CA2255910A1 - Methods of treating hypertension - Google Patents
Methods of treating hypertension Download PDFInfo
- Publication number
- CA2255910A1 CA2255910A1 CA002255910A CA2255910A CA2255910A1 CA 2255910 A1 CA2255910 A1 CA 2255910A1 CA 002255910 A CA002255910 A CA 002255910A CA 2255910 A CA2255910 A CA 2255910A CA 2255910 A1 CA2255910 A1 CA 2255910A1
- Authority
- CA
- Canada
- Prior art keywords
- indol
- piperidin
- compound
- amino
- tachykinin receptor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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- 206010020772 Hypertension Diseases 0.000 title claims abstract description 10
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- 230000000694 effects Effects 0.000 claims abstract description 14
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- YBCLEZSZNMLIAS-YDAOLNNJSA-N N-[(2R)-3-(1H-indol-3-yl)-2-[[2-(4-piperidin-1-ylpiperidin-1-yl)acetyl]amino]propyl]-3-(2-methoxyphenyl)propanamide trihydrate dihydrochloride Chemical compound O.O.O.Cl.Cl.COC1=CC=CC=C1CCC(=O)NC[C@H](NC(=O)CN1CCC(CC1)N1CCCCC1)CC1=CNC2=CC=CC=C12 YBCLEZSZNMLIAS-YDAOLNNJSA-N 0.000 claims description 3
- MVKWXCHZQUBXQB-HHHXNRCGSA-N n-[(2r)-3-(1h-indol-3-yl)-2-[[2-(4-piperidin-1-ylpiperidin-1-yl)acetyl]amino]propyl]-3-(2-methoxyphenyl)propanamide Chemical compound COC1=CC=CC=C1CCC(=O)NC[C@H](NC(=O)CN1CCC(CC1)N1CCCCC1)CC1=CNC2=CC=CC=C12 MVKWXCHZQUBXQB-HHHXNRCGSA-N 0.000 claims description 3
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- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract
This invention provides methods of inhibiting pulmonary hypertensive disease which comprise administering to a mammal in need thereof a compound having activity as a tachykinin receptor antagonist.
Description
CA 022~910 1998-11-23 Title METHODS OF TREATING HYPERTENSION
Priority Claim This application claims the benefit of United States Provisional Patent application 60/018266, filed May 24, 1996.
B~(~k~round of the Invention Tachykinins are a family of peptides which share a common amidated carboxy termin~l sequence. Substance P was the first peptide of this family to be isolated, although its pllrific~tion and the det~rmin~tion of its primary sequence did not occur until the early 1970's.
Between 1983 and 1984 several groups reported the isol~tion of two novel m~mm~ n tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin a), and neurokinin B (also known as neuromedin K and neurokinin ~). See, J.E. Maggio, Peptides, 6 (Supplement 3):237-243 (1985) for a review of these discoveries.
Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
The m~mm~ n tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
Substance P is believed inter alia to be involved in the neurotr~n.~mi.~.~ion of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as in~qmm~tory bowel disease. Tachykinins CA 022~910 1998-11-23 have also been implicated as playing a role in numerous other maladies, as discussed infra.
Tachykinins play a major role in mediating the s~n.~ion and tr~nsmi.s.~ion of pain or nociception, especially migraine headaches.
see~ e.r., S.L. Shepheard, et al., British Journal of PharmacoloFy. 108 20 (1993); S.M. Moussaoui, et al., European Journal of Ph~rm?,colo~y, 238:421-424 (1993); and W.S. Lee, et al., British Journal of Pharmacolo~y, 112:920-924 (1994).
In view of the wide number of ~linic~l m~l~(lies associated 0 with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these ~linic:~l conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited ph :~rm$l~eutical utility because of their metabolic instability.
Recent public~tionq have described novel classes of non-peptidyl tachykinin receptor antagonists which generally have greater oral bioav~ hility and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in United States Patent 5,491,140, issued February 13, 1996; United States Patent 5,328,927, issued July 12, 1994; United States Patent 5,360,820, issued November 1, 1994; United States Patent 5,344,830, issued September 6, 1994; United States Patent 5,331,089, issued July 19, 1994; European Patent Pllhlic~tion 591,040 A1, published April 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published January 20, 1994; Patent Cooperation Treaty publication WO 94/04494, published March 3, 1994;
Patent Cooperation Treaty publication WO 93/011609, published January 21, 1993; Canadian Patent Application 2154116, published January 23, 1996; European Patent Publication 693,489, published January 24, 1996;
and Canadian Patent Application 2151116, published December 11, 1995.
