GB2282807A - Tryptophan esters and amides as tachykinin receptor antagonists - Google Patents
Tryptophan esters and amides as tachykinin receptor antagonists Download PDFInfo
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- GB2282807A GB2282807A GB9420262A GB9420262A GB2282807A GB 2282807 A GB2282807 A GB 2282807A GB 9420262 A GB9420262 A GB 9420262A GB 9420262 A GB9420262 A GB 9420262A GB 2282807 A GB2282807 A GB 2282807A
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- benzyl
- propionate
- trifluoromethyl
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- indolyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Compounds of formula II: <IMAGE> or a pharmaceutically acceptable salt thereof, wherein: Z is O, or NR<8>, wherein R<8> is H or CH3; R<1> is unsubstituted C4-12alkyl, or substituted C1-12alkyl wherein the substituents on the alkyl are selected from the group consisting of: (1) phenyl, (2) halo, (3) pyridyl, and (4) -NR<6>R<7>, wherein R<6> and R<7> are independently selected from the group consisting of: (1) hydrogen, (2) C1-6alkyl, unsubstituted or substituted with: (a) -NR<9>R<10>, wherein R<9> and R<10> are independently selected from: (i) hydrogen, and (ii) C1-6alkyl; R<2> is independently selected from the group consisting of: (1) hydrogen, and (2) C1-6alkyl; R<4> is selected from: (1) hydrogen, and (2) C1-6alkyl; R<5> is phenyl unsubstituted or substituted by 1, 2 or 3 groups selected from: (a) C1-6alkyl, (b) -O-C1-6alkyl, (c) halo, and (d) trifluoromethyl, are tachykinin receptor antagonists useful in the treatment of inflammatory diseases, pain or migraine, and asthma and calcium channel blockers useful in the treatment of cardiovascular conditions such as angina, hypertension or ischemia. Tryptophan compounds closely related to formula II but not quite falling within its scope are also disclosed.
Description
TITLE OF THE INVENTION TRYPTOPHAN ESTERS AS TACHYKINE RECEPTOR
ANTAGONISTS
SUMMARY OF THE INVENTION
This invention is concerned with novel compounds represented by structural formula I:
wherein R 1, R2, R3, R4, R5, Q, X, Y and Z are hereinafter defined.
The invention is also concerned with pharmaceutical formulations with these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders.
The compounds of this invention are tachykinin receptor antagonists and are useful in the treatment of inflammatory diseases, pain or migraine and asthma.
Also, some of these compounds are calcium channel blockers and are useful in the treatment of cardiovascular disorders such as angina, hypertension or ischemia.
BACKGROUND OF THE INVENTION
Analgesia has historically been achieved in the central nervous system by opiates and analogs which are addictive, and peripherally by cyclooxygenase inhibitors that have gastric side effects.
Substance P antagonists induce analgesia both centrally and peripherally.
In addition, substance P antagonists are inhibitory of neurogenic inflammation.
The neuropeptide receptors for substance P (neurokinin-1,
NK-I) are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev., 1983, 35, 85-141). The NK1 and NK2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci., 42: 1295-1305 (1988)).
The receptor for substance P is a member of the superfamily of G protein-coupled receptors. This superfamily is an extremely diverse group of receptors in terms of activating ligands and biological functions. In addition to the tachykinin receptors, this receptor superfamily includes the opsins, the adrenergic receptors, the muscarinic receptors, the dopamine receptors, the serotonin receptors, a thyroid-stimulating hormone receptor, a luteinizing hormonechoriogonadotropic hormone receptor, the product of the oncogene ras, the yeast mating factor receptors, a Dictvostelium cAMP receptor, and receptors for other hormones and neurotransmitters (see A.D. Hershey, etal.,J. Biol. Chem., 1991,226,4366-4373).
Substance P (also called "SP" herein) is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH2.
In addition to SP the known mammalian tachykinins include neurokinin
A and neurokinin B. The current nonmenclature designates the receptors for SP, neurokinin A, and neurokinin B as NK-1, NK-2, and
NK-3, respectively.
More specifically, substance P is a pharmacologically-active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence. (Chang et al., Nature New Biol. 232, 86 (1971); D.F. Veber et al., U.S. Patent No. 4*680=283).
Substance P acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R.C.A.
Frederickson et al., Science 199, 1359 (1978); P. Oehme et al., Science, 208, 305 (1980)) and plays a role in sensory transmission and pain perception (T.M. Jessell, Advan. Biochem. Psychopharmacol. 28, 189 (1981)). For example1 substance P is believed inter alia to be involved in the neurotransmission of pain sensations [Otsuka et al, "Role of
Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic
Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation
Symposium 91, 13-34 (published by Pitman) and Otsuka and
Yanagisawa, "Does Substance P Act as a Pain Transmitter?" TIPS (Dec.
1987) 8 506-510]. In particular, substance P has been shown to be involved in the transmission of pain in migraine (see B.E.B. Sandberg et al.. Journal of Medicinal Chemistrv, 25, 1009 (1982)), and in arthritis (Levine et al. Science, (1984) 226 547-549). These peptides have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease, ulcerative colitis and Crohn's disease, etc. (see Mantyh et al., Neuroscience. 25 (3), 817-37 (1988) and
D. Regoli in "Trends in Cluster Headache" Ed. F. Sicuteri et al.,
Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).
It is also hypothesized that there is a neurogenic mechanism for arthritis in which substance P may play a role (Kidd et al., "A
Neurogenic Mechanism for Symmetric Arthritis" in The Lancet, 11
November 1989 and Gronblad et al., "Neuropeptides in Synovium of
Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol.
(1988) 15(12) 1807-10). Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis (O'Byrne et al., in Arthritis and Rheumatism (1990) 33 1023-8).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardivascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitus, inflammatory diseases of the gut including ulcerative colitis and Chrohn disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyperreflexia is reviewed in "Tachykinin Receptors and Tachykinin Receptor
Antagonists," C.A. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J.
Auton, Pharmacol, (1993) 13, 23-93. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions (Hamelet et al., Can. J. Pharmacol. Physiol. (1988) 66 1361-7), immunoregulation (Lotz et al., Science (1988) 241 1218-21, Kimball et al., J. Immunol. (1988) 141 (10) 3564-9 and A. Perianin, et al.,
Biochem. Biophvs. Res. Commun. 161,520 (1989)) vasodilation, bronchospasm, reflex or neuronal control of the viscera (Mantyh et al.,
PNAS (1988) 85 3235-9) and, possibly by arresting or slowing - amyloid-mediated neurodegenerative changes (Yankner et al., Science, (1990) 250, 279-82) in senile dementia of the Alzheimer type,
Alzheimer's disease and Downs Syndrome.Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et. al., poster to be presented at C.I.N.P. XVIIIth Congress, 28th June-2nd July, 1992, in press]. Antagonists selective for the substance P and/or the neurokinin
A receptor may be useful in the treatment of asthmatic disease (Frossard et al., Life Sci., 49, 1941-1953 (1991); Advenier, et al., Biochem.
Biophvs. Res. Comm., 184(3), 1418-1424 (1992)). Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC) (Langdon et al., Cancer
Research (1992) 52, 4554-7).
It has furthermore been suggested that tachykinins have utility in the following disorders: depression, dysthymic disorders,
chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupus erythmatosis (EPO
Publication No. 0.436.334) conjunctivitis, vernal conjunctivitis, contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis (EPO Publication No. 0.394.989) and emesis (EPO Publication No.
0.533.280).
In the recent past, some attempts have been made to provide peptide-like substances that are antagonists for substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases listed above. See for example Lowe, Drugs of the Future, (1992), 17 (12) 1115-1121, and European patent applications (EPO Publication Nos. 0,347,802, 0,401,177 and 0,412,452) which disclose various peptides as neurokinin A antagonists.
Also, PCT Patent Publication WO 93/14113 discloses certain peptides as tachykinin antagonists. In addition, EPO Publication No. 0.336.230 discloses heptapeptides which are substance P antagonists useful in the treatment of asthma. Merck U.S. Patent No. 4.680.283 also discloses peptidal analogs of substance P.
Certain inhibitors of tachykinins have been described in
U.S. Patent No. 4 501733, by replacing residues in the substance P sequence by Trp residues.
A further class of tachykinin receptor antagonists, comprising a monomeric or dimeric hexa- or heptapeptide unit in linear or cyclic form, is described in GB-A-2216529.
The peptide-like nature of such substances make them too labile from a metabolic point of view to serve as practical therapeutic agents in the treatment of disease. The non-peptidic antagonists of the present invention, on the other hand, do not possess this drawback, as they are expected to be more stable from a metabolic point of view than the previously-discussed agents.
It is known in the art that baclofen (-(aminoethyl)-4- chlorobenzenepropanoic acid) in the central nervous system effectively blocks the excitatory activity of substance P, but because in many areas the excitatory responses to other compounds such as acetylcholine and glutamate are inhibited as well, baclofen is not considered a specific substance P antagonist. Pfizer WIPO patent applications (PCT
Publication Nos. WO 90/05525, WO 90/05729, WO 91/18899, WO 92/12151 and WO 92/-12152) and publications (Science, 251, 435-437 (1991); Science, 251, 437-439 (1991); J. Med.Chem., 35, 2591-2600 (1992)) disclose 2-arylmethyl-3-substituted amino-quinuclidine derivatives which are disclosed as being useful as substance P antagonists for treating gastrointestinal disorders, central nervous system disorders, inflammatory diseases and pain or migraine. A Glaxo
European patent application (EPO Publication No. 0.360.390) discloses various spirolactam-substituted amino acids and peptides which are antagonists or agonists of substance P. A Pfizer WIPO patent application (PCT Publication No. WO 92/06079) discloses fused-ring analogs of nitrogen-containing nonaromatic heterocycles as useful for the treatment of diseases mediated by an excess of substance P. A Pfizer
WIPO patent application (pCT Publication No.WO 9^/15585 discloses 1 -azabi cyclol 3 .2.2]nonan-3-amine derivatives as substance P antagonists.
