichloromethane (5 ml) was added phenyl isocyanate (0.177 g) gradually with stirring at ambient temperature. The reaction mixture was stirred two hours at ambient temperature after which time a cream precipitate was separated by filtration to provide the title compound (0.413 g).
1H NMR (300MHz, DMSO-d6): d 4.97 (d, J= 7.5 Hz, 1H), 6.88-6.97 (m, 3H), 7.13-7.47 (m, 12H), 9.16 (s, 1H), 10.78 (br s, 1H); TLC (CH2Cl2/CH3OH,19:1): Rf= 0.21
Intermediate 9
N-isopropyl-N-phenyl-2-(2-phenvlaminophenylamino)-acetamide
Potassium carbonate (6.9 g) was added to a solution of N-phenylphenylene diamine (9.2 g) in DMF and 2-bromo-N-isopropyl-N-phenyl acetamide (12.7 g) in DMF (200 ml) and the mixture was allowed to stir overnight. The DMF was evaporated in vacuo and the residue was dissolved in ethyl acetate (400 ml) and washed exhaustively with aqueous 1N HCI (4 x 250 ml). The organic layer was washed with water (2 x 200 ml), dried (Na2SO4) and evaporated to give 17.8 gm of crude alkylated product. The oil was purified by chromatography on silica gel (600 g) using first CHCI3 (8000mL), then hexane;ethyl acetate (2:1, 8000 ml) as eluents to give the title compound (10 g), as an oil. 1H-NMR (300 MHz, CDCI3): d 7.42 - 6.8 (m, 14 H), 6.36 (d, 1H), 4.95 (m, 1H), 3.22 (s, 2H), 1.05 (d, 6H); MS (FAB) = 360 (MH+) ; TLC, Rf = 0.18 (CHCI3).
AP/P/ 94/00635
G1055
Intermediate 10
2-(2. 4-dioxo-5-phen vl-3-( phen vlh vdrazono )-2,3.4,5-tetrahvdro benzo[b1[1,41diazepin-1-vll-N-isopropyl-N-phenvlacetamide
N-isopropyl-N-phenyl-2-(2-phenylaminophenylamino)-acetamide (10 g) and
2-(phenyl-hydrazono)-propanedioyl dichloride (6.83 g), were each dissolved in THF (100 ml) and added simultaneously, with stirring, to a flask containing THF (100 ml) at 0°C, under nitrogen. The reaction mixture was allowed to warm to R.T. and stirred four hours. The THF was evaporated in vacuo and the residue was dissolved in ethyl acetate (200 ml). The ethyl acetate solution was washed with 10% aqueous sodium carbonate (2 x 200 ml) and ; water (2 x 200 ml), dried (Na2SO4), and concentrated in vacuo. The residual foam was treated with diethyl ether (50 ml) to precipitate the title compound as a bright yellow solid (7.5 g). The mother liquor was concentrated to a tan foam (2.5 g). 1H-NMR (300 MHz, CDCI3): d 11.4 and 10.85 (s, 1H), 7.66.8 (m, 19 H), 5.05 (m, 1H), 4.4 (m, 2H), 1.05 (m, 6H); MS (FAB) = 532 (MH+); TLC, Rf = 0.19 (hexane:ethyl acetate, 2:1).
Intermediate 11
2-(3-Amino-2.4-dioxo-5-phenvl-2.3.4,5-tetrahvdrobenzo-iblf1,4ldiazepin-1-vl)N-isopropyl-N-phenylacetam ide
Zinc powder (9.1 g) was added in portions to a slurry of 2-[2,4-dioxo-5phenyl-3-(phenylhydrazono)-2,3,4,5-tetrahydro benzo[b][1,4]-diazepin-1 -y I]( 25 N-isopropyl-N-phenylacetamide (7.5 g), in glacial acetic acid, cooled to 0°C.
( The reaction was allowed to warm to R.T. and stirred an additional hour. The zinc was filtered through a celite pad and the glacial acetic acid was evaporated in vacuo. The residue was dissolved in ethyl acetate (200 ml) and washed with 10% aqueous sodium carbonate (2 x 100 ml) and water (2 x
100 ml), dried (Na2SO4) and evaporated to a tan oil. Trituration with hexane and ethyl acetate provided the title compound as a light tan powder (6.3 g). 1H-NMR (300 MHz, CDCI3): d 7.6-6.8 (m, 14H), 5.05 (m, 1H), 4.3-4.0 (m, 3H) 1.05 (d, 6H); MS (FAB) = 448 (MH+) ; TLC, Rf = 0.25 (chloroform:methanol, 9:1).
Intermediate 12
2-(3-Amino-2, 4-dioxo-5-phenvl-2. 3. 4. 5-tetrahvdro-benzo fbl 11. 41 diazepine-1-vl)-N-isopropyl-N-(4-methoxv-phenvl)-acetamide
S £ 9 0 0 ! Ί 6 /d/dV
G1055
To a stirred solution of 2-[2,4-dioxo-5-phenyl-3-(phenyl-hydrazono)-2,3,4,5tetrahydro-benzo[b][1,4]diazepine-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)acetamide (4.28g) in acetic acid (50mL) at ambient temperature, was added zinc dust (4.11g) and stirred three hours. The zinc was filtered off, the filtrate concentrated in vacuo, and the resultant oil partitioned between water (60mL) and ethyl acetate (100mL). The pH was adjusted to 8 with 6N sodium hydroxide and the phases separated. The aqueous phase was extracted with ethyl acetate (2 x 75mL) and the organics combined, dried with magnesium sulfate, filtered and concentrated in vacuo to give a yellow foam. The crude product was purified via flash chromatography on silica gel (80g) eluted successively with ethyl acetate (260mL) (to remove impurity) and methylene chloride/methanol (19:1, 200ml) (to elute product). Appropriate fractions were combined and concentrated to give the title compound (2.58g) as a yellow foam.