Patent Cooperation Treaty Patent Publication WO 96/11000, published Ap~il 18, 1996 and European Patent Publication EP 705,600, published April 10, 1996, describe a synergistic effect on the combination of a serotonin agonist and a tachykinin receptor antagonist in treating migraine. United States Patent Application 08/387,056, filed February CA 022~910 1998-11-23 W097/44035 PCT~S97/09225 10, 1995, describes a synergistic effect on the combination of a serotonin agonist and a tachykinin receptor antagonist in treating a variety of psychiatric disorders. United States Patent Application 08/408,238, filed ~ March 22, 1995, describes a synergistic effect on the comhin~tion of a serotonin agonist and a tachykinin receptor antagonist in treating a variety of types of pain and nociception. United States Patent Application 60/000074, filed June 8, 1995, describes a synergistic effect on the comhin?.tion of a serotonin agonist and a tachykinin receptor antagonist in treating the common cold or allergic rhinitis.
0 European Patent Application 0 577 394, published January 5,1994, teaches a series of morpholinyl and thiomorpholinyl tachykinin receptor antagonists. Patent Cooperation Treaty Patent Application WO
95/18124, published July 6,1995, teaches another series of substituted morpholines for use as tachykinin receptor antagonists. None of these references, nor any comhin~tion of them, teach the tachyl~inin receptor antagonists of the present invention.
Pulmonary hypertension represents a serious, life threatening spectrum of diseases of multiple etiology. These include congenital abnormalities of the lung, thorax and diaphragm, congenital or 2 o acquired valvular or myocardial disease, obstructive lung disease, and can be a complication of autoimmune diseases, vasculitis and collagen based diseases (Rubin, Chest. 104: 236,1993). Patients with pulmonary hypertension frequently present with symptoms including dyspnea, fatigue, syncope, and chest pain, and have increased pulmonary artery 2 5 pressure and demonstrate prominence of the main pulmonary artery, hilar vessel enlargement and decreased peripheral vessels on chest radiographs ~ich, Ann. Internal. Med.. 107: 216,1987).
While pulmonary hypertension has multiple etiologies, primary pulmonary hyperten~ion appears to involve an autoimmune 3 0 component and has been reported as a complication in patients with mixed connective tissue disease, rheumatoid arthritis, Sjogren's syndrome, systemic sclerosis and lupus (Sato, Hum. Path., 24: 199,1993).
Primary pulmonary hypertension occurs in females 1.7 times more frequently than males with the greatest pre(lomin~nce between the third 3 5 and fourth decades of life (Rich, Ann. Internal. Med., 107: 216,1987). The . , ,, .. .. ,_ CA 022~910 1998-11-23 W097/44035 PCTrUS97/09225 increased incidence of primary pulmonary hypertension in women of child bearing age as well as the ~linic~l observations that the disease can be exacerbated by pregnancy and oral contraceptives ~ller, Ann. Rheum.
~.46: 159,1987; and cited in Farhat et al., J PET., 261: 686,1992) 5 suggests a role for estrogen in the disease process. To this extent, Farhat et al. have demonstrated that estradiol potentiates the vasopressor response to a thromboxane mimetic in perfused rat lungs (J PET, 261:
686,1992). However, the role of estrogen in pulmonary hypertension is complex and may be dependent on the etiology of the disease process. In 0 a rat model of pulmonary hypertension induced by injection of monocrotaline pyrrole (Reindel, Tox. Ap~l. Pharm., 106: 179,1990) progressive pulmonary hypertension, right ventricular hypertrophy and interstitial edema around the large airways and blood vessels becomes apparent, simil~r to the pathology observed in man. Estradiol treatment 15 decreased right ventricular hypertrophy and prevented interstitial edema in this model (Farhat ~1., Br. J. Pharm., 110: 719,1993) as well as attenuating the hypoxic vasoconstrictive response in isolated sheep lungs (Gordon et al., J. Appl. Physiol., 61: 2116,1986).