A Pfizer BIPO patent application (PCT Publication No. WO 93/10073) discloses ethylenediamine derivatives as substance P antagonists. A
Sanofi publication (Life Sci., 50, PL101-PL106 (1992)) discloses a 4phenyl piperidine derivative as an antagonist of the neurokinin A (NK2) receptor.
Howson et al. (Biorg. & Med. Chem. Lett., 2 (6), 559-564 (1992)) disclose certain 3-amino and 3-oxy quinuclidine compounds and their binding to substance P receptors. EPO Publication 0.499,313 discloses certain 3-oxy and 3-thio azabicyclic compounds as tachykinin antagonists. U.S. Patent No. 3.506.673 discloses certain 3-hydroxy quinuclidine compounds as central nervous system stimulants. A Pfizer
EPO Patent application (EPO Publication 0.436.334) discloses certain 3aminopiperidine compounds as substance P antagonists. U.S. Patent No.
5.064*838 discloses certain 1 ,4-disubstituted piperidinyl compounds as analgesics. PCT Publication No. WO 92/12128 discloses certain piperidine and pyrrolidine compounds as analgesics. Peyronel, et al.
(Biorg & Med. Chem. Lett., 2 (1), 37-40 (1992)) disclose a fused ring pyrrolidine compound as a substance P antagonists. EPO Publication
No. 0.360.390 discloses certain spirolactam derivatives as substance P antagonists. U.S. Patent No. 4.804.661 discloses certain piperazine compounds as analgesics. U.S. Patent No. 4.943.578 discloses certain piperazine compounds useful in the treatment of pain.
PCT Publication No. WO 92/01679 discloses certain 1,4-disubstituted piperazines useful in the treatment of mental disorders in which a dopaminergic deficit is implicated. PCT Publication No. WO 93/01169 discloses certain aromatic compounds as tachykinin receptor antagonists.
MacLeod, et al. (J. Med. Chem., 36, 2044-2045 (1993)) disclose N-acyl
L-tryptophan benzyl esters as substance P receptor antagonists.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of this invention are represented by structural formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Q is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted indolyl, optionally substituted benzthiophenyl, optionally substituted benzofuranyl, optionally substituted benzyl or optionally substituted indazolyl;
Z is 0, S or NR8, where R8 is H or C1-6alkyl;
X and Y each are H or X and Y together form a group =0; R1 is C1-l2alkyl wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of: :
(1) hydroxy,
(2) oxo,
(3) C1-6 alkoxy,
(4) phenyl-C1-3 alkoxy,
(5) phenyl,
(6) -CN,
(7) halo, (8) pyridyl,
(9) -NR6R7, wherein
R6 and R7 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl, unsubstituted or substituted with one or
more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) Cl -6 alkoxy,
(d) phenyl-Cl 3 alkoxy,
(e) phenyl,
(f) -CN,
(g) halo,
(h) -NR9R1 0, wherein R9 and R10 are
independently selected from::
(i) hydrogen,
(ii) C1-6 alkyl,
(iii) hydroxy-C1-6 alkyl, and
(iv) phenyl,
(i) -NR9COR10, wherein R9 and R10 are as
defined above,
(j) -NR9C02R10 wherein R9 and R10 are as
defined above,
(k) -CONR9R10, wherein R9 and R10 are as
defined above,
(1) -COR9, wherein R9 is as defined above,
(m) -CO2NR9R10, wherein R9 and R10 are as
defined above; and
(n) heteroaryl, wherein the heteroaryl is selected
from the group consisting of:
(A) pyridyl,
(B) imidazole, and
(C) triazole; (3) phenyl, unsubstituted or substituted with one or more
of the substituent(s) selected from:
(a) hydroxy,
(b) C1-6 alkoxy,
(c) C1-6 alkyl,
(d) C2-5 alkenyl,
(e) halo,
(f) -CN,
(g) -N02,
(h) -CF3,
(i) -(CH2)m-NR9R10, wherein m is 0-1 and R9
and R10 are as defined above, (j) -NR9COR10, wherein R9 and R10 are as
defined above
(k) -NR9C02R10, -NCO2NR9R10 wherein R9
and R10 are as defined above,
(1) -CONR9R10, wherein R9 and R10 are as
defined above,
(m) -CO2R9, wherein R9 is as defined above,
(n) -COR9, wherein R9 is as defined above;
R2 is independently selected from the group consisting of:
(1) hydrogen, and
(2) C1-6alkyl;
R3 is selected from:
(1) hydrogen, and
(2) Cl -6 alkyl;
R4 is selected from:
(1) hydrogen,
(2) C1-6 alkyl; and
(3) phenyl, wherein the phenyl is unsubstituted or
substituted by 1, 2 or 3 groups
selected from:
(a) C1-6 alkyl,
(b) C2-6 alkenyl,
(c) C2-6 alkynyl,
(d) halo,
(e) cyano,
(f) nitro,
(g) trifluoromethyl,
(h) trimethylsilyl.
(i) -OR9, 1) -SR9, (k) -SOR9,
(1) -NR9R10
(m) -NR9CoR10, (n) -NR9CO2R10,
(o) -CO2R9, and
(p) -CONR9R10, wherein R9 and R10 are as defined above;
R5 is phenyl unsubstituted or substituted by 1, 2 or 3 groups selected from:
(a) C 1-6 alkyl,
(b) C2-6 alkenyl,
(c) C2-6 alkynyl,
(d) halo,
(e) cyano,
(f) nitro,
(g) trifluoromethyl,
(h) trimethylsilyl,
(i) -OR9,
(j) -SR9,
(k) -SOR9, (1) -NR9R 10 (m) -NR9COR10, (n) -NR9C02R10, (o) -CO2R9, and
(p) -CONR9R10, wherein R9 and R10 are as defined above.
The compounds of the present invention have asymmetric centers and this invention includes all of the optical isomers and mixtures thereof.
In addition compounds with carbon-carbon double bonds may occur in Z- and E- forms with all isomeric forms of the compounds being included in the present invention.
When any variable (e.g., alkyl, aryl, R6, R7, R8, R9, R10, R11, R12 R13, etc.) occurs more than one time in any variable orin Formula I, its definition on each ocurrence is independent of its definition at every other occurrence.
As used herein, the term "alkyl" includes those alkyl groups of a designated number of carbon atoms of either a straight, branched, or cyclic configuration. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, iso- sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. "Alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy and pentoxy.
"Alkenyl" is intended to include hydrocarbon chains of a specified number of carbon atoms of either a straight- or branched- configuration and at least one unsaturation, which may occur at any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, dimethylpentyl, and the like, and includes E and Z forms, where applicable. "Halogen" or "halo", as used herein, means fluoro, chloro, bromo and iodo.
The term "aryl" means phenyl or naphthyl either unsubstituted or substituted with one, two or three substituents selected from the group consisting of halo, C1-4-alkyl, C1-4-alkoxy, N02, CF3, Cl 4-alkylthio, OH, -N(R6)2, -C02R6, Cl 4-perfluoroalkyl, C3 -6perfluorocycloalkyl, and tetrazol-5-yl.
The term "heteroaryl" means an unsubstituted, monosubstituted or disubstituted five or six membered aromatic heterocycle comprising from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are members selected from the group consisting of -OH, -SH, -Cl 4-alkyl, -C1.4-alkoxy, -CF3, halo, -NO2, -C02R9,-N(R9R10) and a fused benzo group.
In the compounds of formula lit is prefered that:
Q is 3-indolyl;
X and Y together form a group =0; Z is O, or NR8, where R8 is H or C1-6alkyl;
R1 is Cm 12alkyl wherein the alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of:
(1) phenyl,
(2) halo,
(3) pyridyl, and
(4) -NR6R7, wherein
R6 and R7 are independently selected from the group consisting of:
(1) hydrogen,
(2) Ci 6 alkyl, unsubstituted or substituted with:
(a) -NR9R10, wherein R9 and R10 are
independently selected from:
(i) hydrogen, and
(ii) C1-6 alkyl;
R2 is independently selected from the group consisting of:
(1) hydrogen, and
(2) C1-6 alkyl;
R3 is hydrogen;
R4 is selected from: :
(1) hydrogen,
(2) C1-6 alkyl; and
(3) phenyl, wherein the phenyl is unsubstituted or
substituted by 1, 2 or 3 groups
selected from:
(a) C1-6 alkyl,
(d) halo, and
(g) trifluoromethyl;
R5 is phenyl unsubstituted or substituted by 1, 2 or 3 groups selected from:
(a) C1-6 alkyl,
(b) -O-C1 6 alkyl,
(c) halo, and
(d) trifluoromethyl.
In the compounds of the present invention it is preferred that the stereochemistry at the carbon atom to which Q-CH2- is attached is identical to that in L-tryptophan.
A preferred subgroup of compounds according to formula I is represented by compounds of structural formula II:
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R5 and Z are each as defined in formula I.
In the compounds of formula II it is prefered that:
Z is O, or NR8, wherein R8 is H or CH3;
R1 is unsubstituted C4 12alkyl, or substituted C1-12alkyl wherein the substituents on the alkyl are selected from the group consisting of:
(1) phenyl,
(2) halo.
(3) pyridyl, and
(4) -NR6R7, wherein R6 and R7 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl, unsubstituted or substituted with:
(a) -NR9R10, wherein R9 and R10 are
independently selected from:
(i) hydrogen, and
(ii) C1-6 alkyl;
R2 is independently selected from the group consisting of:
(1) hydrogen, and
(2) C1-6 alkyl;
R4 is selected from:
(1) hydrogen, and
(2) C1-6 alkyl;
R5 is phenyl unsubstituted or substituted by 1, 2 or 3 groups selected from:
(a) C1-6 alkyl,
(b) -O-C1 6 alkyl,
(c) halo, and
(d) trifluoromethyl.
