Claims
- 1. A compound of the formula: ##STR7## wherein R.sub.1 is --(CH.sub.2).sub.m C(O)OR.sub.4 wherein m is 1 to 4 and R.sub.4 is loweralkyl, loweralkenyl, loweralkynyl, aryl, substituted aryl, arylalkyl or (substituted aryl)alkyl;
- R.sub.2 is loweralkyl, lowralkenyl, aryl, substituted aryl, arylalkyl, (substituted aryl)alkyl or --(CH.sub.2).sub.m cycloalkyl wherein m is independently selected from 0,1,2,3 and 4;
- R.sub.3 is --OR.sub.4 wherein R.sub.4 is independently selected from loweralkyl, loweralkenyl, loweralkynyl, aryl, substituted aryl, arylalkyl and (substituted aryl)alkyl; wherein
- R.sub.5 is hydrogen, loweralkyl, cycloalkyl, loweralkenyl, loweralkynyl, hydroxy, halogen, trihalomethyl, nitro, --CN, --NH.sub.2, thioalkoxy, --NHOH, carboxy, carboalkoxy or carboxamide;
- and n is 1 to 3; or a pharmaceutically acceptable salt thereof.
- 2. The compound of claim 1 wherein R.sub.1 is --(CH.sub.2).sub.m C(O)OR.sub.4 wherein m is 1 to 4 and R.sub.4 is loweralkyl; R.sub.2 is arylaklyl; R.sub.3 is --OR.sub.4 wherein R.sub.4 is arylalkyl; R.sub.5 is hydroxy and n is 1 to 3.
- 3. The compound of claim 2 wherein m is 1; R.sub.1 is --CH.sub.2 C(O)OEt; R.sub.4 is --O(benzyl); R.sub.2 is benzyl and n is 2.
- 4. The compound having the formula: ##STR8##
- 5. A pharmaceutical composition useful for antagonizing CCK comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.
- 6. The composition of claim 5 wherein the compound is ##STR9##
- 7. A method for antagonizing CCK comprising administering to a human or animal in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 8. The method of claim 7 wherein the compound is: ##STR10##
TECHNICAL FIELD
This is a continuation-in part of U.S. Pat. application Ser. No. 099,866, filed Sept. 21, 1987, now abandoned.
The present invention relates to novel organic compounds and compositions which antagonize cholecystokinin, processes for making such compounds, synthetic intermediates employed in these processes, a composition and a method for antagonizing CCK, and a composition and a method for treating gastrointestinal disorders, cancers of the gall bladder and pancreas, hyperinsulinemia, central nervous system disorders, or potentiating pain, or regulating appetite with such compounds.
Cholecystokinins (CCK) are a family of amino acid polypeptide hormones. CCK.sub.33, a 33 amino acid fragment of CCK was first isolated from hog intestine. Matt and Jorpes, Biochem. J. 125 628 (1981)). Recently the CCK.sub.33 fragment has been found in the brain, where it appears to be the precursor of two smaller fragments, an octapeptide and a tetrapeptide CCK.sub.4. (Dockray, [Nature 264 4022 (1979)).
CCK.sub.8, the carboxyl terminal octapeptide fragment of CCK, is the most potent peptide in the CCK family and is the predominant form of CCK in the brain. (Larson and Rehfeld, Brain Res. 165 41 (1981)). The localization of CCK fragments in the cortex of the brain suggests that CCK may be an important neuromodulator of memory, learning and control of primary sensory and motor functions. CCK and its fragments are believed to play an important role in appetite regulation and satiety. (Della Fera, Science 206 471 (1979); Gibbs et al., Nature 289 599(1981); and Smith, Eating and Its Disorders, eds., Raven Press, New York, 67 (1984)).
CCK antagonists are useful in the treatment and prevention of CCK-related disorders of the gastrointestinal (GI), central nervous (CNS) and appetite regulatory systems of animals, especially man. CCK antagonists are also useful in potentiating and prolonging opiate induced analgesia and thus have utility in the treatment of pain. (Faris et al., Science 226 1215 (1984)).