Current therapy for pulmonary hypertension is inadequate 2 0 and is largely dependent on the use of vasodilators, diuretics, and anticoagulants ~ubin, DruFs, 43: 37,1992; Palevsky, JAMA. 265:1014, 1991). Vasodilators are effective in only a small subpopulation of patients with primary pulmonary hypertension and is complicated by systemic hypotensive responses. Prostacyclin infusion and high dose calcium 2 5 channel blockers are also being used with limited efficacy. Heart-lung and single lung transplantation have been used on patients which do not respond to vasodilator therapy, however, due to surgical morbidity and mortality, this approach is usually limited to those patients who continue to deteriorate despite aggressive therapy at centers experienced in 3 o mZ~nz~gement of this disease. Patients frequently die of right heart failureand those individuals which have signs of right heart failure have a mean survival of 6-12 months ~ubin, Dru~, 43: 37,1992).
Therefore, pulmonary hypertensive diseases are characterized by inadequate therapies, necessity of organ transplantation 3 5 and poor prognosis, and a need exists for new therapies.
CA 022.7.7910 1998 - 1 1 - 23 W O 97/44035 PCTrUS97/09225 Summary of the Invention This invention provides methods of inhibiting pulmonary 5 hypertensive disease in a m~mm~l which comprise a-lmini.~tering to a m~mm?ll in need thereof an effective amount of a compound having activity as a tachykinin receptor antagonist.
Detailed Description and Plerelled F,mhodiments The terms and abbrevi~tion.~ used in the instant preparations and examples have their normal me~ning.s unless otherwise designated. For example "~C" refers to degrees Celsius; "N" refers to normal or normality; "mmol" refers to millimole or millimoles; "g" refers to 5 gram or grams; "ml" means milliliter or milliliters; "L" means liter or liters; "M" refers to molar or molarity; "MS" refers to mass spectrometry;
"IR" refers to infrared spectroscopy; and "NMR" refers to nuclear magnetic resonance spectroscopy.
The term "inhibit" includes its generally accepted meaning 2 0 which includes prohibiting, preventing, restraining, and slowing, stopping or reversing progression, severity or a resultant symptom. As such, the present method includes both medical therapeutic and/or prophylactic 1mini.~tration, as appropriate.
Pulmonary hypertensive diseases include all conditions 2 5 characterized by an increase in the blood pressure within the blood vessels supplying the lungs and can increase the complications associated with pulmonary embolism, heart failure, valvular disease, chronic lung diseases and autoimmunity.
- The methods of the present invention employ various 3 0 tachykinin receptors. In recent publications many different groups of non-peptidyl tachykinin receptor antagonists have been described. The present invention, however, is not limited to any one of the specific compound or class of compound. The present invention encompasses any compound effective as a tachykinin receptor antagonist.
Patent Cooperation Treaty publication WO 94/01402, published January 20, 1994, rles~ribes a series of compounds best typified by the following compound.
~CF3 H3C~N~ ~NH
~N~J~H~ \CF3 O
European Patent Pllblic~tion 591,040 Al, published April 6, 1994 describes a series of compounds typified by the following compound:
CH
H3 C CH3 ~l C 1 Cl where A iS a ph~rm~(~.eutically acceptable anion.
Patent Cooperation Treaty pllhlic~tion WO 94/04494, published March 3, 1994, describes a series of compounds typified by the 15 following compound.
H3C~-- C ~
WO 97/44035 rCT/US97/09225 Patent Cooperation Treaty publication WO 93/01169, published January 21, 1993, describes a series of compounds typified by the following compound.
--~CF3 H O'~
~ CF3 Another group of tachykinin receptor antagonists is characterized by the compound of the formula:
1 o ~N~OCH 3 having the ~le.cign~tion (~)-CP 96345. These compounds and their syntheses are described in E.J. Warawa, et al., Journal of Me~licinal Chemistry. 18:357 (1975).
Yet another group of tachykinin receptor antagonists is characterized by the compound of the formula:
NH ~
NJ~J
o~ OCH3 H ~=~
having the ~le.cign~tion RP 67580. These compounds and their syntheses are described in C. Garret, et al., Proceedin~s of the National Academy of Sciences (IJSA)~ 88: 10208- 10211 (1991) and the references cited therein.
Patent Cooperation Treaty publication WO 94/07843 describes a series of cyclohexylamine derivatives typified by the following compound ~.~'\~~ ~ CH~
which are useful as tachykinin receptor antagonists.
Another group of compounds useful as tachykinin receptor antagonists is typified by the following compound.