In the compounds of formula II it is more prefered that: Zis 0, or NH;
R1 is substituted C1-l2alkyl wherein the substituents on the alkyl are selected from the group consisting of:
(1) phenyl,
(2) halo,
(3) pyridyl, and
(4) -NR6R7, wherein
R6 and R7 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl;
R2 is independently selected from the group consisting of:
(1) hydrogen, and
(2) CH3; R4 is selected from:
(1) hydrogen, and
(2) CH3; R5 is phenyl unsubstituted or substituted by 1, 2 or 3 groups selected from:
(a) CH3,
(b) -O-CH3,
(c) halo, and
(d) trifluoromethyl.
Particularly preferred groups within the definition of R1 include: benzyl; 3,3 -diphenylpropionyl; 5-bromopentanoyl; 6-bromohexanoyl; 7-bromoheptanoyl; 8-bromooctanoyl; 5-phenylhexanoyl; 6-phenylhexanoyl; 2-dimethylamino-3 ,3diphenylpropionyl; 3 -(dimethylamino)propionyl; 4- (dimethyl amino)butanoyl; 5-(dimethylamino)pentanoyl; 6-(dimethylamino)hexanoyl;7-(dimethylamino)heptanoyl; 2-pyridylmethyl; 3 -pyridylmethyl; 4-pyridylmethyl; and 3-(3-pyridyl)propionyl.
Also particularly preferred are the compounds wherein R5 is phenyl or 3,5 -bis 3,5-bis(trifluoromethyl)phenyl.
As will be understood by those skilled in the art, pharmaceutically acceptable salts include, but are not limited to salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate or pamoate, salicylate and stearate. Similarly pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
Specific compounds within the scope of the present invention include: 1) N-(3 , 3 -diphenylpropionyl)-L-tryptophan, N'-benzyl-N'-methyl
amide; 2) N-(3 ,3 -diphenylpropionyl)-L-tryptophan, N' ,N'-dipentylamide; 3) N-(3,3 -diphenylpropionyl)-L-tryptophan, N'-3 ,5-bis (trifluoro- methyl)benzyl-N'-methyl amide; 4) N -(3,3-diphenylpropionyl)-L-tryptophan, 3,5 -bis (trifluoro- methyl)benzyl ester; 5) 3 ,5-bis(trifluoromethyl)benzyl S-2-(1,1 -dimethyiethoxy- carbonyl-amino)-3-(3-indolyl) propionate; 6) 3 ,5-bis(trifluoromethyl)benzyl S-2-amino-3 -(3 -indolyl)- propionate; 7) 3,5-bis (trifluoromethyl)benzyl S-2-(6-bromohexanoylamino)- 3 -
(3-indolyl) propionate; 8) 3 ,5-bis (trifluoromethyl)benzyl S-2-(5-bromopentanoylamino)-3
(3-indolyl) propionate; 9) 3,5-bis(trifluoromethyl)benzyl S-2-(7-bromoheptanoylamino)-3
(3-indolyl) propionate; 10) 3 ,5-bis (trifluoromethyl)benzyl S-2-(8-bromooctanoylamino)-3
(3-indolyl) propionate; 11) 3,5-bis(trifluoromethyl )benzyl S-2-(6-phenylhexanoylamino)-3
(3-indolyl) propionate; 12) 3,5-bis(trifluoromethyl)benzyl S-2-lauroylamino-3-(3-indolyl)- propionate; 13) 3,5 -bis (trifluoromethyl )benzyl S-2-(dimethylaminoacetylamino)- 3-(3-indolyl) propionate; 14) 3 ,5-bis (trifluoromethylbenzyl) S-2-(3-(dimethylamino) propionylamino)-3 -(3 -indolyl) propionate; 15) 3,5 3 3,5-bis(trifluoromethyl)benzyl S -2-(4-(dimethylamino) butanoylamino)-3-(3-indolyl) propionate; 16) 3 ,5-bis(trifluoromethyl)benzyl S-2-(3-dimethylaminocarbonyl) propionylamino)-3 -(3-indolyl) propionate; 17) 3,5-bis(trifluoromethyl) S-2-(2-pyridylmethylcarbonylamino)-3
(3-indolyl) propionate; 18) 3 ,5-bis(trifluoromethyl)benzyl S-2-(3 -pyridylmethyl- carbonylamino)-3 -(3-indolyl) propi onate; 19) 3 ,5-bis(trifluoromethyl)benzyl S-2-(4-pyridylmethyl
carbonylamino)-3-(3-indolyl) propionate; 20) 3 ,5 -bi s (trifluoromethyl )benzyl S-2-(3-(3-pyridyl)acrylo ylamino)-3-(3 -indolyl) propionate; 21) 3 ,5-bis (trifluoromethyl)benzyl S-2-(3-(3-pyridyl) propionylamino)-3-(3-indolyl) propionate; 22) 3,5-bis(trifluoromethyl)benzyl S-2-(6-(dimethylamino)hexanoyl- amino)-3-(3-indolyl) propionate; 23) 3,5-bis(trifluoromethyl)benzyl S-2-(5-(dimethylamino)
pentanoylamino)-3-(3-indolyl) propionate; 24) 3 ,5-bis(trifluoromethyl)benzyl S-2-(7-(dimethylamino)
heptanoylamino)-3-(3-indolyl) propionate; 25) R-a-methyl-3,5-bis(trifluoromethyl)-benzyl S-2-(t-butoxy
carbonylamino)-3-(3 -indolyl)propionate; 26) S-a-methyl-3,5-bis(trifluoromethyl)-benzyl S-2-(t-butoxy carbonylamino)-3 -(3 -indolyl)propionate; 27) R-a-methyl-3,5 -bis(trifluoromethyl)-benzyl S -2-amino-3 -(3
indolyl) propionate; 28) S -a-methyl-3 ,5-bis(trifluoromethyl)-benzyl S-2-amino-3-(3
indolyl) propionate; 29) R-a-methyl-3 ,5-bis(trifluoromethyl)benzyl-S -2-(6 bromohexanoylamino)-3 -(3 -indolyl) propionate; 30) Scx-methyl-3,5-bis(trifluowmethyl)benzyl-S-2-(6- bromohexanoylamino)-3-(3-indolyl) propionate; 31) benzyl 2-((2-dimethylamino-3 ,3-diphenylpropionyl)amino)-3 -(3 - indolyl)propionate; 32) 3 ,5-bistrifluoromethylbenzyl 2-((2-dimethylamino-3 ,3 -diphenyl- propionyl)amino)-3-(3 -indolyl)propionate; 33) N-benzyl-N-methyl-2-((2-dimethylamino-3 ,3 -diphenyl- propi onyl)-amino)-3 -(3-indolyl)propionamide; 34) benzyl 2-((2-acetylamino-3-hydroxy-butyryl)amino)-3-(3- indolyl)propionate; and pharmaceutically acceptable salts thereof.
TACHYKININ ANTAGONISM ASSAY
The compounds of this invention are useful for antagonizing tachykinins, in particular substance P and neurokinin A in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, pain or migraine and asthma in a mammal in need of such treatment. This activity can be demonstrated by the following assay.
A. Receptor Expression in COS
To express the cloned human neurokinin-1 receptor (NK1R) transiently in COS, the cDNA for the human NK1R was cloned into the expression vector pCDM9 which was derived from pCDM8 (INVITROGEN) by inserting the ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+) into the Sac II site.
Transfection of 20 Rg of the plasmid DNA into 10 million COS cells was achieved by electroporation in 800 Ful of transfection buffer (135 mM Nail, 1.2 mM CaCl2, 1.2 mM MgC12, 2.4 mM K2HPO4, 0.6 mM
KH2PO4, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 uF using the IBI GENEZAPPER (IBI, New Haven, CT). The cells were incubated in 10% fetal calf serum, 2 mM glutamine, 100U/ml penicillinstreptomycin, and 90% DMEM media (GIBCO, Grand Island, NY) in 5% CO2 at 37"C for three days before the binding assay.
B. Stable Expression in CHO
To establish a stable cell line expressing the cloned human
NK 1 R, the cDNA was subcloned into the vector pRcCMV (INVITROGEN). Transfection of 20 !lg of the plasmid DNA into CHO cells was achieved by electroporation in 800 ,ul of transfection buffer suplemented with 0.625 mg/ml Herring sperm DNA at 300 V and 950 uF using the IBI GENEZAPPER (IBI). The transfected cells were incubated in CHO media [10% fetal calf serum, 100 U/ml pennicilinstreptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg/ml G418 (GIBCO)] in 5% C02 at 37"C until colonies were visible. Each colony was separated and propagated.The cell clone with the highest number of human NKIR was selected for subsequent applications such as drug screening.
C. Assav Protocol using COS or CHO
The binding assay of human NK1R expressed in either COS or CHO cells is based on the use of 125I-substance P (125I-SP, from
DU PONT, Boston, MA) as a radioactively labeled ligand which competes with unlabeled substance P or any other ligand for binding to the human NK1R. Monolayer cell cultures of COS or CHO were dissociated by the non-enzymatic solution (SPECIALTY MEDIA,
Lavallette, NJ) and resuspended in appropriate volume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon) such that 200 ,ul of the cell suspension would give rise to about 10,000 cpm of specific 1251-SP binding (approximately 50,000 to 200,000 cells).In the binding assay, 200 ul of cells were added to a tube containing 20 pLl of 1.5 to 2.5 nM of 1251-SP and 20 11 of unlabeled substance p or any other test compound. The tubes were incubated at 4"C or at room temperature for 1 hour with gentle shaking. The bound radioactivity was separated from unbound radioactivity by GF/C filter (BRANDEL, Gaithersburg, MD) which was pre-wetted with 0.1 % polyethylenimine. The filter was washed with 3 ml of wash buffer (50 mM Tris pH 7.5, 5 mM MnC12, 150 mM NaCl) three times and its radioactivity was determined by gamma counter.