Previously four distinct chemical classes of CCK receptor antagonists have been reported. The first class comprises derivatives of cyclic nucleotides as represented by dibutyryl cyclic GMP (N. Barlos et al., Am. J. Physiol., 242, G 161 (1982) and references therein). The second class is represented by C-terminal fragments of CCK (see Jensen et al. Biochem. Biophys. Acta, 757, 250 (1983) and Spanarkel J. Biol. Chem. 758, 6746 (1983)). The third class comprises amino acid derivatives of glutamic acid and tryptophan as indicated by proglumide and benzotript (see Hans et al. Proc. Natl. Acad. Sci. U.S.A., 78, 6304 (1981) and Jensen et al. Biochem. Biophys. Acta. 761, 269 (1983)). The fourth and most recent class is comprised of 3-substituted benzodiazepines, represented by L 364,718 (see: Evans et al. Proc. Natl. Acad. Sci. U.S.A., 83 4918 (1986)).
With the exception of the benzodiazepine based class, all of these compounds are relatively weak antagonists of CCK demonstrating IC.sub.50 values between 10.sup.-4 and 10.sup.-6 M. The benzodiazepine CCK antagonists or their metabolites may have undesirable effects in vivo due to their interaction with benzodiazepine receptors.
The C terminal pentapeptide fragment of CCK is the same as the C terminal pentapeptide fragment of another polypeptide hormone, gastrin. Gastrin, like CCK, exists in both the GI and CNS systems. Gastrin antagonists are useful in the treatment and prevention of gastrin related disorders of the GI system such as ulcers, Zollinger Ellison syndrome and central G cell hyperplasia. There are no known effective receptor antagonists of the in vivo effects of gastrin. (Morely, Gut Pept. Ulcer Proc., Hiroshima Symp. 2nd, 1, (1983)).
It has now been found that the compounds of the invention are antagonists of cholecystokinin (CCK) and bind specifically to CCK receptors. These CCK antagonists are useful in the treatment and prevention of CCK-related disorders of the gastrointestinal, central nervous and appetite regulatory systems of animals and humans. These compounds are useful in the treatment and prevention of gastrointestinal ulcers, cancers of the gall bladder and pancreas, pancreatitis, hyperinsulinemia, Zollinger-Ellison syndrome, central G cell hyperplasia, irritable bowel syndrome, the treatment or prevention of neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis, Gilles de la Tourette syndrome, disorders of appetite regulatory systems, the treatment of pain and the treatment of substance abuse.
In accordance with the present invention, there are cholecystokinin antagonists of the formula: ##STR2## wherein R.sub.1 and R.sub.2 are independently selected from
(1) hydrogen,
(2) C.sub.1 -C.sub.8 loweralkyl,
(3) cycloalkyl,
(4) loweralkenyl,
(5) --(CH.sub.2).sub.m (C(O)).sub.r cycloalkyl wherein m and r are not both. 0,
(6) --(CH.sub.2).sub.m CN,
(7) --(CH.sub.2).sub.m OR.sub.9 wherein R.sub.9 is loweralkyl, aryl, substituted aryl wherein the aryl group is substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, nitro, trihalomethyl, hydroxy, amino, and NH(loweralkyl), arylalkyl or (substituted aryl)alkyl wherein substituted aryl is as defined above,
(8) adamantyl,
(9) --(CH.sub.2).sub.m (C(O)).sub.r NR.sub.6 R.sub.7 wherein
R.sub.6 and R.sub.7 are independently selected from hydrogen, loweralkyl, cycloalkyl, loweralkenyl,
--(CH.sub.2).sub.m aryl,