CA 022~910 1998-11-23 ~¢~ NN\>----~
H3 C¦ Br CH3 \~
The synthesis of these compounds is described in European Patent Application Pllhlic~tion 694,535, published January 31, 1996.
The compound (S)-1-(2-methoxybenzyl)-2-[(4-phenyl-1-piperazinyl)methyl]-4-(lH-indol-3-ylmethyl)-2-imidazoline and related compounds are (le.s~rihed in European Patent Pllhlic~t.ion 699,665, published March 6, 1996. This compound has the following structure.
H
N~
The above groups of compounds are only illustrative of the tachykinin receptor antagonists which are currently under development.
This listing of groups of compounds is not meant to be comprehensive, the 15 methods of the present invention may employ any tachykinin receptor antagonist and is not limited to any particular class of compound.
A most preferred class of tachykinin receptor antagonists are those compounds of the following structure ., ,, ........ , .. ~ .. ., .. , .. .. ,.. . . . ,. . ~
H o=<~ CH3 R2 CH2 ~
~/Y
where R1 and R2 are independently selected from the group 5 consisting of hydrogen, methyl, methoxy, chloro, and trifluoromethyl, with the proviso that no more than one of Rl and R2 can be hydrogen; and Yis N--O N--N~ N
CH--N~ CH--O , CH {~
N-Ra, or CH-NRbRC
where Ra, Rb, and Rc are independently selected from the group consisting of hydrogen and C1-C6 alkyl;
or a pharmaceutically acceptable salt or solvate thereo~ The syntheses of these compounds are (lesrrihed in Patent Cooperation Treaty Pllhlic~tions WO 95/14017, published May 26, 1995, and WO 96/01819, published 2 o January 25, 1996. The syntheses of two typical compounds from this class are detailed in~
CA 022~910 1998-11-23 Synthesis of (R)-2-[N-(2-((4-cyclohexyl)piperazin-1-yl)acetyl)amino]-3-(lH-indol- 3 -yl) - 1- [N - (2 -methoxybenzyl) acetylamino]prop ane /=\ OCH3 C~2 N
~ ~N ~O
(a) Preparation of (R)-3-(lH-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid [N-trityltryptophan]
Tritylation ~OH ~ ~~
H H trityl Chlorotrimethylsilane (70.0 ml, 0.527 mol) was added at a moderate rate to a stirred slurry of D-tryptophan (100.0 g, 0.490 mol) in 15 anhydrous methylene chloride (800 ml) under a nitrogen atmosphere.
This mixture was continuously stirred for 4.Z5 hours. Triethylamine - (147.0 ml, 1.055 mol) was added, followed by the arl(lition of a solution of triphenylmethyl chloride (147.0 g, 0.552 mol) in methylene chloride (400 ml) using an adllition funnel. The mixture was stirred at room 2 0 temperature, under a nitrogen atmosphere for at least 20 hours. The reaction was quenched l~y the addition of methanol (500 ml).
The solution was concentrated on a rotary evaporator to near dryness and the mixture was redissolved in methylene chloride and ethyl acetate. An aqueous work-up involving a 5% citric acid solution (2X) and CA 022~910 1998-11-23 brine (2X) was then performed. The organic layer was dried over anhydrous sodium sulfate, f;ltered, and concentrated to dryness on a rotary evaporator. The solid was dissolved in hot diethyl ether followed by the addition of hexanes to promote crystallization. By this process 173.6 g (0.389 mol) of analytically pure (R)-3-(lH-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid was isolated as a white solid in two crops giving a total of 79% yield.
FDMS 446 (M+).
H NMR (DMSO-d6) ~ 2.70 (m, lH), 2.83 (m, 2H), 3.35 (m, lH), 6.92-7.20 0 (mj 12H), 7.30-7.41 (m, 8H), 10.83 (s, lH), 11.73 (br s, lH).
Analysis for C30H26N2o2:
Theory: C, 80.69; H, 5.87; N, 6.27.
Found: C, 80.47; H, 5.92; N, 6.10.