The activation of phospholipase C by NK 1 R may also be measured in CHO cells expressing the human NKIR by determining the accumulation of inositol monophosphate which is a degradation product of IP3. CHO cells are seeded in 12-well plate at 250,000 cells per well.
After incubating in CHO media for 4 days, cells are loaded with 0.025 uCi/ml of 3H-myoinositol by overnight incubation. The extracellular radioactivity is removed by washing with phosphate buffered saline.
LiCI is added to the well at final concentration of 0.1 mM with or without the test compound, and incubation is continued at 370C for 15 min. Substance P is added to the well at final concentration of 0.3 nM to activate the human NK1R. After 30 min of incubation at 37"C, the media is removed and 0.1 N HC1 is added. Each well is sonicatPd at 4"C and extracted with CHCl3/methanol (1:1). The aqueous phase is applied to a 1 ml Dowex AG 1X8 ion exchange column. The column is washed with 0.1 N formic acid followed by 0.025 M ammonium formate-0.1 N formic acid. The inositol monophosphate is eluted with 0.2 M ammonium formate-0.1 N formic acid and quantitated by beta counter.
In the foregoing assay, the compounds of the Examples were found to have IC50 values less than 100 nM.
The compounds of the present invention are useful in the prevention and treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin, in particular substance P, activity.
These conditions may include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; demyelinating diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS;Lou Gehrig's disease) and other neuropathological disorders such as peripheral neuropathy, for example AIDS related neuropathy, diabetic neuropathy, chemotherapyinduced neuropathy, and postherpetic and other neuralgias; epilepsy; small cell carcinoma such as small cell lung cancer; respiratory diseases such as chronic obstructive airways disease, bronchopneumonia, bronchospasm and asthma; diseases characterized by neurogenic mucus secretion, such as cystic fibrosis; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis; oedema, such as oedema caused by thermal injury; addiction disorders such as alcholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; emesis, including acute, delayed and anticipatory emesis, for example, induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorder, motion, surgery, migraine and variations in intercranial pressures (except quaternary salts); disorders of bladder function such as cystitis and bladder detrusor hyperreflexia; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions especially the transmission of pain in migraine. Hence, these compounds are readily adapted to therapeutic use for the treatment of physiological disorders associated with an excessive stimulation of tachykinin receptors, especially neurokinin-l, and as neurokinin-l antagonists in the control and/or treatment of any of the aforesaid clinical conditions in mammals, including humans.
For example, the compounds of the present invention may suitably be used in the treatment of disorders of the central nervous system such as anxiety, psychosis and schizophrenia; neurodegenerative disorders such as senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; adverse immunological reactions such as rejection of transplanted tissues; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; disorders of blood flow caused by vasodilation; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions or the transmission of pain in migraine.
The compounds of the present invention are particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example: neuropathy, such as diabetic or peripheral neuropathy and chemotherapy-induced neruopathy; postherpetic and other neuralgias; asthma; osteoarthritis; rheumatoid arthritis; and especially migraine. The compounds of the present invention are also particularly useful in the treatment of diseases characterized by neurogenic mucus secretion, especially cystic fibrosis.
In the treatment of the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin. colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, calcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solution, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
Compositions for inhalation or insufflation include solutions and suspensions in phannaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
For the treatment of the clinical conditions and diseases noted above, the compounds of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
For the treatment of certain conditions it may be desirable to employ a compound of the present invention in conjunction with another pharmacologically active agent. For example, for the treatment of respiratory diseases such as asthma, a compound of the present invention may be used in conjunction with a bronchodilator, such as a 2-adrenergic receptor agonist or tachykinin antagonist which acts at
NK-2 receptors. The compound of the present invention and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination.
The compounds of this invention may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize.
In the treatment of a condition associated with an excess of tachykinins, an appropriate dosage level will generally be about 0.001 to 50 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/ke per day; more preferably about 0.05 to about 10 mg/kg per day. For example, in the treatment of conditions involving the neruotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Rll, R12 and R13 are as defined above.
ABBREVIATIONS USED IN SCHEMES AND EXAMPLES
TABLE 1
Reagents:
Et3N triethylamine
Ph3P triphenylphosphine
TFA trifluoroacetic acid
NaOEt sodium ethoxide
DCC N,N'-dicyclohexylcarbodiimide
DCU N,N'-dicyclohexylurea
CDI 1,1 '-carbonyldiimidazole
MCPBA m-chloroperbenzoic acid
DBU 1 ,8-diazabicyclo[5 .4.0]undec-7-ene Cbz-Cl benzyl chloroformate iPr2NEt or DIEA N,N-diisopropylethylamine
NHS N-hydroxysuccinimide
DIBAL diisobutylaluminum hydride
Me2SO4 dimethyl sulfate
HOBt 1 -hydroxybenzotriazole hydrate
EDAC 1 -ethyl-3 -(3 -dimethylaminopropyl)- carbodiimide hydrochloride
Solvents:
DMF dimethylformamide rnIF tetrahydrofuran
MeOH methanol
EtOH ethanol
AmOH n-amyl alcohol
AcOH acetic acid
MeCN acetonitrile
DMSO dimethylsulfoxide
Others::
Ph phenyl
Ar aryl
Me methyl
Et ethyl iPr isopropyl
Am n-amyl
Cbz carbobenzyloxy (benzyloxycarbonyl)
Boc tert-butoxycarbonyl
PTC phase transfer catalyst cat. catalytic
FAB-MS fast atom bombardment mass
spectrometry rt room temperature
SCHEME 1
SCHEME 2
SCHEME 3
SCHEME 4
Compounds of the present invention where X and Y together form =0 and Z is either 0 or N may be prepared by the general route outlined in Scheme 1.Thus, the nitrogen of an amino acid ester such as a tryptophan benzyl ester may be acylated by reaction with an acid chloride or an anhydride (wherein R = R1). Alternatively the amide may be prepared by condensing the amino acid ester with an acid in the presence of a dehydrating agents such as DCC EDAC,
HOBT-EDAC and a tertiary amine. The benzyl ester may be removed by hydrogenation to give the free acid, which may be reacted with an alkylating agent and a base (e.g. DIEA or K2C03) or reacted with an
alcohol under dehydrating conditions to obtain an ester (Z = 0)
(wherein R' = CHR4R5).Or, the acid obtained after the removal of the
benzyl group may be reacted with a primary or a secondary amine and
the appropriate reagents to remove water to obtain an amide (Z = N)
(wherein R" = R8).
Alternatively, the compounds of this class may also be
prepared starting from a nitrogen protected amino acid such as N-t
butyloxycarbonyl-tryptophan as illustrated in Scheme 2 for the
compounds where Z is O (wherein R = R1, R'= CHR4R5, and R" = R8)
and in Scheme 3 for the compounds where Z is N (wherein R = R1, R'=
CHR4R5, and R" = R8). Here, the acid function may be modified first to prepare an ester (Scheme 2) or an amide (Scheme 3) and then the nitrogen protecting group may be removed. The Boc protecting group may be easily removed by treatment with a strong acid such as trifluoroacetic acid, formic acid or HCI in an inert solvent. The resulting amine may be acylated as described in Scheme 1 to furnish the desired compounds.
The amino acid derivatives obtained from the methods described in
Scheme 1-3 may be further elaborated. One method for such a modification is outlined in Scheme 4. If the product of acylation contains a leaving group such as a halide, mesylate or a tosylate, then this substituent may be displaced by a nuclephile such as a primary or secondary amine to obtain compounds where R1 is -(CH2)nNR6R7 (wherein n=1-12).
The object compounds of Formula I obtained according to the reactions as explained above may be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
The compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, methanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, succinate, tartrate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine and so forth. Also, the basic nitrogencontaining groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides like benzyl bromide and others.
The non-toxic physiologically acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
Although the reaction schemes described herein are reasonably general, it will be understood by those skilled in the art of organic synthesis that one or more functional groups present in a given compound of formula I may render the molecule incompatible with a particular synthetic sequence. In such a case an alternative route, an altered order of steps, or a strategy of protection and deprotection may be employed. In all cases the particular reaction conditions, including reagents, solvent, temperature, and time, should be chosen so that they are consistent with the nature of the functionality present in the molecule.
The following examples are given for the purpose of illustrating the present invention and shall not be construed as being limitations on the scope or spirit of the instant invention.
EXAMPLE 1 N-(3 3-diphenylprnpionyl-L-Tryptophan Benzvl Ester
A mixture of 205 mg (0.91 mmole) of 3,3-diphenylpropionic acid, 300 mg (0.91 mmole) of L-tryptophan benzyl ester hydrochloride salt, 28 mg (0.23 mmole) of DMAP and 348 microliters (2.0 mmole) of DEA was dissolved in 4 mL of CH2C12. The resulting solution was cooled to OOC under an atmosphere of nitrogen and was treated with 209 mg (0.91 mmole) of EDAC. The mixture was allowed to warm to room temperature over 16 hours, and was then treated with 25 mL of 10% aqueous citric acid. The mixture was extracted with 3x25 mL of ethyl acetate, the extracts were dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash chromatography on 36 g of silica gel with 1 L of 67:23 hexanes: ethyl acetate to give a colorless oil.
Mass Spectrum (FAB): m/Z 503 (M+H, 100%), 277 (55%).
NMR (CDCl3, 200 MHz, ppm): 3 2.8-3.3 (m, 4H), 4.65 (t, 1H), 4.95.15 (m, 3H), 5.95 (d, 1H), 6.18 (d, 1H), 7.0-7.5 (m, 19H), 7.9 (br s, 1H).
EXAMPLE 2
N-(3 3-diphenvipropionvi )-L-Trvptophan
A solution of 197 mg (0.39 mmole) of N-(3,3-diphenyl propionyl)-L-tryptophan benzyl ester in 3 mL of ethanol was treated with 16 mg of 10% Pd/C and the resulting suspension stirred under a balloon of hydrogen at room temperature for 18 hours. The mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by flash chromatography on 24 g of silica gel with 100:4: 0.15 CH2Cl2: methanol: acetic acid to give a clear oil.