--(CH.sub.2).sub.m (substituted aryl) wherein substituted aryl is as defined above, and --(CH.sub.2).sub.m heterocyclic,
(10) cyclic groups wherein R.sub.1 and R.sub.2 taken together with the adjacent nitrogen atom are morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl or other substituted cyclic groups represented by ##STR3## wherein E and J are independently selected from (CH.sub.2).sub.p, (CH.dbd.CH).sub.r, CH.sub.2 C(O), C(O)CH.sub.2, QCH.sub.2, CH.sub.2 Q, C(O)Q, and QC(O) wherein Q is S, O, or NR.sub.10 wherein R.sub.10 is hydrogen, --(C(O)).sub.r (C.sub.1 -C.sub.8 loweralkyl), --(C(O)).sub.r cycloalkyl, --(C(O)).sub.r loweralkenyl, --(C(O)).sub.r loweralkynyl, thioalkoxy, --(C(O)).sub.r (CH.sub.2).sub.m aryl, --(C(O)).sub.r (CH.sub.2).sub.m (substituted aryl) wherein substituted aryl is as defined above, --(CH.sub.2).sub.m carboxyl, --(CH.sub.2).sub.s (C(O)).sub.r aryl, --(CH.sub.2).sub.s (C(O)).sub.r (substituted aryl), --(CH.sub.2).sub.m carboalkoxy, --(CH.sub.2).sub.m carboxamide, --(CH.sub.2).sub.m carboaryloxy, --C(X).sub.3 wherein X is halogen, --(C(O)).sub.r (CH.sub.2).sub.s R.sub.11 wherein R.sub.11 is hydrogen, loweralkyl, loweralkenyl, cycloalkyl, --(CH.sub.2).sub.m aryl, --(CH.sub.2).sub.m (substituted aryl) wherein substituted aryl is as defined above, --(CH.sub.2).sub.m heterocyclic, nitro, halogen, --CN, --OH, --NH.sub.2, --NHOH, --NR.sub.6 R.sub.7 wherein R.sub.6 and R.sub.7 are as previously defined, --NR.sub.4 OH wherein R.sub.4 is hydrogen, --(C(O)).sub.r loweralkyl, --(C(O)).sub.r loweralkenyl, --(C(O)).sub.r cycloalkyl, --(C(O)).sub.r loweralkynyl, --(C(O)).sub.r (CH.sub.2).sub.m aryl, --(C(O)).sub.r (CH.sub.2).sub.m (substituted aryl) wherein susbstituted aryl is as defined above, --(CH.sub.2).sub.m OR.sub.4 wherein R.sub.4 is as defined above, or --(CH.sub.2).sub.m SR.sub.4 wherein R.sub.4 is as defined above; Y is S, 0, CH.sub.2 or NR.sub.10 ; and R.sub.5 is one, two or three substituents independently selected from hydrogen, --(C(O)).sub.r (C.sub.1 -C.sub.8 loweralkyl), --(C(O)).sub.r cycloalkyl, decahydronaphthyl, --(C(O)).sub.r loweralkenyl, --(C(O)).sub.r loweralkynyl, thioalkoxy, --(C(O)).sub.r (CH.sub.2).sub.m aryl, --(C(O)).sub.r (CH.sub.2).sub.m (substituted aryl) wherein substituted aryl is as defined above, --(CH.sub.2).sub.s (C(O))aryl --(CH.sub.2).sub.s (C(O))(substituted aryl) wherein substituted aryl is as defined above, --(CH.sub.2).sub.m carboxyl, --(CH.sub.2).sub.m carboalkoxy, --(CH.sub.2).sub.m carboxamide, --(CH.sub.2).sub.m carboaryloxy, --C(X).sub.3, --(C(O)).sub.r (CH.sub.2).sub.m R.sub.6, nitro, halogen, --CN, --OH, NH.sub.2, --NHOH, --NR.sub.6 R.sub.7 wherein R.sub.6 and R.sub.7 are as defined above, --(CH.sub.2).sub.m OR.sub.4, --(CH.sub.2).sub.m SR.sub.4 and --NR.sub.4 OH wherein R.sub.4 is as defined above;
(11) --(C(R.sub.5).sub.2).sub.m aryl wherein R.sub.5 is as defined above with the proviso that not all R.sub.5 substituents are hydrogen,
(12) (CR.sub.5).sub.2).sub.m)substituted aryl) wherein R.sub.5 is defined as above with the proviso that not all R.sub.5 substituents are hydrogen and wherein substituted aryl is as defined above, and
(13) --(C(R.sub.5).sub.2).sub.m C(O)R.sub.3, wherein R.sub.5 is as defined above and wherein R.sub.3 is --OH, --OR.sub.4 wherein R.sub.4 is as defined above, --NR.sub.6 R.sub.7 wherein R.sub.6 and R.sub.7 are as defined above, --NHR.sub.4 wherein R.sub.4 is as defined above, or --NR.sub.4 OH wherein R.sub.4 is as defined above;