(b) Preparation of (R)-3-(lH-indol-3-yl)-N-(2-methoxybenzyV-2-~-triphenylmethylamino)propanamide Coupling ~ OH ~ ~ H ~C~
H trityl H trityl R
To a stirred solution of (R)-3-(lH-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid (179.8 g, 0.403 mol), 2-methoxybenzylamine (56.0 ml, 0.429 mol), and hydroxybenzot~ole hydrate (67.97 g, 0.429 mol) in anhydrous tetrahydrofuran (1.7 L) and anhydrous N,N-dimethylformamide (500 ml) under a nitrogen atmosphere at 0~C, were added triethylamine (60.0 ml, 0.430 mol) and 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride (82.25 g, 0.429 mol). The mixture was allowed to warm to room temperature under 30 a nitrogen atmosphere for at least 20 hours. The mixture was concentrated on a rotary evaporator and then redissolved in methylene chloride and an aqueous work-up of 5% citric acid solution (2X~, saturated sodium bicarbonate solution (2X), and brine (2X) was performed. The CA 022~9l0 l998-ll-23 organic layer was dried over anhydrous sodium sulfate and concentrated to dryness on a rotary evaporator. The desired product was then recrystallized from hot ethyl acetate to yield 215.8 g (0.381 mol, 95%) of analytically pure material.
5 FDMS 565 ~+).
H NMR (CDCl3) ~ 2.19 (dd, J=6.4 Hz, ~o=14.4 Hz, lH), 2.64 (d, J=6.5 Hz, lH), 3.19 (dd, J=4.3 Hz, ~=14.4 Hz, lH), 3.49 (m, lH), 3.63 (s, 3H), 3.99 (dd, J=5.4 Hz, ~o=14.2 Hz, lH), 4.25 (dd, J=7. 1 Hz, ~v=14.2 Hz, lH), 6.64 (d, J=2.1 Hz, lH), 6.80 (d, J=8.2 Hz, lH), 6.91 (t, J-7.4 Hz, lH), 7.06-7.38 (m, 21 H), 7.49 (d, J=7.9 Hz, lH), 7.75 (s, lH).
Analysis for C38H3sN3O2:
Theory: C, 80.68; H, 6.24; N, 7.43.
Found: C, 80.65; H, 6.46; N, 7.50.
(c) Preparation of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)amino] -2-(N-triphenylmethylamino)propane Reduction of Carbonyl ~ N C~ Rl 2 0 H trityl R2 H trityl R2 RED-AL~ [a 3.4 M, solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahy~ofuian (400 ml) was slowly added using 2 5 an addition funnel to a refluxing solution of the acylation product, (R)-3-(~H-indol-3-yl)-N-(2-methoxybenzyl)-2-(N-triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra, in anhydrous tetrahydrofuran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution. The reaction was quenched 3 0 after at least 20 hours by the slow addition of excess saturated Rochelle's salt solution (potassium sodium tartrate tetrahydrate). The organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No CA 022~9l0 l998-ll-23 further pllrific~tion was done and the product was used directly in the next step.
(d) Preparation of (l?v)-3-(lH-indol-3-yl)- 1-[N-(2-5 methoxybenzyl)-acetylamino]-2-(N-t~iphenylmethylamino)propane Acylation of Secondary Amine N. NH 2 N. ¦ H3 C 2 H trityl R H R
trityl To a stirring solution of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 moV
in anhydrous tetrahydrofuran (1.2 L) under a nitrogen atmosphere at 0~C
was added triethylamine (66.5 ml, 0.477 mol) and acetic anhydride (45.0 ml, 0.477 mol). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2X) and brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of (R)-3-(lH-indol-3-yl)- 1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure m ate~
- Analysis for C4oH3sN3o2:
Theory: C, 80.91; H, 6.62; N, 7.08.
Found: C, 81.00; H, 6.69; N, 6.94.
(e) Preparation of (R)-2-amino-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino~propane Deprotection CA 022~910 1998-11-23 ~ ? ~ c trityl Formic acid (9.0 ml, 238.540 mmol) was added to a stirring 5 solution of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane (14.11 g, 23.763 mmol) in anhydrous methylene chloride under a nitrogen atmosphere at 0~C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0 N hydrochloric acid. The aqueous 10 layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4X). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound (R)-2-amino-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further p~ c~tion was necessary.
(f) Preparation of (R)-2-amino-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride trityl ~2 HCl - A stirring solution of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane in two 25 volumes of methylene chloride was cooled to between -40~C and -50~C.
Anhydrous hydrogen chloride gas was added at such a rate that the temperature of the reaction mixture did not exceed 0~C. The reaction mixture was stirred for 30 minutes to one hour at 0-10~C.