1H (300MHz, CDCI3): d 1.08 (d, J=6.6Hz, 6h), 2.22 (br s, 2H), 3.85 (s, 3H), 4.12-4.35 (m, 3H), 5.01 (m, 1H), 6.91-7.00 (m, 3H), 7.12 (m, 2H), 7.22-7.43 (m, 8H)
TLC (CH2CI2/CH3OH (19:1)): Rf= 0.25
Intermediate 13
2-f2,4-dioxo-5-phenvl-3-(ohenvl-hvdrazono)-2.3,4,5-tetrahvdrobenzofb1f1,41diazepine-1-vn-N-isopropyl-N-(4-methoxv-phenvl)-acetamide
Solutions of N-isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylaminophenylamino)-acetamide(3.00g) in THF (30mL) and 2-(phenyl-hydrazono) propandioyl dichloride (1.89g) in THF (30mL) were added concomitantly dropwise with stirring in an ice/methanol bath over a 30 minute period. After complete addition, the solution was allowed to warm to room temperature and stirred over night. The solvent was evaporated under reduced pressure and the resultant oil taken into ethyl acetate (250mL), washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.28g) as a yellow foam.
1H (300MHz, CDCI3): d 1.13 (m, 6H), 3.87 (s, 3H), 4.17-4.55 (m, 2H), 5.05 (m, 1H), 6.88-7.60 (m,18H), 10.68 (s, 0.5H), 11.44 (s, 0.5H)
TLC (EtOAc/Hex (2:3)): Rf= 0.38
G1055
AF c: o5 12
Intermediate 14
N-lsopropvl-N-(4-methoxv-phenvl)-2-(2-phenylamino-phenvlamino)acetamide
To a solution of N-phenyl-benzene-1, 2-diamine(3.08g) in DMF (35ml_) was added potassium carbonate (2.31 g) and 2-bromo-N-isopropyl-N-(4-methoxyphenyl)-acetamide (4.79g) and stirred 18h at ambient temperature. The solvent was evaporated in vacuo and the resultant oil was dissolved in ethyl acetate(250ml_), washed with 1N HCI (4 x 100mL), dried over sodium sulfate, filtered, and concentrated to a brown oil. The oil was subjected to flash chromatogaraphy on silica gel (70g) eluted with ethyl acetate/hexanes (1:4, 1L). Fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound as a tan foam (3.95g).
1H NMR (300MHz, CDCI3). d 1.05 (d, J=6.9Hz, 6H), 3.44 (s, 2H), 3.87 (s, 3H), 4.97 (m, 1H), 5.37 (br s, 1H) 6.36 (d, J=7.4Hz, 1H), 6.69 (t, 1H), 6.717.21 (m, 11H)
TLC (EtOAc/Hexane (1:4)): Rf= 0.18
Intermediate 15
2-Bromo-N-isopropyl-N-(4-methoxv-phenvl)-acetamide
To a solution of isopropyl-(4-methoxy-phenyl)-amine (25.11 g) in dichloromethane (250mL) was added triethylamine (15.38g) with stirring at ambient temperature: · The solution was cooled in an ice bath (<3°C) and bromoacetyl bromide (30.68g) dissolved in dichloromethane (100mL) was added dropwise over a 45 minute period with stirring and cooling in an ice bath. The reaction mix was stirred overnight at ambient temperature, washed with 0.3N HCI (300mL) and brine (300mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a dark brown oil. The oil was filtered through a pad of silica gel (150g) which was eluted with ethyl acetate/hexane (1:1, 900mL) and the filtrate evaporated under reduced pressure to afford the title compound (41,05g) as a brown oil which crystallized on standing.
1H NMR (300MHz, CDCI3): d 1.04(d, J= 6.8Hz, 6H), 3.53(s, 2H), 3.84(s, 3H), 4.93(m, 1H), 6.93(d, J= 9.1Hz, 2H), 7.10(d, J= 9.1Hz, 3H)
TLC (EtOAc/Hexane(3 17)): Rf=0.18
AP/P/ 9 4/ 0 0 6 3 5
G1055
APO Ο Ο ·» t 2
Intermediate 16 lsopropyl-(4-methoxy-phenyl)-amine
To a stirred solution of 4-methoxy-phenylamine (1.24g) in methanol (15mL) at ambient temperature was added successively, glacial acetic acid (415mg), acetone (669mg), and 1M sodium cyanoborohydride in THF (12.7mL). The reaction mixture was stirred overnight at room temperature. The pH was adjusted to 2 with 6N HCI and stirred for 30 minutes after which time the excess sodium cyanoborohydride was completely quenched. The pH was then adjusted to 8.5 with 1N NaOH and the resultant solution extracted with diethyl ether (2 x 50mL) and ethyl acetate (50mL). The oganic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1 42g) as a yellow oil.
1H NMR (300MHz, CDCI3): d 1.18(d, J= 6.1Hz, 6H), 2.92(br s, 1H), 3.55(m, 1H), 3.75(s, 3H), 6.57(d, J= 9.1Hz, 2H), 6.78(d, J= 8.8Hz, 2H)
TLC (EtOAc/Hex (2:3)): Rf= 0.72
Intermediate 17
3-Am inobenzeneacetonitri Ie
A solution of 3-nitrobenzeneacetonitril (8.0g) in EtOH (100ml) was hydrogenated at 1 atm and room temperature over 5% palladium on carbon (0.8g) for 4hrs. The catalyst was removed by filtration through Hyflo and the filtrate was evaporated. The residue was chromatographed, eluting with EA:Hexane (1:2) to give the title compound (5.25q) as an orange oil.
T.I.c. hexane:EA (2:1) Rf 0.45; NMR (300 MHz, CDCI3) d 3.792H.S); 3.9(2H,br); 6.7(3H,m); 7.2(H,M).