(1) (CH.sub.2).sub.m,
(2) (CR.sub.5 =CR.sub.5).sub.q wherein R.sub.5 is as defined above,
(3) LCH.sub.2 wherein L is O, S, or NR.sub.5 wherein R.sub.5 is as defined above,
(4) CH.sub.2 L wherein L is as defined above, or
(5) NR.sub.5 wherein R.sub.5 is as defined above;
(1) --C(O)R.sub.3 wherein R.sub.3 is as defined above or
(2) ##STR4## Z is
(1) C(O),
(2) C(S), or
(3) S(O).sub.2 ;
Ar is a heterocyclic group,
The compounds of the invention wherein n=1-3, D is --C(O)R.sub.3 wherein R.sub.3 is --OH or --NR.sub.6 R.sub.7 wherein R.sub.6 and R.sub.7 are independently selected from hydrogen, loweralkyl, cycloalkyl, C.sub.2-4 loweralkenyl, benzyl, phenethyl and naphthylmethyl; R.sub.1 and R.sub.2 are independently selected from hydrogen, loweralkyl, cycloalkyl, C.sub.2-4 loweralkenyl, benzyl, phenethyl and naphthylmethyl; Z is C=0; B is a bond or a C.sub.1-5 alkylene, C.sub.2-5 alkenylene or C.sub.4-6 alkadienylene group; and Ar is thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolivinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, tetrahydrofuryl, pyranyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, triazinyl, thiazinyl, benzothienyl, benzofuryl, isobenzofuryl, indolyl, isoindolyl, indazolyl, purinyl, guinolyl, isoguinolyl, naphthyridinyl, quinoxadinyl, chromanyl, indolinyl, isoimdolinyl, or chromenyl, unsubstituted or substituted by at least one substituent selected from halogen, hydroxyl, amino, carboxyl, C.sub.1-8 alkyl, oxo, C.sub.1-8 alkoxy, phenyl, naphthyl, chlorophenyl, benzyl, phenethyl, naphthylmethyl, (2,3,4- or 3,4,5-)trimethoxybenzyl, amino C alkyl, di --C.sub.1-4 alkylamino-C.sub.1-4 alkyl, hydroxy-substituted C.sub.1-4 alkyl, C.sub.1-5 alkanoyloxy, strylcarbonyl, 3,4,5-trimethoxystyrylcarbonyl, benzyloxycarbonylamino, benzyloxycarbonylaminomethyl, benzoylamino, 3,4,5-trimethoxybenzoylamino, pyrrolidinylcarbonylmethyl, piperidylcarbonylmethyl, piperazinylcarbonylmethyl and morpholinylcarbonylmethyl are disclosed as anti-ulcer agents in U.S. Pat. No. 4,610,983.
The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 8 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-diethylbutyl, n-heptyl, n-octyl and the like.
The term "cycloalkyl" as used herein refers to an alicyclic ring having 3 to 8 carbon atoms, including, but not limited to cyclopropyl, cyclopentyl, cyclohexyl and the like.
The term "loweralkenyl" or "alkylene group" as used herein refers to a (CH.sub.2).sub.y radical where y is 1 to 8, such as methylene, ethylene, propylene, tetramethylene and the like.
The term "loweralkynyl" as used herein refers to a lower alkyl radical which contains at least one carbon-carbon triple bond.
The term "alkenylene group" as used herein refers to a C.sub.2 C.sub.8 chain of carbon atoms which contains at least one carbon carbon double bond, such as vinylene, propenylene, butenylene and the like.
The term "alkadienylene group" as used herein refers to a C.sub.4 -C.sub.8 chain of carbon atoms containing at least two carbon-carbon double bonds, such as 1,3-butadienylene and the like.
The term "halogen" as used herein refers to F, Cl, Br or I.
The terms "alkoxy" and "thioalkoxy" as used herein refer to R.sub.8 O-- and R.sub.8 S-- respectively, wherein R.sub.8 is a loweralkyl group.
The term "alkoxyalkyl" as used herein refers to an alkoxy group appended to a loweralkyl radical, including, but not limited to methoxymethyl, 2-methoxyethyl and the like.