Mass Spectrum (FAB): m/Z 451 (M+K, 10%), 435 (M+Na, 25%), 413 (M+H, 70%), 204 (55%), 167 (100%).
NMR (CDCl3, 400 MHz, ppm): 6 2.8 (m, 2H), 3.13 (qd, 2H), 4.48 (t, 1H), 4.79 (app q, 1H), 6.02 (d, 1H), 6.55 (d, 1H), 7.0-7.3 (m, 13H), 7.39 (d, 1H), 8.03 (br s, 1H).
EXAMPLE 3 N-(3 ,3-diphenylpropionyl)-L-Tryptophan, N'-benzyl-N'methvl amide
A mixture of 67 mg (0.16 mmole) of N-(3,3-diphenylpropionyl)-L-tryptophan, 31 microliters (0.24 mmole) of N-methylbenzylamine, 5 mg (0.04 mmole) of DMAP, and 28 microliters (0.16 mmole) of DIEA was dissolved in 1.5 mL of CH2Cl2 and the solution was cooled to 0 C under an atmosphere of nitrogen. The mixture was treated with 39 mg (0.20 mmole) of EDAC, and the solution was allowed to warm to room temperature over 27 hours. The mixture was treated with 20 mL of 10% aqueous citric acid and was extracted with 2x30 mL of ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash chromatography on 16 g of silica gel with 1 L of 60:40 hexanes: ethyl acetate to give 62 mg (74it) of an oil.
Mass Spectrum (FAB): m/Z 538 (M+Na, 10or), 517 (-M+H, 90gas), 395 (65%), 367 (70%), 290 (100%).
NMR (CDCl3, 400 MHz, ppm): 5 2.4 and 2.67 (major and minor rotomers, s, 3H), 2.8-3.1 (m, 4H), 4.05-4.2 (m, 1H), 4.4-4.5 (m, 1H), 4.55-4.65 (m, lH), 5.15-5.25 (m, 1H), 6.45-6.55 (minor and major d, 1H), 6.69 and 6.76 (minor and major br s, 1H), 6.9-7.4 (m, 18H), 6.45 and 6.60 (minor and major d, 1H), 8.03 and 8.10 (major and minor br s, 1H).
EXAMPLE 4 N-(3.3-diphenvlpropionvl)-L-Trvptophan. N'.N'-dipentylamide A mixture of 26 mg (0.063 mmole) of N-(3,3-diphenylpropionyl)-L-tryptophan, 32 microliters (0.158 mmole) of di-npentylamine, and 2 mg (0.016 mmole) of DMAP was dissolved in 0.75 mL of CH2Cl2 and the solution was cooled to OOC under an atmosphere of nitrogen. The mixture was treated with 15 mg (0.20 mmole) of
EDAC, and the solution was allowed to warm to room temperature over 3 days. The mixture was treated with 20 mL of ethyl acetate and 6 mL of 10% aqueous citric acid, the phases were separated, and the aqueous phase was extracted with 15 mL of ethyl acetate. The combined organic phase was washed with 2x15 mL of water, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash chromatography on 12 g of silica gel eluting with 75:25 hexanes: ethyl acetate to give a clear oil.
Mass Spectrum (FAB): m/Z 553 (~M+H,, 35%), 395 (55%), 367 (80%), 326 (100%), 213 (65%).
NMR (CDCl3, 400 MHz, ppm): 6 0.8-1.8 (m, 18H), 3.5-4.0 (m, 6H), 3.1-3.3 (m, 2H), 4.47 (t, 1H), 5.0-5.1 (m, lH), 6.33 (d, 1H), 6.77 (d, lH), 7.0-7.35 (13H), 7.63 (d, 1H), 7.90 (br s, 1H).
EXAMPLE 5 N-(3,3 -diphenylpropionyl)-L-Tryptophan, N'-3 ,5-bis (trifluoro- methyl)benzvl-N'-methvl amide
Step A: 3 .5-bis(trifluoromethv1 )-N-methvlbenzvlamine A mixture of 1.00 g (4.13 mmole) of 3,5-bis(trifluoro methyl)benzaldehyde and 1.11 g (16.5 mmole) of monomethylamine hydrochloride in 5 mL of methanol was cooled to 0 C and was treated with 1.55 mL (11.2 mmole) of triethylamine. The cooling bath was removed, the mixture was treated with 0.208 g (3.3 mmole) of sodium cyanoborohydride, and was allowed to stir at room temperature for 24 hours. The mixture was partly concentrated in vacuo and the residue was treated with 15 mL of 5% aqueous sodium hydroxide and was extracted with 40 mL of ethyl acetate.The organic phase was washed with 2x10 mL of water and then 10 mL of saturated sodium chloride solution, and was dried over sodium sulfate, filtered and concentrated in vacuo to give 0.55 g (52%) of a clear volatile oil.
NMR (CDCl3, 200 MHz, ppm): 6 2.5 (s, 3H), 3.92 (s, 2H), 7.78 (s, 1H), 7.82 (s, 2H).
Step B: N-(3,3-diphenylpropionyl)-L-Tryptophan, N'-3,5 bis(trifluoromethvl)benzvl-N'-methvl amide
A mixture of 40 mg (0.097 mmole) of N-(3,3-diphenylpropionyl)-L-tryptophan, 63 mg (0.24 mmole) of 3,5-bis(trifluoromethyl)-N-methylbenzylamine and 3 mg (0.024 mmole) of DMAP in 1 mL of CH2Cl2 was cooled to 0 C under an atmosphere of nitrogen and was treated with 23 mg (0.12 mmole) of EDAC. The mixture was allowed to warm to room temperature over several hours and was then stirred at room temperature for 3 days. The mixture was treated with 35 mL of ethyl acetate and 10 mL of 10% aqueous citric acid, the phases were separated, the organic phase was washed with 2x 10 mL of water, dried over sodium sulfate, filtered and concentrated in vacuo.
The residue was purified by flash chromatography on 13 g of silica gel eluting with 67:33 hexanes: ethyl acetate to provide 53 mg (84qc) of an oil.
Mass Spectrum (FAB): m/Z 652 (M+R, 6%), 442 (6%), 426 (40%), 395 (25%), 367 (45%), 256 (10%), 227 (100%).
NMR (CDC13, 400 MHz, ppm): 6 2.40 and 2.70 (major and minor s, 3H), 2.8-3.0 (m, 4H), 4.10 (m, 1H), 4.3-4.5 (AB dd, 2H), 4.5-4.6 (m, 1H), 5.2 (m, 1H), 6.35 (d, 1H), 6.73 and 6.81 (major and minor s, 1H), 7.0-7.4 (m, 13H), 7.44 and 7.60 (minor and major d, 1H), 7.50 and 7.77 (major and minor s, 2H), 7.63 and 7.99 (minor and major br s, 1H).
EXAMPLE 6 N-(3 ,3 -diphenylpropionyl)-L-Tryptophan, 3,5 -Bis(trifluoromethyl)- benzvl Ester
A mixture of 43 mg (0.10 role) of N-(3,3-diphenylpropionyl)-L-tryptophan, 76 mg (0.31 mmole) of 3,5-bis(trifluoromethyl)benzyl alcohol and 3 mg (0.16 mmole) of DMAP was cooled to 0 C under an atmosphere of nitrogen and was treated with 30 mg (0.16 mmole) of EDAC. The cooling bath was allowed to expire over 4 hours, and the mixture was stirred for an additional 17 hours. The mixture was treated with 30 mL of ethyl acetate and 10 mL of 10% citric acid. The phases were separated and the aqueous phase was extracted with 25 mL of ethyl acetate. Each organic extract was washed separately with 10 mL of water, the extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by flash chromatography on 16 g of silica gel eluting with 500 mL of 75: 25 hexanes: ethyl acetate to give 50 mg (75%) of a clear oil.
Mass Spectrum (FAB): m/Z 661 (M+Na, 5%), 639 (M+H, 50%), 431 (20%), 414 (45%), 226 (15%), 167 (100%).
NMR (CDCl3, 200 MHz, ppm): 6 2.8-3.3 (m, 4H), 4.43 (t, 1H), 4.8-5.1 (m, 3H), 5.95 (d, 1H), 6.58 (d, 1H), 7.0-7.5 (m, 14H), 7.6 (s, 2H), 7.85 (s, 1H), 8.03 (br s, 1H).
EXAMPLE 7 3 ,5-Bis(trifluoromethyl)benzyl S-2-(1,1 -dimethylethoxy-carbonyl amino-3 -(3 -indolyl) propionate
To a mixture of 4.56 g of N-a-Boc-L-tryptophan and 2.5 g ethyldiisopropylamine in 100 mL of methylene chloride was added a solution of 4.4 g 3,5 bis(trifluoromethyl )benzyl bromide. After 4 hours the reaction mixture was concentrated and the residue chromatographed on silica gel. Elution with 0-5% ethyl acetate in methylene chloride gave 4.67 g of the title compound.
Mass Spectrum (EI) 163, 227, 414, 431, 475, 531 (M+1).
EXAMPLE 8 3 ,5-Bis(trifluoromethyl)benzyl S-2-amino-3-(3 -indolyl)-propionate trifluoroacetic acid salt
To a solution of the material from Example 7 (3.67 g) in 20 mL of methylene chloride was added 5 mL of trifluoroacetic acid.
The reaction mixture was stirred at room temperature for 2 hours then concentrated in vacuo. Trituration of the residue with hexanes containing a small amount of ether afforded the title compound (2.84 g) as a tan solid.
Mass Spectrum (FAB) 227, 277, 431 (M+1).