To this reaction mixture was added two volumes of methyl t-30 butyl ether and the resulting mixture was allowed to stir for 30 minutes CA 022~910 1998-11-23 to one hour at 0- 10~C. The resulting crystalline solid was removed by filtration and then washed with methyl t-butyl ether. The reaction product was dried under vacuum at 50~C. (Yield >98%) Analysis for C21H2sN3O2 ~ 2 HCl:
Theory: C, 59.44; H, 6.41; N, 9.90.
Found: C, 60.40; H, 6.60; N, 9.99.
(g) Preparation of 2-((4-cyclohexyl)piperazin-1-yl)acetic acid potassium salt hydrate Cyclohexylpiperazine (10.0 g, 0.059 mol) was added to ten volumes of methylene chloride at room temperature. To this mixture was added sodium hydroxide (36 ml of a 2N solution, 0.072 mol) and tetrabutylammonium bromide (1.3 g, 0.004 mol). After the addition of the sodium hydroxide and tetrabutylammonium bromide, methyl bromoacetate (7.0 ml, 0.073 mol) was added and the reaction mixture was stirred for four to six hours. The progress of the reaction was monitored by gas chromatography.
The organic fraction was separated and the aqueous phase was back-extracted with methylene chloride. The organic phases were combined and washed twice with deionized water, once with saturated sodium bicarbonate solution, and then with brine. The organic phase was dried over magnesium sulfate and the solvents were removed in vacuo to yield methyl 2-((4-cyclohexyl)piperazin-1-yl)acetate as a yellowish oil.
The title compound was prepared by dissolving the methyl 2-((4-cyclohexyl)piperazin-1-yl)acetate (10.0 g, 0.042 mol) in ten volumes of diethyl ether. This solution was cooled to 15~C and then potassium trimethylsilanoate (5.9 g, 0.044) was added. This mixture was then stirred for four to six hours. The reaction product was removed by filtration, washed twice with five volumes of diethyl ether, then washed twice with five volumes of hexanes, and then dried in a vacuum oven for 12-24 hours at 50~C.
Analysis for Cl2H2lKN202 ~ 1.5 H20:
Theory: C, 49.63; H, 7.98; N, 9.65.
Found: C, 49.54; H, 7.72; N, 9.11.
CA 022~910 1998-11-23 (h) Preparation of (R)-2-[N-(2-((4-cyclohexyl)piperazin-1-yl)acetyl)amino] -3-(lH-indol-3-yl)- 1 - [N-(2-- methoxybenzyl)acetylamino]propane - The title compound was prepared by Iirst cooling 2-((4-cyclohexyl)piperazin-l-yl)acetic acid potassium salt to a temperature between -8~C and -15~C in 5 volumes of anhydrous methylene chloride.
To this mixture was added isobutylchloroformate at a rate such that the o temperature did not exceed -8~C. The resulting reaction mixture was stirred for about 1 hour, the temperature being maintained between -8~C
and - 15~C.
To this mixture was then added (R)-2-amino-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride at such a rate that the temperature did not exceed 0~C. Next added to this mixture was N-methyl morpholine at a rate such that the temperature did not exceed 0~C. This mixture was then stirred for about 1 hour at a temperature between -15~C and -8~C.
The reaction was quenched by the addition of 5 volumes of water. The organic layer was washed once with a saturated sodium bicarbonate solution. The organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent. To the filtrate was then added 2 equivalents of concentrated hydrochloric acid, followed by 1 volume of isopropyl alcohol. The methylene chloride was then çx~h~nged with isopropyl alcohol under vacuum by dist~ on.
The final volume of isopropyl alcohol was then concentrated to three volumes by vacuum. The reaction mixture was cooled to 20~C to 25~C and the product was allowed to crystallize for at least one hour. The desired product was then recovered by filtration and washed with sllffi~ient isopropyl alcohol to give a colorless filtrate. The crystal cake was then dried under vacuum at 50~C. MS 560 (M+l+).
lH NMR (CDCl3) o 1.09-1.28 (m, 5H), 1.64 (d, J=10 Hz, lH), 1.80-1.89 (m, 4H), 2.10 (s, 3H), 2.24-2.52 (m, 9H), 2.90 (s, 2H), 2.95 (d, J=7 Hz, lH), 3.02 (d, J=7 Hz, lH), 3.12 (dd, J=5, 14 Hz, lH), 3.77 (s, 3H), 4.01 (dd, J=10, 14 Hz, lH), 4.49 (ABq, J-17 Hz, 43 Hz, 2H), 4.56 (m, lH), 6.79-6.87 .. ...