The term "aryl" or "aryl group" as used herein refers to phenyl, naphthyl, indanyl, fluorenyl, (1,2,3,4)-tetrahydronaphthyl, indenyl or isoindenyl.
The term "substituted aryl" as used herein refers to an aryl group substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, carboxy, carboalkoxy, nitro, trihalomethyl, hydroxy, amino, and NH(loweralkyl).
The term "arylalkyl" as used herein refers to an aryl group appended to a loweralkyl radical, including, but not limited to benzyl, phenethyl, naphthylmethyl and the like.
The term "(substituted aryl)alkyl" as used herein refers to a substituted aryl group appended to a loweralkyl radical, including, but not limited to halobenzyl, alkoxynaphthylmethyl and the like.
The term "heterocyclic" or "heterocyclic group" as used herein refers to mono-, bi-, and tricyclic ring systems containing from one to four heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; and having from 0 to 7 double bonds. Preferred heterocyclics are: thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, triazolyl, etrazolyl, tetrahydrofuryl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, thiazinyl, oxadiazinyl, azepinyl, thiapinyl, thionaphthyl, benzofuryl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, anthranyl, benzopyranyl, coumarinyl, isocoumarinyl, purinyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, diazepinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl, carbolinyl, xanthenyl, and acridinyl and ##STR5## wherein E is selected from, (CH.sub.2).sub.p, (CH=CH).sub.r, C(O)CH.sub.2, CH.sub.2 C(O), QCH.sub.2, CH.sub.2 Q, C(O)Q, and YC(0) wherein Q is S, O or NR.sub.10 or wherein R.sub.10 is hydrogen, --(C(O)).sub.r (C.sub.1 -C.sub.8 loweralkyl), --(C(O)).sub.r cycloalkyl, --(C(O)).sub.r loweralkenyl, --(C(O)).sub.r loweralkynyl, thioalkoxy, --(C(O)).sub.r (CH.sub.2).sub.m aryl, --(C(O)).sub.r (CH.sub.2).sub.m (substituted aryl) wherein substituted aryl is as defined above, --(CH.sub.2).sub.m carboxyl, --(CH.sub.2).sub.s (C(O)).sub.r aryl, --(CH.sub.2).sub.s (C(O)).sub.r (substituted aryl), --(CH.sub.2).sub.m carboalkoxy, --(CH.sub.2).sub.m carboxamide, --(CH.sub.2).sub.m carboaryloxy, --C(X).sub.3 wherein X is halogen, --(C(O)).sub.r (CH.sub.2).sub.s R.sub.11 wherein R.sub.11 is hydrogen, loweralkyl, loweralkenyl, cycloalkyl, --(CH.sub.2).sub.m aryl, --(CH.sub.2).sub.m) (substituted aryl) wherein substituted aryl is as defined above, --(CH.sub.2).sub.m heterocyclic, nitro, halogen, --CN, --OH, --NH.sub.2, --NHOH, --NR.sub.6 R.sub.7 wherein R.sub.6 and R.sub.7 are as previously defined, --NR.sub.4 OH wherein R.sub.4 is hydrogen, --(C(O)).sub.r loweralkyl, --(C(O)).sub.r loweralkenyl, --(C(O)).sub.r cycloalkyl, --(C(O)).sub.r loweralkynyl, --(C(O)).sub.r (CH.sub.2).sub.m aryl, --(C(O)).sub.r (CH.sub.2).sub.m (substituted aryl) wherein susbstituted aryl is as defined above, --(CH.sub.2).sub.m OR.sub.4 wherein R.sub.4 is as defined above, or --(CH.sub.2).sub.m SR.sub.4 wherein R.sub.4 is as defined above; with the proviso that Y and W are not both C; Y and W are independently selected from S, O, C, CH, CH.sub.2 and NR.sub.10 with the proviso that Y is not C, CH or CH.sub.2 when W is C, CH or CH.sub.2 ; and wherein R.sub.5 is one, two or three substituents independently selected from hydrogen, --(C(O)).sub.r (C.sub.1 --C.sub.6 loweralkyl,), --(C(O)).sub.r cycloalkyl, decahydronaphthyl, --(C(O)).sub.r loweralkenyl, --(C(O)).sub.r loweralkynyl, thioalkoxy, --(C(O)).sub.r (CH.sub.2).sub.m aryl, --(C(O)).sub.r (CH.sub.2).sub.m (substituted aryl), --(CH.sub.2).sub.m)carboxyl, --(CH.sub.2).sub.s (C(O))aryl, --(CH.sub.2).sub.s (C(O))(substituted aryl), --(CH.sub.2).sub.m carboalkoxy, --(CH.sub.2).sub.m carboxamide, --(CH.sub.2).sub.m carboaryloxy, --C(X).sub.3 wherein X is halogen, --(CO).sub.r (CH.sub.2).sub.m R.sub.6 wherein R.sub.6 is as previously defined, nitro, halogen, --CN, --OH, --NH.sub.2, --NHOH, --NR.sub.6 R.sub.7 wherein R.sub.6 and R.sub.7 are as previously defined, --NR.sub.4 OH wherein R.sub.4 is as previously defined, --(CH.sub.2).sub.m OR.sub.4 wherein R.sub.4 is as defined above, --(CH.sub.2).sub.m SR.sub.4 wherein R.sub.4 is as defined above; m is 0 to 4, p is 0 to 2, r is 0 to 1 and s is 1 to 4.