EXAMPLE 9 3 ,5-Bis(trifluoromethyl)benzyl S-2-(6-bromohexanoyl-amino)-3-(3indolvl) propionate
To a mixture of 3,5-bis(trifluoromethyl)-benzyl 2-amino3-(3-indolyl) propionate trifluoroacetic acid salt (Example 8) (0.544 g) and 0.5 g of ethyl diisopropylamine in 25 mL of methylene chloride was added a solution of 0.250 g 6-bromohexanoyl chloride in 2 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight after which time it was concentrated in vacuo.
The residue was partitioned between 50 ml of 1:1 etherethylacetate and 2N HCI (25 ml). The organic phase was separated and washed with 25 ml of saturated sodium bicarbonate solution, dried through sodium sulfate and concentrated in vacuo to yield the title compound (0.683 g).
Mass Spectrum (FAB) 130, 158, 185, 413, 414, 431, 527, 563, 607, 609.
The following compounds were also prepared using the procedure of Examples 7 - 9:
EXAMPLE 10 3,5 Bis(trifluoromethyl)benzyl S -2-(5 -bromopentanoyl-amino)-3 -(3- indolvl) propionate
Mass Spectrum (FAB) 130, 158, 185, 414, 415, 593, 595.
EXAMPLE 11 3 ,5-Bis(trifluoromethyl)benzyl S-2-(7-bromoheptanoyl-amino)-3 -(3- indolvl) propionate
Mass Spectrum (FAB) 129, 158, 185, 413, 414, 620, 622.
EXAMPLE 12 3 ,5-Bis(trifluoromethyl)benzyl S-2-(8-bromooctanoyl-amino)-3 -(3 indolvl) propionate
Mass Spectrum (FAB) 186, 413, 414, 431, 634, 636.
EXAMPLE 13 3,5-Bis(trifluoromethyl)benzyl S-2-(6-phenylbexanoylamino)-3-(3- indolvl) propionate
Mass Spectrum (FAB) 130, 158, 185, 414, 415, 605.
EXAMPLE 14 3,5-Bis(trifluoromethyl)benzyl S-2-lauroylamino-3-(3-indolyl) propionate
Mass Spectrum (FAB) 130, 158, 182, 200, 255, 414, 415, 613.
EXAMPLE 15 3,5-Bis(trifluoromethyl)benzyl S-2-(dimethylaminoacetyl-amino)-3 (3-indolvl) propionate
Method A:
To a mixture of 0.272 g of 3,5-bis(tri-fluoromethyl)benzyl S-2-amino-3-(3-indolyl)propionate trifluoroacetic acid salt (Example 41), 0.140 gm N,N-dimethylglycine hydrochloride and 0.200 g ethyldiisopropylamine in 15 mL of methylene chloride was added 0.206 g of dicyclohexylcarbodiimide. The reaction mixture was stirred - 40 hrs at room temperature, then concentrated in vacuo and the residue stirred in 50 mL ethylacetate and 50 mL saturated sodium bicarbonate solution. The organic layer was filtered through sodium sulfate and concentrated in vacuo.Chromatography of the residue on silica gel eluting with 0-15is acetone in methylene chloride gave 3,5bis(trifluoromethyl)benzyl S-2-dimethylaminoacetyl-amino)-3-(3indolyl) propionate.
Mass Spectrum (FAB) 130, 144, 158, 226, 290, 516.
Method B:
To a mixture of 0.200 g of 3,5-bis(tri-fluoromethyl)benzwl S-2-amino-3-(3-indolyl)propionate trifluoroacetic acid salt (Example 41) and 0.500 g of triethylamine in 10 mL methylene chloride was added the acid chloride prepared from 0.150 dimethylamino glycine hydrochloride (oxalyl chloride method). The reaction mixture was stirred overnight at room temperature, worked up as in Method A and the residue chromatographed as in Method A to yield the title compound 3,5-bis(trifluoromethyl)benzyl S-2-(dimethylaminoacetylamino)-3 -(3 - indolyl) propionate.
The following compounds were prepared in a similar manner to Example 15.
EXAMPLE 16 3,5 -Bis(trifluoromethylbenzyl) S -2-(3 - [dimethylamino] -propionyl- amino)-3-(3-indolvl) propionate
Mass Spectrum (FAB) 130, 143, 144, 227, 531.
EXAMPLE 17 3 ,5-Bis(trifluoromethyl)benzyl S-2-(4-[dimethylamino]-butanoylamino)- 3-(3-indolvl) propionate
Mass Spectrum (FAB) 114, 129, 142, 226, 413, 499, 544.
EXAMPLE 18 3 ,5-Bis(trifluoromethyl)benzyl S-2-(3 -dimethylamino-carbonyl)- propionvlamino)-3-(3-indolyl) propionate
Mass Spectrum 128, 130, 145, 226, 414, 559.
Using the appropriate acid, triethylamine and 1 -(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (in place of
DCC) in the procedure of Example 15, Method A the following compounds were obtained.
EXAMPLE 19 3 ,5-Bis(trifluoromethyl) S-2-(2-pyridylmethylcarbonyl-amino)-3 -(3 - indolvl) propionate
Mass Spectrum (FAB) 130, 158, 226, 414, 550.
EXAMPLE 20 3,5-Bis (trifluoromethyl)benzyl S-2-(3-pyridylmethyl-carbonylamino) 3-(3-indolyl) propionate
Mass Spectrum (FAB) 130, 158, 226, 413, 550.
EXAMPLE 21 3 ,5-Bis(trifluoromethyl)benzyl S-2-(4-pyridylmethyl-carbonylamino) 3-(3-indolvl) propionate
Mass Spectrum (FAB) 130, 158, 226, 412, 550.
EXAMPLE 22 3,5-Bis(trifluoromethyl)benzyl S-2-(3-[3-pyridyl]acrylo-ylamino)-3-(3 indolvl) propionate
Mass Spectrum (FAB) 130, 158, 226, 412, 413, 562.
EXAMPLE 23 3,5-Bis(trifluoromethyl)benzyl S-2-(3-[3-pyridyl]-propionylamino)-3 (3-indolvl) propionate
Mass Spectrum (FAB) 130, 158, 226, 434, 564.
EXAMPLE 24 3.5-Bis(trifluoromethyl)benzyl S -2-(6- [ dimethylamino] -hexanoyl- amino)-7-(3-indolvl) propionate
A mixture of 0.300 g 3,5-bis(trifluoromethyl)benzyl 2-(6bromohexanoylamino)-3-(3-indolyl)propionate in 15 mL of toluene and 2 mL of 40% aqueous dimethylamine was stirred vigorously at room temperature overnight. The reaction mixture was poured into ethyl acetate (-25 ml) and washed with saturated sodium bicarbonate solution.
The organic layer was dried through sodium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel and elution with methylene chloride then methylene chloride/methanol/ammonium hydroxide (92.5n.5/0.75) gave the desired product 3,5-bis(trifluoromethyl)-benzyl 2-(6- [dimethylamino]hexanoylamino)-3 -(3-indolyl) propionate.
Mass Spectrum (FAB) 130, 142, 226, 414, 442, 572.
In a similar manner to Example 24 were prepared the following:
EXAMPLE 25 3,5-Bis(trifluoromethyl)benzyl S -2-(5- [dimethylamino] -pentanoyl- amino)-3-(3-indolvl) propionate
Mass Spectrum (FAB) 130, 143, 226, 332, 414, 558.
EXAMPLE 26 3,5-B is(trifluoromethyl)benzyl S-2-(7- [dimethylamino] -heptanoyl amino)-3-(3-indolvl) propionate
Mass Spectrum (FAB) 130, 156, 226, 414, 586.
EXAMPLE 27 a-Methyl-3,5-bis(trifluoromethyl)benzyl S-2-(t-butoxycarbonylamino)3-(3-indolvl) propionates
To a mixture of 0.89 g a-Methyl-3,5-bis(trifluoromethyl)benzyl alcohol and 1.15 g of N-a-Boc-L-tryptophan in 25 ml of methylene chloride was added 1.0 g of 1 -(3-dimethylaminopropyl)-3- ethyl-carbodiimide and 0.01 g 4-dimethylaminopyridine. The reaction mixture was stirred overnight at room temperature, then poured into ethyl acetate (60 ml) and washed with water and saturated sodium bicarbonate solution. The organic layer was dried through sodium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel eluting with a mixture of hexanes/methylene chloride/ethyl acetate 7/2/1 and/or 8/1/1 afforded the diastereomeric esters.
Isomer A: R or S-a-Methyl-3,5-bis(trifluoromethyl)-benzvl S-2-(t
butoxycarbonylamino)-3 -(3 -indolyl)propionate.
Mass Spectrum (FAB) 130, 158, 428, 445, 489, 544.
Isomer B: S or R-a-Methyl-3,5-bis(trifluoromethyl)-benzyl S-2-(t
butoxycarbonylamino)-3 - (3-indolyl)propionate.
Mass Spectrum (FAB) 130, 158, 428, 445, 489, 544.
EXAMPLE 28
When the t-butylcarbamate derivatives prepared in
Example 27 were treated with trifluoro-acetic acid, according to the procedure of Example 8, the corresponding amine trifluoroacetic acid salts were obtained.
Isomer A: R or S-a-Methyl-3,5-bis(trifluoromethyl)-benzyl S-2 amino-3 -(3 -indolyl) propionate trifluoroacetic acid salt.
Isomer B: S or R-a-Methyl-3,5-bis(trifluoromethyl)-benzyl S-2
amino-3-(3-indolyl) propionate trifluoroacetic acid salt.
EXAMPLE 29
When the diastereomeric amine salts obtained in Example 28 were treated with 6-bromohexanoyl chloride, according to the procedure of Example 9, the following compounds were obtained:
A. R or S-a-Methyl-3,5-bis(trifluoromethyl)benzyl S -2-(6-bromohexanoylamino)-3-(3 -indolyl) propionate.
Mass Spectrum (FAB) 187, 204, 240, 427, 621, 623.