C 9 0 0 / ) 6 ,'d'dV
Intermediate 18
3-(2H-Tetrazol-5-yl)-phenvlamine hydrochloride
3-Aminobenzonitrile (10.0 g) and tributyltinazide (42 g) were heated together at 160°C under nitrogen for 120 minutes. The cooled mixture was diluted with ether (300 ml), extracted with 2N aqueous HCI (2 x 200 ml) and the combined aqueous extracts cooled in an ice-methanol bath for 30 minutes. The resulting precipitate was separated by filtration washed with ether (100 ml) and dried to give a pale pink solid. This was recrystalized from methanol (600 ml) to give the title compound as an off-white solid (12.1 g). 1H NMR
G1055
APC 0 C 5 1 2 (300MHz, DMSO-dg): d 7.32(d, J= 7.8Hz, 1H), 7.57(t, 1H), 7.82(m, 2H)
m.p.: 256-262°C (dec).
Using the general processes A-E outlined above, the following compounds of 5 the invention have also been made and are set forth below in Tables 1-9 for convenience as well as the synthesis routes for preparing them.
Embodiments (A)-(H) have been provided to correlate with Tables 1-9, respectively, for convenience in illustration and for ease in identification of compounds. Groups R13'21 have been provided in the Tables 1-9 merely for convenience in illustration and for ease in identification of compounds.
N
AP/P/ 9 4/ 0 0 6 3 5
Compound R4_R5_Process
1 | ch3 | 2-CI-C6H4- | C |
2 | ch3 | 2-CH3-C6H4- | c |
3 | ch3 | 2-COOCH3C6H4- | c |
4 | ch3 | 4-OCH3C6H4- | c |
5 | ch3 | 4-COOCH3C6H4- | c |
6 | (CH3)2CH- | C6H5- | c |
7 | ch3ch2ch2- | C6H5- | c |
G1055.2
8 | CH3CH2CH2CH2- | c6h5- | c |
9 | cyclohexyl | C6H5- | c |
10 | C6H5- | C6H5- | c |
11 | (CH3)2CH- | C6H5CH2- | c |
12 | (CH3)2CH- | (CH3)2CH- | c |
Table 2 (B) ComDound | R13 | R14 | R15 | General Process |
13 | H | H | H | D |
14 | 2-NH2 | 4-CI | H | D |
15 | 2-NH2 | H | H | D |
16 | 2-NH2 | 4-F | H | D |
17 | 2-COOH | H | H | D |
18 | 3-COOH | H | H | D |
19 | 2-OH | 4-CI | OCH3 | D |
20 | 2-F | 4-CI | och3 | D |
21 | 2-NH2 | 4-CI | och3 | D |
AP/P/ 9 4/ 0 0 6 3 5
G 1055.2
Table 3_(£}
General
5 | Compound | R3 | R8 | R9 | R16 Process | |
22 | C6H5- | H | H | H | D | |
23 | C6H5- | -CH2COOH | H | H | E | |
24 | C6H5 | -CH2CH2CH2COOH | H | H | E | |
25 | C6H5- | H | 5-OCH3 | H | D | |
10 | • 26 | C6H5- | -CH2COOH | 5-OCH3 | H | E |
27 | C6H5- | -CH2COOH | 5-CI | H | E | |
28 | C6H5- | H | 5-CH3 | H | D | |
29 | C6H5- | -CH2COOH | 5-CH3 | H | E | |
30 | L6H5- | H | 5-OH | H | D | |
15 | 31 | C6H5- | H | 7-NO2 | H | D |
32 | C6H5- | H | 7-NH2 | H | D | |
33 | C6H5- | H | H | OCH3 | D | |
34 | C6H5- | H | H | N(CH3)2 | D | |
35 | C6H5- | H | H morpholino | D | ||
20 | 36 | ch3 | H | H | H | D |
37 | ch3 | -CH2COOH | H | H | E | |
38 | H | H | H | H | D | |
39 | H | H | H | OCH3 | D |
AP/P/ 94/00635
G1055.2
Table 4 (D)
General
5 | Comoound | R17 | R18 | Process |
40 | H | 3-OH | A | |
41 | H | 3-NH2 | A | |
42 | H | 3-tetrazolyl | A/B | |
43 | H | 3-COOCH2CH3 | A | |
10 | 44 | H | 3-COOH | A |
45 | H | 3-NHSO2CF3 | A | |
46 | H | 3-OCH3 | A | |
47 | H | 3-SCH3 | A | |
48 | H | 3-N(CH3)2 | A | |
15 | 49 | H | 3-SOCH3 | A |
50 | H | 3-SOOCH3 | A | |
51 | H | 3-F | A | |
52 | H | 3-CH2COOH | A | |
53 | H | 3-OCH2COOH | A | |
20 | 54 | 4-OH | H | C |
55 | 4-OCH3 | H | C | |
56 | 4-OCH3 | 3-COOCH2CH3 | A | |
57 | 4-OCH3 | 3-COOH | A | |
58 | 4-N(CH3)2 | H | C | |
25 | 59 | 4-N(CH3)2 | 3-OH | A |
60 | 4-N(CH3)2 | 3-NH2 | A |
AP/P/ 9 4/ 0 0 6 3 5
G1055.2 ft.P Ο Ο Λ 5 1 2
61 | 4-morpholino | H | C |
62 | 4-morpholino | COOH | C |
63 | 4-N(CH3)2 | 3-COOCH2CH3 | A |
64 | 4-N(CH3)2 | 3-COOH | A |
Table 5 (Ε)
General
10 | ComDOund | R6 | R7 | R19 | Process |
65 | H | H | H | C | |
66* | -CH3 | H | H | C | |
67* | -CH3 | H | H | C | |
68*** | -CH3 | H | 3-OH | A | |
15 | 69*** | -ch3 | H | 3-OH | A |
70*' | -ch3 | H | 3-COOH | A | |
71*' | -CH3 | H | 3-COOH | A | |
72**' | -ch3 | 6-F | H | C | |
73**' | -ch3 | 6-F | H | C | |
20 | 74***' | -ch3 | 6-OCH3 | H | C |
75***' | -ch3 | 6-OCH3 | H | C |
AP/P/ 94/00635 ' denote pairs of diastereomers
G1055.2
4C
(F)
Table 6_(E) ComDcund | R7 | R8 | R9 | General Process |
76 | H | H | H | D |
77* | F | H | 7-NH2 | D |
78* | F | H | 7-NH2 | D |
*, ** denotes pairs of diastereomers |
ch3
(G)
Table 7 (G)
Compound R20
Synthesis fi21_Scheme
G1055.2
AP Ο 9 51 1
AP/
D
G1055.2
ΑΡΓ η ·/ ί»1 2
Table 8 (Η)
ro jO
Ο <O
Synthesis
Comoound | R22 | R23 | R3 | Scheme |
88 | H | H | ch3 | C |
89 | H | 3-COOH | ch3 | A |
90 | H | 3-COOH | H | A |
91 | H | 2-OH | ch3 | A |
G1055
ΛΡ Ο Ο 9 fi 1 2
GUINEA PIG GALL BLADDER ASSAY
Tissue Preparation:
Gallbladders were removed from guinea pigs sacrificed by cervical dislocation. The isolated gallbladders were cleaned of adherent connective tissue and cut into two rings from each animal (2-4 mm in length). The rings were subsequently suspended in organ chambers containing a physiological salt solution of the following composition (mM): NaCl (118.4); KCI (4.7);
MgSO4 x H2O (1.2); CaCI2 x 2H2O (2.5); KH2PO3 (1.2); NaHCO3 (25) and dextrose (11.1). The bathing solution was maintained at 37°C and aerated with 95% 02/5%C02. Tissues were connected via gold chains and stainless steel mounting wires to isometric force displacement transducers (Grass,
Model FT03 D). Responses were then recorded on a polygraph (Grass,
Model 7E). One tissue from each animal served as a time/solvent control and did not receive test compound. <o o
Assay:
Rings were gradually stretched (over a 120 min. period) to a basal resting tension of 1 gm which was maintained throughout the experiment. During the basal tension adjustment period, the rings were exposed to acetylcholine (ACH, 10*6 M) four times to verify tissue contractility. The tissues were then exposed to a submaximal dose of sulfated CCK-8 (Sigma, 3 X 10-9 M). After obtaining a stable response, the tissues were washed out 3 times rapidly and every 5 to 10 minutes for 1 hour to reestablish a stable baseline.
Compounds were dissolved in dimethylsulfoxide (DMSO) then diluted with water and assayed via a cumulative concentration-response curve to test compound (10*11 to 3 X W*6 M) followed by a concentration-response curve to sulfated CCK-8 (10’1° to 10*6 M) in the presence of the highest dose of the test compound. As a final test, ACH (Ί0 mM) was added to induce maximal contraction. A minimum of three determinations of activity were made for each test compound.
Table 10 set forth below lists experimental data for representative compounds of general Formula (I). Agonist activity in the guinea pig gall
G1055
APn 6 · · *> 1 2 bladder (GPGB) is listed as the % maximal contraction induced by acetylcholine (Ach) at a 30μΜ concentration of the test compound.
It will be appreciated by those skilled in the art that the compounds of the 5 present invention can be administered therapeutically within the aforementioned dosage regimen up to without toxic effects as indicated by data which showed no toxic effects in rats even at dosages up to 12 mg/kg.
18-HOUR DEPRIVATION-INDUCED FEEDING PARADIGM
Male, Long-Evans rats (Charles River Co., Raleigh, NC), weighing 300-375 grams, were acclimated individually for at least a week in hanging, stainless steel mesh cages (17.8 X 25.4 X 17.8 cm high) with ad libitum access to water (delivered through automatic drinking spouts at the rear of the cage) ( 15 and food (Lab Blox, Purina Rodent Laboratory Chow #5001) on a 12-hour light/dark cycle (lights on from 0500-1800 hours, or h) at approximately 22.8eC. Prior to testing, all chow, but not water, was removed at 1600 h. At 0900 h the next morning, rats were weighed. At 0945 h, rats were injected intraperitoneally (i.p), orally (per os, or p.o.) or through an indwelling, intra20 duodenal cannulea with a test compound or vehicle (2 ml/kg) and returned to their home cages. Food was presented at 1000 h. At 1030 h, remaining food and spillage was weighed.
GUINEA PIG GALL BLADDER ASSAY
C
C
Compound #
GPGB % Contraction (relative to Ach) 30nM
42%
66%
34%
43%
43%
46%
64%
55%
AP/P/ 9 4/ 0 0 6 3 5
G1055 > , .·. Λ . 2
G1055
Pharmacy Examples
Tablets
Active ingredient | 50mg |
Lactose anhydrous USP | 163mg |
Microcrystalline Cellulose NF | 69mg |
Pregelatinised starch Ph.Eur. | 15mg |
Magnesium stearate USP | 3mg |
Compression weight | 300m g |
V
The active ingredient, microcrystalline cellulose, lactose and pregelatinised starch are sieved through a 500 micron sieve and blended in a suitable mixer. The magnesium stearate is sieved through a 250 micron sieve and blended with the active blend. The blend is compressed into tablets using suitable punches.
b. Active ingredient | 50mg |
Lactose monohydrate USP | 120mg |
Pregelatinised starch Ph.Eur. | 20m g |
Crospovidone NF | 8mg |
Magnesium stearate USP | 2mq |
Compression weight | 200mg |
The active ingredient, lactose and pregelatinised starch | are blended |
together and granulated with water. The wet mass is dried and milled. The magnesium stearate and Crospovidone are screened through a 250 micron sieve and blended with the granule. The resultant blend is compressed using suitable tablet punches.