The symbols used to define the heterocyclic groups in which R.sub.5 is attached to a bond which extends across 2 or 3 rings is meant to indicate that R.sub.5 groups may be bonded to one, two or three of the rings of the heterocyclic ring system.
The term "arlyoxy" as used herein refers to R.sub.9 O--, wherein R.sub.9 is an aryl or substituted aryl group.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the compounds or to increase the solubility of the compounds and includes but is not limited to sulfonyl, acyl, acetyl, pivaloyl, t-butyloxycarbonyl (Boc), carbonylbenzyloxy (Cbz), benzoyl or an L or D-aminoacyl residue, which may itself be N-protected similarly.
The term "C protecting group" as used herein refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures and includes but is not limited to substituted methyl ethers, for example methoxymethyl, benzylozymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and benzylidene acetal; cyclic ortho esters, for example, methoxymethylene; cyclic carbonates; and cyclic boronates.
The terms "Glu" and "Asp" as used herein refer to glutamic acid and aspartic acid respectively.
The compounds of the invention may be made as shown in Scheme I. Compounds with DL, L, or D configuration may be used in the synthetic schemes.
As illustrated in Scheme I, N-protected omega-benzyl esters of alpha aminodicarboxylic acids 1 (preferably Boc (gamma-benzyl ester)-D-glutamic acid or Cbz-(gamma-benzyl ester)D-glutamic acid) are coupled with a primary or secondary amine (preferably dialkylamines, diaryl amines, or alkylaryl amines) using bis(2-oxo 3-oxazolidinyl)phosphinic chloride (BOPCl) or a conventional peptide coupling reagent (isobutyl chloroformate (IBCF), phosphorus pentachloride (PCl.sub.5) and the like). The product amide 2 (P is Boc) is deprotected (preferably with hydrochloric acid (HCl) in dioxane) to provide the hydrochloride salt 3or 2 is dideprotected (P is Cbz) to provide the free amine 4 (preferably using a transfer hydrogenolysis technique). The hydrochloride 3 is coupled with an arylcarboxylic acid (preferably indole 2-carboxylic acid or guinoline 3-carboxylic acid) using 1-ethyl 30(3-dimethylaminopropyl)carbodiimide (EDCI) and triethyl amine in dimethylformamide (DMF) as solvent. Other conventional peptide coupling techniques may also be used. Substituents R'CH.sub.2 can be introduced using the appropriate aldehyde (R'CHO) and amine hydrochloride 3 in a reductive amination reaction (preferably sodium cyanoborohydride or sodium borohydride in methanol or other alcohols as solvents) to provide compound 3a which can be coupled in analogous fashion to 3 to provide 5. Alternatively, the hydrochloride 3 can be directly alkylated with an alkylating agent (R'CH.sub.2 X wherein X is Cl, Br, I, OTs and the like) to provide the substituted amine 3a. The product amide 5 is debenzylated utilizing transfer hydrogenation techniques (preferably cyclohexadiene and palladium on carbon (Pd/C) in ethanol or other alcohols) to provide acid 6. Acid 6 also can be obtained from 5 through standard saponification conditions (aqueous hydroxide in alcohol, THF or dioxane). Alternatively the product 6 is obtained by coupling the amine 4 with active esters of arylcarboxylic acids (preferably indole-2-carboxy 2,4,6-trichlorophenyl ester). The acid 6 and alcohol (R.sub.4 OH) are coupled using dicyclohexylcarbodiimide (DCC) or other conventional peptide coupling reagent to provide ester 7. Acid 6 and secondary amine (NHR.sub.6 R.sub.7) likewise are coupled with DCC (or other conventional peptide coupling reagent) to provide product 8. Alternatively the primary amine (R.sub.4 NH.sub.2) can be used in place of the secondary amine to provide product 9. Product 9 is also obtained by the direct reaction of benzyl ester 5 and the primary amine (R.sub.4 NH.sub.2) at high temperatures and/or pressures.