B. S or R-a-Methyl-3 ,5 -bis (trifluoromethyl)benzyl S-2-(6-bromohexanoylamino)-3-(3-indolyl) propionate.
Mass Spectrum (FAB) 187, 204, 240, 427, 427, 621, 623.
EXAMPLE 30
Benzyl 2-((2-dimethylamino-3,3-diphenylpropionyl)amino)-3-(3- indolvl)propionate To a suspension of 0.22 g (0.89 mmol) of N,N-dimethyldiphenylalanine in 4 ml of CH2C12 were added 0.2 ml of Nmethylmorpholine, 0.243 g of EDC and 0.166 g of 1hydroxybenzotriazole. After stirring the solution for 10 min, a solution of 0.298 g of L-tryptophan benzyl ester hydrochloride in 2 ml of
CH2Cl2 was added. The reaction mixture was stirred for 2 hr, then concentrated in vacuo. The residue was partitioned between water and ethyl acetate (EtOAc) and the aqueous layer was extracted with EtOAc.
The EtOAc solution was washed with saturated NaCl, dried with
Na2S04 and concentrated. The residue was purified on a flash column using a gradient of 30-40% EtOAc-hexane to isolate 0.114 g (26% yield) of diastereomer A (Rf = 0.67, SiO2, 50% EtOAc-Hexane) 1H
NMR (400 MHz, CDCl3) 6 2.25 (s, 6 H), 2.72 (dd, 1H, J=16 Hz and J=6
Hz), 3.06 (dd, 1 H, J=16 Hz and J=6 Hz), 3.67 (d, 1 H, J=12 Hz), 4.52 (d, 1 H, J=12 Hz), 4.85 (m, 1 H), 4.96 (s, 2 H), 5.91 (br d, 1 H, j=7 Hz), 6.14 (d, 1 H, J=2 Hz), 7.03-7.35 (m, 19 H), 7.85 (s, 1 H); and 0.102 g (23 % yield) of diastereomer B (Rf = 0.57, SiO2, 50% EtOAc-Hexane) 1H NMR (400 MHz, CDCl3): 6 2.25 (s, 6 H), 3.1 (m, 2 H), 3.7 (d, 1 H, J=12 Hz), 4.37 (d, 1 H, J=12 Hz), 4.66 (m, 1 H), 4.9 (ABq, 2 H, J=12
Hz), 6.09 (br s, 1 H), 6.73 (s, 1 H), 6.96-7.5 (m, 19 H), 7.98 (s, 1 H). A 0.19 g of a mixed fraction was also obtained.
EXAMPLE 31 3 ,5-Bistrifluoromethylbenzyi 2-((2-dimethylamino-3,3-diphenyl propionyl)amino)-3-(3-indolvl)propionate A solution of 0.22 g of the benzyl 2-((2-dimethylamino 3, 3 diphenyl-propionyl)amino)-3 -(3-indolyl)propiate, diastereomer A, in 2 ml of ethanol containing 35 mg of 10% Pd/C was hydrogenated on a
Parr apparatus. After 4 hours the catalyst was filtered and washed with
EtOAc. The filtrate was concentrated, the residue was dissolved in 2 ml of CH2Cl2 and 20 ml of N-methyl-morpholine. EDC (33 mg) and 1 hydroxybenzotriazole were added and the mixture was stirred for 10 min., at which time 30 mg of 3,5-bistrifluoromethylbenzyl alcohol was added. After for 4 hours the solution was concentrated and the residue was partitioned between EtOAc and water.The water layer was extracted with EtOAc The organic layer was washed with water, saturated NaCl and dried. The filtrate was concentrated and the residue was chromatographed using 20-30% EtOAc/hexane to isolate two products stereoisomeric at the tryptophan center. Isomer A (higher Rf) 1H NMR (400 MHz, CDCl3) 6 2.35 (s, 6 H), 2.70 (dd, 1 H, J=16 Hz and 6 Hz), 3.0 (dd, 1 H, J=16 Hz and 6 Hz), 3.4 (m, 1 H), 4.5 (d, 1 H, J=16
Hz), 4.71 (m, 1 H), 4.95 (ABq, 2 H, J= 12 Hz), 6.44 (br s, 1 H), 7.387.7 (m, 15 H), 7.49 (s, 2 H), 7.78 (s, 1 H), 7.88 (s, 1 H) abd Isomer B (lower Rf) 1H NMR (400 MHz, CDCl3) 3 2.32 (s, 6 H), 3.2 (m, 2 H), 3.5 (m, 1 H), 4.42 (m, 1 H), 4.6 (m, 1 H), 5.9 (ABq, 2 H, J=12 Hz), 6.9-7.35 (m, 16 H), 7.45 (m, 2 H), 7.79 (s, 1 H), 8.0 (s, 1 H).
EXAMPLE 32
N-Benzyl-N-methyl-2-((2-dimethylamino-3,3-diphenyl-propionyl) amino)-3-(3 -indolvl)propionamide Following the procedure of Example 30, reaction of 93 mg of L-tryptophan-N-benzyl-N-methyl-amide and 68 mg of N,Ndimethyl-diphenylalanine furnished 15 mg of the title compound. 1H
NMR (400 MHz, CDCl3): 8 2.22, 2.27, 2.36 and 2.6 (4 s, 9 H), 3.1 (m, 2 H), 3.86 (m, 1 H), 4.28 (ABq, 2 H, J=14 Hz), 4.45 (t, 1 H, J=10 Hz), 5.06 (m, 1 H), 6.64 (d, 1 H, J=7 Hz), 6.85-7.38 (m, 18 H), 7.4 and 7.67 (2 d, 1 H, J=8 Hz), 7.98 and 8.08 (2 br s, 1 H).
EXAMPLE 33
Benzyl 2-((2-acetylamino-3-hydroxy-butyryl)amino)-3 -(3 - indolvl)propionate
Following the method of Example 30, 0.225 g of Ltryptophan benzyl ester hydrochloride and 0.1 g of N-acetyl-Lthreonine were reacted to obtain 0.27 g (100% yield) of the title compound after column chromatography. 1H NMR(400 MHz, CDCl3): 6 1.06 (d, 3 H, J=8 Hz), 1.80 (s, 3 H), 3.3 (m, 2 H), 4.27 (m, 2 H), 4.89 (q, 1 H, J=8 Hz), 5.11 (ABq, 2 H, J=12 Hz), 6.22 (d, 1 H, J=7 Hz), 6.8 (d, 1 H, J=2 Hz), 7-7.32 (m, 9 H), 7.5 (d, 1 H, J=8 Hz), 8.04 (s, 1 H).
EXAMPLE 34
Typical Pharmaceutical Compositions Containing a Compound of the
Invention
A: Dry Filled Capsules Containing 50 mg of Active Ingredient Per
Capsule
Ingredient Amount per capsule (mg)
Active ingredient 50
Lactose 149
Magnesium stearate
Capsule (size No. 1) 200
The active ingredient can be reduced to a No. 60 powder and the lactose and magnesium stearate can then be passed through a No.
60 blotting cloth onto the powder. The combined ingredients can then be mixed for about 10 minutes and filled into a No. 1 dry gelatin capsule.
B: Tablet
A typical tablet would contain the active ingredient (25 mg), pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).
C: Suppositorv
Typical suppository formulations for rectal administration contain the active ingredient (0.08-1.0 mg), disodium calcium edetate (0.25-0.5 mg), and polyethylene glycol (775-1600 mg). Other suppository formulations can be made by substituting, for example, butylated hydroxytoluene (0.04-0.08 mg) for the disodium calcium edetate and a hydrogenated vegetable oil (675-1400 mg) such as
Suppocire L, Wecobee FS, Wecobee M, Witepsols, and the like, for the polyethylene glycol.
D: Injection
A typical injectible formulation contains the acting ingredient sodium phosphate dibasic anhydrous (11.4 mg), benzyl alcohol (0.01 ml) and water for injection (1.0 ml).
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the casual variations, adaptations, modifications, deletions, or additions of procedures and protocols described herein, as come within the scope of the following claims and its equivalents.
Claims (10)
1. A compound of structural formula II:
or a pharmaceutically acceptable salt thereof, wherein:
Z is 0, or NR8, wherein R8 is H or CH3; R1 is unsubstituted C4 12alkyl, or substituted C1 -12alkyl wherein the substituents on the alkyl are selected from the group consisting of:
(1) phenyl,
(2) halo,
(3) pyridyl, and
(4) -NR6R7, wherein
R6 and R7 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl, unsubstituted or substituted with:
(a) -NR9R10, wherein R9 and R10 are
independently selected from:
(i) hydrogen, and
(ii) C1-6 alkyl;
R2 is independently selected from the group consisting of:
(1) hydrogen, and
(2) C1-6 alkyl;
R4 is selected from::
(1) hydrogen, and
(2) C1-6 alkyl;
R5 is phenyl unsubstituted or substituted by 1, 2 or 3 groups selected from: (a) C1-6 alkyl,
(b) -0-Ci -6 alkyl,
(c) halo, and
(d) trifluoromethyl.
2. The compound of Claim 1 wherein:
Zis O, orNH;
R1 is substituted C1-l2alkyl wherein the substituents on the alkyl are selected from the group consisting of:
(1) phenyl,
(2) halo,
(3) pyridyl, and
(4) -NR6R7, wherein
R6 and R7 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1 -6 alkyl; R2 is independently selected from the group consisting of:
(1) hydrogen, and
(2) CH3; R4 is selected from:
(1) hydrogen, and
(2) CH3;
R5 is phenyl unsubstituted or substituted by 1, 2 or 3 groups selected from: (a) CH3, (b) -O-CH3,
(c) halo, and
(b) trifluoromethyl.