( 25 f
AP/P/ 94/ 0 0 6 3 5
Capsules
a. Active ingredient 50mg
Pregelatinised Starch Ph.Eur. 148mg
Magnesium stearate USP 2mg
Fill weight 200mg
The active ingredient and pregelatinised starch are screened through a 500 micron mesh sieve, blended together and lubricated with magnesium
G1055 /\Ρ Ο '' < 5 1 2 stearate (meshed through a 250 micron sieve). The blend is filled into hard gelatin capsules of a suitable size.
Active ingredient | 50mg |
Lactose monohydrate USP | 223mg |
Povidone USP | 12mg |
Crospovidone NF | 12mg |
Magnesium stearate | 3mq |
Fill weight | 300mg |
The active ingredient and lactose are blended together and granulated with a solution of Povidone. The wet mass is dried and milled. The magnesium stearate and Crospovidone are screened through a 250 micron sieve and blended with the granule. The resultant blend is filled into hard gelatin capsules of a suitable size.
Claims (16)
1. A compound of Formula (I) and physiologically salts and solvate thereof wherein:
X is either hydrogen, trifluoromethyl, alkyl, C-|-4alkylthio, -O(Ci-4alkyl) or 10 halogen;
R1 is either Formula II or -NR4r5.;
(II)
R2 is either * ( (1) a heterocycle linked at its 2- position and selected from pyrrole, tetrahydropyrrole, indole, benzofuran, thiophene, benzothiophene, indoline, quinoline or 4-oxobenzopyran and wherein said pyrrole,
20 tetrahydropyrrole, indole or indoline may optionally be substituted on the ring nitrogen thereof by the group R® as defined hereunder and said indole, indoline, quinoline, benzofuran, benzothiophene or 4-oxobenzopyran may optionally be substituted in the benzo ring thereof by the group R® as defined hereunder or (2) phenyl or phenyl mono- or disubstituted independently with halogen, hydroxy, cyano, carboxy, -O(Ci-4alkyl), -O(CH2C6H5), -COO(Ci-4alkyl), amino, dimethylamino, -NHR^, 1 -pyrrolidinyl or tetrazolyl; or
AP/P/ 94/00635
-49(3) pyridine or pyridinyl mono- or disubstituted independently with halogen, methyl, hydroxy, nitro, cyano, carboxy, -0(Ci-4 alkyl), -O(CH2C6Hs), COO(Cv4alkyl), amino or dimethylamino; or
5 (4) -NHR11 where R11 is defined hereinunder or R11 is 7-indazolyl containing a group R10 at the N-1 position;
R3 is hydrogen, Ci-ealkyl, C3-6cycloalkyl, phenyl or phenyl mono- or disubstituted independently with halogen;
R4 represents C3-ealkyl, cyclohexyl, or phenyl, and R5 represents C3-6alkyl, or phenyl optionally substituted in the para position by hydroxy, dimethylamino, methoxy, fluorine, pyrrolidino or morpholino.
15 R6 is methyl;
•ό
R7 is hydrogen, hydroxy, fluoro, or methoxy; rs
- s
R8 is -<CH2)bCOOH;
τ
RO is methyl, chloro, nitro, hydroxy, methoxy or -NHR10, (*· · r10 is hydrogen, acetyl, Cl-4alkyl, -SO3H, -SO2CH3, -SO2CF3 or -SO2C6H5,
C j _4alkoxycarbonyl;
R11 is phenyl or phenyl mono- or disubstituted independently with fluorine, trifluoromethoxy, Ci-4alkylthio, -(CH2)cC00H, -(CH2)cCOO(Ci-4alkyl), -(CH2)cSCH3, -(CH2)cSOCH3, -(CH2)cSO2CH3, -(CH2)cCONH2, -SCH2C00H. -CONH(SO2CH3), -CONH(SO2CF3), -(CH2)cN(Ci-4alkyl)2,
30 -(CH2)cNH(S02CF3),-(CH2)cN(S02CF3)(Cl -4alkyl), -(CH2)cSO2NHCO(Cl 4alkyl), -<CH2)cSO2N(Ci^aikyl)CO(Ci^alkyl), -(CH2)cCONHSO2(Ci-4alkyl), (CH2)cCON(Cl-4alkyl)SO2(Cl-4alkyl), -(CH2)cOR12 -(CH2)cNHR10 or phenyl monosubstituted with -(CH2)c(tetrazolyl), -(CH2)c (carboxamidotetrazolyl) or (CH2)c(py>''Olidinyl) or R11 is selected from pyridine or pyridinyl mono- or
35 disubstituted independently with halogen, methyl, hydroxy, nitro, cyano, carboxy, -O(Ci-4 alkyl), amino, dimethylamino, -NHR10;
AP r r Λ K 4 2
-50R12 is hydrogen, C^alkyl, C3^cycloalkyl, -CH2C5H5, -CH2COOH, CH2CONH2, -CH2CONH(Ci^alkyl), -CH2CON(C1^alkyl)2 or (CHj! CO-N 0 or .(CHJ CON N-R \ / · € \ / z is 1 or 2;
n is 1;
p is an integer from 1-4;
10 b is an integer from 0-3; and c is 0 or 1.
which comprises:
2. A compound according to Claims 1 wherein R1 represents the group NR4Rs and R4 represents propyl or isopropyl and R5 represent phenyl or pheny substituted in the para position by a group selected from hydroxy, methoxy, dimethylamino, fluorine, or morpholino.