Reaction of hydrochloride 3 with arylsulfonylchloride in the presence of base (preferably an organic tertiary amine such as triethyl amine or N-methylmorpholine) provides product 10. Sulfonamide 10 is debenzylated in a similar fashion to 5 via either transfer hydrogenation conditions or saponificatin in alcoholic hydroxide. Reaction of hydrochloride salt 3 with a beta arylacrylic acid (preferably 3-(3'-pyridyl) beta-acrylic acid) utilizing DCC (or other conventional peptide coupling technique) provides benzyl ester 12, which can be deprotected via either transfer hydrogenation conditions or saponification to provide product acid 13.
In addition, the hydrochloride salt 3 can be coupled, in the presence of base, with acylating agents that are available to one skilled in the art of organic synthesis, including, but not limited to isocyanates, isothiocyanates, acylcyanides, chloroformates and the like. These can be deprotected as previously outlined via hydrogenolysis or saponification to provide ureas, thioureas, carbamates and the like.
The N-carbobenzyloxy protected asparagine or glutamine 14 (preferably of the enantiomerically pure R configuration) is converted to its corresponding nitrile 15 by reaction with phosphorus oxychloride and pyridine (alternatively DCC and pyridine). The acid nitrile 15 is coupled with an appropriate amine (preferably dialkyl, diaryl, or alkylarylamine) using DCC (or a conventional coupling reagent) to yield the amide 16. The nitrile 16 is converted to the tetrazole 17 via reaction with sodium azide (NaN.sub.3) in dimethylformamide (DMF). The tetrazole 17 is deprotected using standard hydrogenation (hydrogen atmosphere over palladium on carbon as catalyst) or transfer hydrogenation conditions to provide amine 18, which is reacted with an active ester of the desired arylcarboxylic acid to provide product 19. ##STR6##
US Referenced Citations (4)
Foreign Referenced Citations (5)
| Number |
Date |
Country |
| 0250148 |
Dec 1987 |
EPX |
| 272228 |
Jun 1988 |
EPX |
| 62-138469 |
Jun 1987 |
JPX |
| WO8805774 |
Aug 1988 |
WOX |
| 2160869 |
Jan 1986 |
GBX |
Non-Patent Literature Citations (4)
| Entry |
| F. Makovec et al., Arzneim.-Forsch./Drug Res. 35(II), 1048 (1985) "New Glutaramic Acid Derivatives with Potent Competitive and Specific Cholecystokinin-antagonistic Activity". |
| F. Makovec et al., Arzneim-Forsch./Drug Res. 36(I), 98 (1986) "Differentiation of Central & Peripheral Cholecystokinin Receptors by New Glutaramic Acid Derivatives with Cholecystokinin-antagonistic Activity". |
| J. Regan et al., Eur. J. Pharmacol. 144, 241 (1987) "Fasting and L-364,718 Prevent Cholecystokinin-induced Elevators of Plasma Insulin Levels". |
| L. Rossetti et al., Diabetes 36, 1212 (1987) "Physiological Role of Cholecystokinin in Meal.varies.Induced Insulin Secretion in Conscious Rats-Studies with L364,718, A Specific Inhibitor of CCK-Receptor Binding". |
Continuation in Parts (1)
|
Number |
Date |
Country |
| Parent |
99866 |
Sep 1987 |
|
Patent Grant
4971978