CA 022~910 1998-11-23 (m, 3H), 7.05-7.24 (m, 4H), 7.34-7.41 (m, 2H), 7.67 (d, J=8 Hz, lH), 8.22 (s, lH).
Analysis for C33H4~NsO3:
Theory: C, 70.81; H, 8.10; N, 12.51.
Found: C, 70.71; H, 8.21; N, 12.42.
... ..
Synthesis of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin- l-yl)piperidin- l-yl)acetyl)amino]propane /~\ OCH3 ~''X~~
CH
N
\~ N~
(a) Preparation of 2-(4-(piperidin-1-yl)piperidin-1-yl)acetic acid, potassium salt 4-(Piperidin-1-yl)piperidine (1.20 kg, 7.13 mol) was added to methylene chloride (12.0 L) under a nitrogen atmosphere.
Tetrabutylammonium bromide (0.150 kg, 0.47 mol) and sodium hydroxide (1.7 L of a 5 N solution, 8.5 mol) were then added. The reaction mixture was cooled to 10-15~C and methyl bromoacetate (1.17 kg, 7.65 moV was added and the resulting mixture was stirred for a minimum of 16 hours.
Deionized water (1.2 L) was then added to the mixture and the layers separated. The aqueous layer was back-extracted with methylene chloride (2.4 L). The organic fractions were combined and 2 5 washed with deionized water (3 x 1.2 L), a saturated sodium bicarbonate solution (1.1 L) and a saturated sodium chloride solution (1.1 L). The organic fraction was then dried over anhydrous magnesium sulfate and CA 022~910 1998-11-23 concentrated to an oil on a rotary evaporator to yield 1.613 kg (93.5%) of methyl 2-(4-(piperidin-1-yl)piperidin-1-yl)acetate.
A solution of methyl 2-[4-(piperidin- 1-yl)piperidin- 1-yl]acetate (2.395 kg, 9.96 mol) in methanol (2.4 L) was added to a solution of potassium hydroxide (0.662 kg, 10.0 mol ~ 85% purity) in methanol (10.5 L) under a nitrogen atmosphere. The reaction mixture was heated to 45-50~C for a minimum of 16 hours.
A solvent exch~nge from methanol to acetone (15.0 L) was performed on the solution on a rotary evaporator. This solution was 1 o slowly cooled to room temperature over 16 hours. The resulting solids were filtered, rinsed with acetone (5.0 L) and then dried to yield 2.471 kg (93.8%) of 2-(4-(piperidin-1-yl)piperidin-1-yl)acetic acid, potassium salt.
MS 265 (M+1) (b) Preparation of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin- l-yl)piperidin- 1-yl)acetyl)amino]propane The title compound was prepared by first a-lmixing (R)-2-amino-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride (50.0 g, 0.118 mol) with 100 ml of methylene chloride under a nitrogen atmosphere.
In a second flask, under a nitrogen atmosphere, 2-(4-(piperidin-1-yl)piperidin-1-yl)acetic acid potassium salt (62.3 g, 0.236 mol) was added to 600 ml of methylene chloride. This mixture was cooled to about -10~C and stirring was continued. To this mixture isobutylchloroformate (23 ml, 0.177 mol) was added dropwise such that the temperature of the 2-(4-(piperidin-1-yl)piperidin-1-yl)acetic acid potassium salt mixture never rose appreciably.
This reaction mixture was stirred at about - 10~C for about 1.5 hours at which time the (R)-2-amino-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride/methylene chloride mixture prepared sul~ra was slowly added to the 2-(4-(piperidin-1-yl)piperidin-1-yl)acetic acidpotassium salt/isobutylchloroformate/methylene chloride solution. The resulting CA 022~5910 1998-11-23 W O 97/44035 PCTrUS97/09225 mixture was then stirred for about 1 hour at a temperature between -15~C
and -8~C.
The reaction mixture was removed from the ice bath and allowed to warm to 15-20~C and the reaction was quenched by the addition of 200 ml of water. The pH of the solution was adjusted to 2.3-2.7 by the additon of lN sulfuric acid. The layers were separated and the aqueous layer was washed with 100 ml of methylene chloride.