3. A compound according to claims 1 or 2 wherein R2 represents a group selected from phenyl (optionally substituted by one or two groups which may be same or different and selected from chlorine, fluorine, amino, hydroxy or carboxy,) or NRRi1 wherein R11 is pheny (optionally substituted by fluoro, hydroxy, amino, dimethylamino, trifluorornethylsuiphonylamino, Cu alkoxycarbonyl, carboxy, 1 H-tetrazol-5-yl, acetylamino or OR12 wherein R12 represents hydrogen, methyl, benzyl, CH2CO2H, CH2CONH2, CH2CONHCH3, CH2CON9CH3)2
S Ϊ 9 0 0 / * 6 /d/dV
CHjCON
CHjCON NH or
CH2C0N
NCOjCICH,), )or 7-indazolyl wherein the N-1 substituted is hydrogen, or R2 represents an indole group wherein the nitrogen atom is optionally substituted by the group CH2CO2H and benzo ring is optionally substituted by a group selected from chlorine, methyl, methoxy, nitro, hydroxy or amino.
\_7
ΑΡΠο ο 52
-514. A compound according to any of Claims 1 -3 wherein R2 represents an indole group which is unsubstituted on the nitrogen atom and in which the benzo ring thereof is optionally substituted by a group selected from chlorine,
5 methyl, methoxy, nitro, hydroxy or amino.
5. A compound according to any of Claims 1-4 wherein R3 represents hydrogen, methyl, cyclohexyl,2-fluorophenyl or phenyl.
10
6. A compound according to any of Claims 1-5 wherein R3 represents phenyl.
7. A compound according to any of Claims 1-6 wherein X represents hydrogen.
8. A compound of formula (I) wherein R1 represents NR4R5 and R4 represents isopropyl and R3 represents p-methoxyphenyl; R2 represents an unsubstituted 2-indole group; R3 represents phenyl and X represents hydrogen and enantiomers thereof.
9. A compound according to any of Claims 1 -8 for use in therapy.
10. The use of a compound according to any of Claims 1 to 8 in the manufacture of a medicament for the treatment of condition where a modulation
25 of the affects gastric or CCK is of therapeutic benefit.
11. A method of treatment of a mammal including man for conditions where modulation of the effects of gastric and/or CCK is of a therapeutic benefit comprising administration of an effective amount of a compound according to
30 any of Claims 1 to 8.
12. A pharmaceutical composition comprising a compound according to any of Claims 1 to 8 in a admixture with one or more physiologically acceptable carriers or excipients.
13. A process for the preparation of compound as defined in Claim 1 which comprises:
AP/P/ 9 4/ 0 0 6 3 5
AP P 0 Ή 2
-52(a) reacting a compound of Formula (III) wherein R1, R2, X and z are as defined in Formula (I)
R i
NHZ (III) (
with a compound R11Y (IV) wherein Y is the group -NCO, HNCOCI or NHCORa where Ra is nitro substituted phenoxy group or a 1-imidazole group.
wherein R11 has the meaning defined in Formula (I) or is a group convertible thereto.
(b) reacting a compound of Formula (V) R
AP/P/ 94/00635 f 15 wherein R\ R2 X and z have the meaning defined above and wherein Y is the group -NCO, -NHCOCI or NHCORa wherein Ra is a nitro substituted phenoxy group or a 1-imidazole group with an amine (VI)
H2N-R11 (VI) wherein R11 has the meaning defined in Formula (I) and is a group convertible thereto.
ftp 0 0 ο
-53(c) reacting a compound of Formula (VII) wherein. R3 , R11 and X are as defined in Formula (I) 5 R ° ‘V>
with the compound of Formula (VIII) wherein R1 has the meanings defined in Formula (I)
R1COCH2hal (VIII) c - 10 (d) reacting a compound of Formula (III) wherein R1, R3 X and Z are as defined in Formula (I).
R'
5 2 9 0 0 /^6 /dMV with an acid of Formula (IX) or an activated derivative thereof.
20 HOOC-R2 (IX) wherein R2 has the meanings defined in Formula (I) or is a group convertible thereto;
25 and thereafter, if necessary or desired, converting the required compound into another compound of the invention.
14. A method of treating obesity and related disease states in a mammal which comprises administering to said mammal a therapeutically-effective
Α.Γ Ο 0 η κ 4 (
-54amount of a compound according to claim 1, whereby an anorectic effect is achieved in said mammal.
15. A method for modifying the food intake of a mammal which comprises 5 administering to said mammal a therapeutically-effective amount of a compound according to Claim 1, whereby food intake is modified.
16. A method for inducing satiety in mammal which comprises administering to said mammal a therapeutically-effective amount of a compound
10 according to claim 1, whereby satiety is induced.