3. The compound of Claim 1 wherein R1 is selected from the group consisting of:
benzyl; 3,3-diphenylpropionyl; 5-bromopentanoyl; 6-bromohexanoyl; 7-bromoheptanoyl; 8-bromooctanoyl; 5-phenylhexanoyl; 6-phenylhexanoyl; 2-dimethylamino-3,3diphenylpropionyl; 3-(dimethylamino)propionyi; 4-(dimethylamino)butanoyl; 5-(dimethylamino)pentanoyl; 6-(dimethylamino)hexanoyl; 7-(dimethylamino)heptanoyl; 2-pyridylmethyl; 3-pyridylmethyl; 4-pyridylmethyl; and 3-(3-pyridyl)propionyl.
4. The compound of Claim 1 wherein R5 is phenyl or 3 ,5-bis(trifluoromethyl)phenyl.
5. A compound which is selected from the group consisting of: 1) N-(3 ,3-diphenylpropionyl)-L-tryptophan, N-benzyl-N'-methyl amide; 2) N-(3,3-diphenylpropionyl)-L-tr > rptophan, N',N'-dipentylamide; 3) N-(3 ,3-diphenylpropionyl)-L-tryptophan, N'-3,5-bis(trifluoro
methyl)benzyl-N'-methyl amide; 4) N-(3 ,3 -diphenylpropionyl)-L-tryptophan, 3 ,5-bis(trifluoro- methyl)benzyl ester; 5) 3 ,5-bis (trifluoromethyl)benzyl S-2-(1,1 -dimethylethoxy
carbonyl-amino)-3-(3 -indolyl) propionate; 6) 3 ,5-bis(trifluoromethyl)benzyl S-2-amino-3 -(3 -indolyl )- propionate; 7) 3,5-bis(trifluoromethyl)benzyl S-2-(6-bromohexanoylamino)-3
(3-indolyl) propionate; 8) 3,5-bis(trifluoromethyl)benzyl S-2-(5-bromopentanoylamino)-3
(3-indolyl) propionate; 9) 3,5-bis(trifluoromethyl)benzyl S-2-(7-bromoheptanoylamino)-3- (3-indolyl) propionate; 10) 3 ,5-bis (trifluoromethyl)benzyl S-2-(8-bromooctanoylamino)-3
(3-indolyl) propionate; 11) 3,5-bis(trifluoromethyl)benzyl S-2-(6-phenyihexanoylamino)-3- (3-indolyl) propionate; 12) 3 ,5-bis(trifluoromethyl)benzyl S-2-lauroylamino-3 -(3-indolyl)- propionate; 13) 3,5 -bis(trifluoromethyl)benzyl S-2-(dimethylaminoacetylamino)
3-(3-indolyl) propionate; 14) 3,5-bis(trifluoromethylbenzyl) S-2-(3-(dimethylamino)- propionylamino)-3 -(3-indolyl) propionate; 15) 3,5-bis(trifluoromethyl)benzyl S-2-(4-(dimethylamino)
butanoylamino)-3-(3-indolyl) propionate; 16) 3,5-bis(trifluoromethyl)benzyl S -2-(3 -dimethylaminocarbonyl)- propionylamino)-3-(3-indolyl) propionate; 17) 3,5-bis(trifluoromethyl) S-2-(2-pyridylmethylcarbonylamino)-3
(3-indolyl) propionate; 18) 3 ,5-bis(trifluoromethyl)benzyl S-2-(3 -pyridylmethyl- carbonylamino)-3 -(3 -indolyl) propionate; 19) 3 ,5-bis (trifluoromethyl)benzyl S-2-(4-pyridylmethyl
carbonylamino)-3-(3-indolyl) propionate; 20) 3,5-bis(trifluoromethyl)benzyl S-2-(3-(3-pyridyl)acrylo- ylamino)-3-(3-indolyl) propionate; 21) 3,5-bis(trifluoromethyl)benzyl S-2-(3-(3-pyridyl)
propionylamino)-3-(3-indolyl) propionate; 22) 3,5 -bi s (trifluoromethyl)benzyl S-2-(6-(dimethylamino)hexanoyl
amino)-3-(3-indolyl) propionate; 23) 3 ,5-bis(trifluoromethyl)benzyl S-2-(5-(dimethylamino)
pentanoylamino)-3-(3-indolyl) propionate; 24) 3 ,5-bis(trifluoromethyl)benzyl S-2-(7-(dimethylamino)
heptanoylamino)-3-(3-indolyl) propionate; 25) R-a-methyl-3,5-bis(trifluoromethyl)benzyl S-2-(t-butoxy
carbonylamino)-3-(3 -indolyl)propionate; 26) S -0:-methyl -3 ,5-bis (trifluoromethyl)benzyl S -2-(t-butoxy carbonylamino)-3-(3-indolyl)propionate; 27) R-α-methyl-3,5-bis(trifluoromethyl)benzyl S-2-amino-3-(3
indolyl) propionate; 28) S-a-methyl-3,5-bis(trifluoromethyl)benzyl S -2-amino-3-(3 - indolyl) propionate; 29) R-a-methyl-3,5-bis(trifluoromethyl)benzyl-S-2-(6- bromohexanoylamino)-3-(3-indolyl) propionate; 30) S-α-methyl-3,5-bis(trifluoromethyl)benzyl-S-2-(6- bromohexanoylamino)-3-(3-indolyl) propionate; 31) benzyl 2-((2-dimethylamino-3,3-diphenylpropionyl)amino)-3-(3- indolyl)propionate; 32) 3 ,5-bistrifluoromethylbenzyl 2- ((2-dimethylamino-3 ,3 -diphenyl- propionyl)amino)-3-(3-indolyl)propionate; 33) N-benzyl-N-methyl-2-((2-dimethylamino-3,3-diphenyl-propionyl)- amino)-3-(3-indolyl)propionamide; 34) benzyl 2-((2-acetylamino-3-hydroxy-butyryl)amino)-3-(3
indolyl)propionate; or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the compound of Claim 1.
7. The use of a compound of Claim 1 for the manufacture of a medicament for antagonizing the effect of substance P at its receptor site in a mammal or for the blockade of neurokinin- 1 receptors in a mammal.
8. The use of a compound of Claim 1 for the manufacture of a medicament for treating or preventing pain or nociception attributable to or associated with migraine.
9. The use of a compound of Claim 1 for the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: diabetic neuropathy; peripheral neuropathy; AIDS related neuropathy; chemotherapy-induced neuropathy; and neuralgia.
10. The use of a compound of Claim 1 for the manufacture of a medicament for the treatment or prevention of asthma.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13851593A | 1993-10-15 | 1993-10-15 |
Publications (2)
Publication Number | Publication Date |
---|---|
GB9420262D0 GB9420262D0 (en) | 1994-11-23 |
GB2282807A true GB2282807A (en) | 1995-04-19 |
Family
ID=22482366
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB9420262A Withdrawn GB2282807A (en) | 1993-10-15 | 1994-10-07 | Tryptophan esters and amides as tachykinin receptor antagonists |
Country Status (1)
Country | Link |
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GB (1) | GB2282807A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0964679A1 (en) * | 1996-10-04 | 1999-12-22 | Clarencew Pty Ltd. | Method for the treatment of neurological or neuropsychiatric disorders |
CN1328241C (en) * | 2004-09-06 | 2007-07-25 | 大连绿源药业有限责任公司 | Preparation of N-methy-3,5-ditrifluo-aniline |
WO2007107818A2 (en) * | 2006-03-17 | 2007-09-27 | Miteni S.P.A. | Process for the preparation of 3,5-bis (trifluoromethyl)-n-methylbenzylamine |
WO2009071957A2 (en) * | 2007-12-05 | 2009-06-11 | Biostatin Gyógyszerkutató-Fejlesztö Kft. | Novel peptides and amino acid derivatives, pharmaceutical compositions containing same and the use of these compounds |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1352472A (en) * | 1971-05-18 | 1974-05-08 | Rotta Research Lab | Derivatives of tryptophan |
EP0405506A1 (en) * | 1989-06-30 | 1991-01-02 | Abbott Laboratories | Tetrapeptide type-B CCK receptor ligands |
-
1994
- 1994-10-07 GB GB9420262A patent/GB2282807A/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1352472A (en) * | 1971-05-18 | 1974-05-08 | Rotta Research Lab | Derivatives of tryptophan |
EP0405506A1 (en) * | 1989-06-30 | 1991-01-02 | Abbott Laboratories | Tetrapeptide type-B CCK receptor ligands |
Non-Patent Citations (2)
Title |
---|
J. Med. Chem. (1993) 36(14) 2044-5 and Chemical Abstracts 119:139728 * |
JP040327592 A2 and Chemical Abstracts 119:9173 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0964679A1 (en) * | 1996-10-04 | 1999-12-22 | Clarencew Pty Ltd. | Method for the treatment of neurological or neuropsychiatric disorders |
EP0964679A4 (en) * | 1996-10-04 | 2002-09-11 | Clarencew Pty Ltd | Method for the treatment of neurological or neuropsychiatric disorders |
CN1328241C (en) * | 2004-09-06 | 2007-07-25 | 大连绿源药业有限责任公司 | Preparation of N-methy-3,5-ditrifluo-aniline |
WO2007107818A2 (en) * | 2006-03-17 | 2007-09-27 | Miteni S.P.A. | Process for the preparation of 3,5-bis (trifluoromethyl)-n-methylbenzylamine |
WO2007107818A3 (en) * | 2006-03-17 | 2008-01-31 | Miteni Spa | Process for the preparation of 3,5-bis (trifluoromethyl)-n-methylbenzylamine |
WO2009071957A2 (en) * | 2007-12-05 | 2009-06-11 | Biostatin Gyógyszerkutató-Fejlesztö Kft. | Novel peptides and amino acid derivatives, pharmaceutical compositions containing same and the use of these compounds |
WO2009071957A3 (en) * | 2007-12-05 | 2009-08-27 | Biostatin Gyógyszerkutató-Fejlesztö Kft. | Novel peptides and amino acid derivatives, pharmaceutical compositions containing same and the use of these compounds |
Also Published As
Publication number | Publication date |
---|---|
GB9420262D0 (en) | 1994-11-23 |
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