17. A method for providing appetite regulation in mammal which comprises administering to said mammal a therapeutically-effective amount of a compound according to Claim 1, whereby appetite regulation is achieved.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB939307833A GB9307833D0 (en) | 1993-04-15 | 1993-04-15 | Modulators of cholecystokinin and gastrin |
Publications (2)
Publication Number | Publication Date |
---|---|
AP9400635A0 AP9400635A0 (en) | 1994-04-30 |
AP512A true AP512A (en) | 1996-07-29 |
Family
ID=10733915
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
APAP/P/1994/000634A AP462A (en) | 1993-04-15 | 1994-04-13 | 1,5 Benzodiazepine derivatives. |
APAP/P/1994/000635A AP512A (en) | 1993-04-15 | 1994-04-13 | Derivatives of 1-aminocarbonylmethyl-3-amino-2,4-dioxo-1-5 benzodiazepines having CCKA agonist activity. |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
APAP/P/1994/000634A AP462A (en) | 1993-04-15 | 1994-04-13 | 1,5 Benzodiazepine derivatives. |
Country Status (34)
Country | Link |
---|---|
US (2) | US5646140A (en) |
EP (1) | EP0694039B1 (en) |
JP (1) | JP3406317B2 (en) |
KR (1) | KR100364948B1 (en) |
CN (1) | CN1058487C (en) |
AP (2) | AP462A (en) |
AT (1) | ATE198894T1 (en) |
AU (1) | AU681139B2 (en) |
CA (1) | CA2158973C (en) |
CZ (1) | CZ286695B6 (en) |
DE (1) | DE69426624T2 (en) |
DK (1) | DK0694039T3 (en) |
EC (1) | ECSP941066A (en) |
ES (1) | ES2154674T3 (en) |
FI (1) | FI954853A0 (en) |
GB (1) | GB9307833D0 (en) |
GR (1) | GR3035641T3 (en) |
HK (1) | HK1003943A1 (en) |
HU (1) | HU223467B1 (en) |
IL (2) | IL109315A0 (en) |
IS (2) | IS4147A (en) |
MY (2) | MY131569A (en) |
NO (1) | NO311133B1 (en) |
NZ (1) | NZ265272A (en) |
OA (1) | OA10355A (en) |
PE (2) | PE50994A1 (en) |
PH (1) | PH30897A (en) |
PL (1) | PL178790B1 (en) |
PT (1) | PT694039E (en) |
RU (1) | RU2135486C1 (en) |
SK (1) | SK281211B6 (en) |
TW (1) | TW487703B (en) |
WO (1) | WO1994024149A1 (en) |
ZA (2) | ZA942571B (en) |
Families Citing this family (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3621416B2 (en) * | 1993-12-28 | 2005-02-16 | 塩野義製薬株式会社 | Novel benzodiazepine derivatives |
US5739129A (en) * | 1994-04-14 | 1998-04-14 | Glaxo Wellcome Inc. | CCK or gastrin modulating 5-heterocyclic-1, 5 benzodiazepines |
WO1995028419A1 (en) * | 1994-04-14 | 1995-10-26 | Glaxo Wellcome Inc. | Cck or gastrin modulating 5-heterocyclic-1,5-benzodiazepines |
AU2446295A (en) * | 1994-04-15 | 1995-11-10 | Glaxo Inc. | A method of inducing cholecystokinin agonist activity using 1,4-benzodiazepine compounds |
PE27497A1 (en) * | 1994-04-15 | 1997-08-07 | Glaxo Inc | DERIVATIVES OF 1,5 BENZODIAZEPINA |
GB9420763D0 (en) * | 1994-10-14 | 1994-11-30 | Glaxo Inc | Acetamide derivatives |
US5780464A (en) * | 1994-10-14 | 1998-07-14 | Glaxo Wellcome Inc. | Enteric coated compositions of 1,5-benzodiazepine derivatives having CCK antagonistic or agonistic activity |
GB9420747D0 (en) * | 1994-10-14 | 1994-11-30 | Glaxo Inc | 1,5 benzodiazepine derivatives |
US5910495A (en) * | 1994-10-14 | 1999-06-08 | Glaxo Wellcome Inc. | Use of 1,5-benzo b!1,4-diazepines to control gastric emptying |
GB9420748D0 (en) * | 1994-10-14 | 1994-11-30 | Glaxo Inc | 1,5 benzodiazepine derivatives |
US5750353A (en) * | 1995-12-11 | 1998-05-12 | New England Medical Center Hospitals, Inc. | Assay for non-peptide agonists to peptide hormone receptors |
CA2239293A1 (en) | 1995-12-11 | 1997-06-19 | New England Medical Center Hosptials, Inc. | Assay for and uses of peptide hormone receptor ligands |
ATE248823T1 (en) * | 1996-12-10 | 2003-09-15 | Zeria Pharm Co Ltd | 1,5-BENZODIAZEPINE DERIVATIVES |
JP3553086B2 (en) | 1997-04-15 | 2004-08-11 | シーエスアイアール | Pharmaceutical composition having appetite suppressing activity |
AR022044A1 (en) * | 1999-05-06 | 2002-09-04 | Glaxo Group Ltd | DERIVATIVES OF 1,5-BENZODIAZEPINA |
GB2355657B (en) | 1999-10-27 | 2004-07-28 | Phytopharm Plc | Inhibitors Of Gastric Acid Secretion |
GB2363985B (en) | 2000-06-30 | 2004-09-29 | Phytopharm Plc | Extracts,compounds & pharmaceutical compositions having anti-diabetic activity and their use |
US6768024B1 (en) | 2000-08-04 | 2004-07-27 | Lion Bioscience Ag | Triamine derivative melanocortin receptor ligands and methods of using same |
US20020180095A1 (en) * | 2001-05-29 | 2002-12-05 | Berard Steven O. | Thermally conductive carbon fiber extrusion compounder and method of using same |
MXPA04008073A (en) * | 2002-02-20 | 2004-11-26 | Abbott Lab | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (vr1) receptor. |
US7074805B2 (en) * | 2002-02-20 | 2006-07-11 | Abbott Laboratories | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor |
US6933311B2 (en) * | 2003-02-11 | 2005-08-23 | Abbott Laboratories | Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor |
US7015233B2 (en) | 2003-06-12 | 2006-03-21 | Abbott Laboratories | Fused compounds that inhibit vanilloid subtype 1 (VR1) receptor |
GEP20094723B (en) * | 2004-05-25 | 2009-07-10 | Pfizer Prod Inc | Tetraazabenzo [e] azulene derivatives and analogs thereof |
CN1333077C (en) * | 2005-04-15 | 2007-08-22 | 华南农业大学 | Cascade expression of active fragment of cholecystokinin and application thereof |
CA2661898A1 (en) * | 2006-08-25 | 2008-02-28 | Abbott Laboratories | Indazole derivatives that inhibit trpv1 and uses thereof |
JP2010513557A (en) * | 2006-12-20 | 2010-04-30 | アボット・ラボラトリーズ | N- (5,6,7,8-tetrahydronaphthalen-1-yl) urea derivatives and related compounds as TRPV1 vanilloid receptor antagonists for the treatment of pain |
EP2323989A4 (en) * | 2008-03-20 | 2011-06-22 | Abbott Lab | Methods for making central nervous system agents that are trpv1 antagonists |
CN103102285B (en) * | 2013-01-30 | 2015-07-29 | 淮阴师范学院 | The preparation method of p-aminophenyl acetonitrile |
WO2015074081A1 (en) | 2013-11-18 | 2015-05-21 | Bair Kenneth W | Benzopiperazine compositions as bet bromodomain inhibitors |
BR122019007990B1 (en) | 2013-11-18 | 2021-05-04 | Forma Therapeutics, Inc | COMPOUND, AND, PHARMACEUTICAL COMPOSITION |
LT3324977T (en) | 2015-07-22 | 2022-10-25 | Enanta Pharmaceuticals, Inc. | Benzodiazepine derivatives as rsv inhibitors |
WO2017136727A2 (en) | 2016-02-05 | 2017-08-10 | Denali Therapeutics Inc. | Compounds, compositions and methods |
HRP20220636T1 (en) | 2016-12-09 | 2022-07-22 | Denali Therapeutics Inc. | Compounds useful as ripk1 inhibitors |
US10358441B2 (en) | 2017-02-16 | 2019-07-23 | Enanta Pharmaceuticals, Inc. | Processes for the preparation of benzodiazepine derivatives |
US10752598B2 (en) * | 2017-06-07 | 2020-08-25 | Enanta Pharmaceuticals, Inc. | Aryldiazepine derivatives as RSV inhibitors |
WO2019006295A1 (en) | 2017-06-30 | 2019-01-03 | Enanta Pharmaceuticals, Inc. | Heterocyclic compounds as rsv inhibitors |
US10851115B2 (en) | 2017-06-30 | 2020-12-01 | Enanta Pharmaceuticals, Inc. | Heterocyclic compounds as RSV inhibitors |
EP3687543B1 (en) | 2017-09-29 | 2024-03-20 | Enanta Pharmaceuticals, Inc. | Combinations of pharmaceutical agents as rsv inhibitors |
US10647711B2 (en) | 2017-11-13 | 2020-05-12 | Enanta Pharmaceuticals, Inc. | Azepin-2-one derivatives as RSV inhibitors |
US10975094B2 (en) | 2018-04-11 | 2021-04-13 | Enanta Pharmaceuticals, Inc. | Heterocyclic compounds as RSV inhibitors |
JP2022525893A (en) | 2019-03-18 | 2022-05-20 | エナンタ ファーマシューティカルズ インコーポレイテッド | Benzodiazepine derivative as an RSV inhibitor |
US11179400B2 (en) | 2019-04-09 | 2021-11-23 | Enanta Pharmaceuticals, Inc. | Heterocyclic compounds as RSV inhibitors |
US11505558B1 (en) | 2019-10-04 | 2022-11-22 | Enanta Pharmaceuticals, Inc. | Antiviral heterocyclic compounds |
UY39032A (en) | 2020-01-24 | 2021-07-30 | Enanta Pharm Inc | HETEROCYCLIC COMPOUNDS AS ANTIVIRAL AGENTS |
US11534439B2 (en) | 2020-07-07 | 2022-12-27 | Enanta Pharmaceuticals, Inc. | Dihydroquinoxaline and dihydropyridopyrazine derivatives as RSV inhibitors |
US11945824B2 (en) | 2020-10-19 | 2024-04-02 | Enanta Pharmaceuticals, Inc. | Heterocyclic compounds as anti-viral agents |
TW202334164A (en) | 2022-01-12 | 2023-09-01 | 美商戴納立製藥公司 | Crystalline forms of (s)-5-benzyl-n-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b][1,4]oxazepin-3-yl)-4h-1,2,4-triazole-3-carboxamide |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0376849A1 (en) * | 1988-12-29 | 1990-07-04 | Roussel-Uclaf | 2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine derivatives, process and intermediates for their preparation, their pharmaceutical use and compositions containing them |
WO1993014074A1 (en) * | 1992-01-21 | 1993-07-22 | Glaxo Spa | 1,5-benzodiazepine derivatives and their use in medicine |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2659653B1 (en) * | 1990-03-13 | 1992-05-22 | Rhone Poulenc Sante | DERIVATIVES OF UREA, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM. |
US5206234A (en) * | 1990-10-22 | 1993-04-27 | Merck & Co., Inc. | Benzolactam analogs as antagonists of cck |
JP2904941B2 (en) * | 1991-01-28 | 1999-06-14 | 出光興産株式会社 | Purification method of styrenic polymer |
WO1995028419A1 (en) * | 1994-04-14 | 1995-10-26 | Glaxo Wellcome Inc. | Cck or gastrin modulating 5-heterocyclic-1,5-benzodiazepines |
-
1993
- 1993-04-15 GB GB939307833A patent/GB9307833D0/en active Pending
-
1994
- 1994-01-04 US US08/525,659 patent/US5646140A/en not_active Expired - Lifetime
- 1994-04-11 IS IS4147A patent/IS4147A/en unknown
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- 1994-04-13 AP APAP/P/1994/000634A patent/AP462A/en active
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- 1994-04-14 WO PCT/EP1994/001131 patent/WO1994024149A1/en active IP Right Grant
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- 1994-04-14 AU AU65676/94A patent/AU681139B2/en not_active Ceased
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- 1994-04-14 EP EP94913580A patent/EP0694039B1/en not_active Expired - Lifetime
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-
1995
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1998
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2001
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0376849A1 (en) * | 1988-12-29 | 1990-07-04 | Roussel-Uclaf | 2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine derivatives, process and intermediates for their preparation, their pharmaceutical use and compositions containing them |
WO1993014074A1 (en) * | 1992-01-21 | 1993-07-22 | Glaxo Spa | 1,5-benzodiazepine derivatives and their use in medicine |
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