The organic fractions were combined and washed with water (100 ml). The water wash was back extracted with methylene chloride (50 0 ml) and combined with the aqueous fraction from above. Methylene chloride (500 ml) was added to the combined aqueous layers and the mixture was stirred at room temperature for 15 minutes as basification with 2N sodium hydroxide to a final pH of 9.8 to 10.2 was achieved.
The organic and aqueous fractions were separated. The aqueous fraction was washed with methylene chloride and the methylene chloride was added to the organic fraction. The organic fraction was then washed with a mixture of saturated sodium bicarbonate solution (100 ml) and water (50 ml). The bicarbonate wash was separated from the organic fraction and back extracted with methylene chloride (50 ml). The back 2 o extraction was combined with the methylene chloride fraction and the combined fractions were dried over magnesium sulfate. The m~gn~.~ium sulfate was removed by filtration and the volatiles were removed by vacuum distillation to yield the title product as a foam. (72.5 g, >g8%
yield). MS 559(M+1) NMR (DMSO-d6 3:2 mixture of amide rotamers) ~ 1.25-1.70 (m, lOH), 1.77-2.00 (m, 2H), 1.95 (s, 3/5-3H), 2.04 (s, 2/5-3H), 2.10-2.97 (m, 9H), 3.10-3.65 (m, 3H), 3.72 (s, 2/5-3H), 3.74 (s, 3/5-3H), 4.26-4.68 (m, 3H), 6.76-7.12 (m, 6H), 7.13-7.35 (m, 2H), 7.42-7.66 (m, 2H), 10.80 (br s, lH).
Analysis for C33H4sNsO3:
Theory: C, 70.81; H, 8.10; N, 12.51.
Found: C, 70.57; H, 8.05; N, 12.39.
CA 022~910 1998-11-23 Preparation of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin- l-yl)piperidin- l-yl)acetyl)amino]propane dihydrochloride trihydrate oCH3 ~ I
~N~ C=~3 + > H o=~
N~--N
~ N~N- CH2 ~ CO2 K+ 2 HCl Under a nitrogen atmosphere 2-(4-(piperidin-1-yl)piperidin-l-yl)acetic acid, potassium salt (0.75 kg, 2.84 mol) was added to methylene chloride (7.5 L). The resulting mixture was cooled to -15 to -8~C and isobutyl chloroformate (0.29 kg, 2.12 mol) was added at such a rate so as to maintain the temperature of the reaction mixture below -8~C.
After the addition the resulting reaction mixture was stirred for 90 minutes between -15 and -8~C.
The reaction mixture was then cooled to -35~C and solid (R)-2-amino-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyVamino]propane dihydrochloride (0.60 kg, 1.14 mol) was added at such a rate that the reaction temperature was maintained at less than -20~C. After the addition, the reaction mixture was stirred for about one hour with the temperature being maintained between -37~C and -20~C. The reaction 2 0 was quenched by the addition of (i~icmi7ed water (7.5 L). The reaction mixture was basified to pH 12.8-13.2 by the addition of 5 N sodium hydroxide. The aqueous fraction was removed and retained. Additional deionized water (3.75 L) was added to the organic fraction as was sufficient 5 N sodium hydroxide to re-adjust the pH to 12.8-13.2.
2 5 The two aqueous fractions were combined, back-extracted with methylene chloride (1.5 L) and then discarded. The organic fractions were combined and washed with deionized water (4 x 3.5 L). These CA 022~910 1998-11-23 WO 97/44035 PCTtUS97/09225 extracts were comhined, back-extracted with methylene chloride (1.5 L), and then discarded. The two organic layers were combined and washed with a saturated sodium chloride solution (3.7 L).
The organic fraction was dried over anhydrous magnesium 5 sulfate, filtered, and solvent exchanged from methylene chloride to acetone (3.75 L) on a rotary evaporator. An aqueous solution of hydrochloric acid (0.48 L of 6 N solution, 2.88 mol) and seed crystals (2 g) were added and mixture was stirred for 30-90 minutes. Acetone (13.2 L) was then added and the slurry stirred for one hour. The resulting solid was then filtered, washed with acetone (2 x 1.4 L), and dried to yield 633 g (90%) of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin- 1-yl)piperidin- 1 -yl)acetyl)amino]propane dihydrochloride trihydrate.
The biological efficacy of a compound believed to be effective as a tachykinin receptor antagonist may be confirmed by employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK- 1 and NK-2 receptor sites.
2 o Assays useful for evaluating tachykinin receptor antagonists are we~l known in the art. See~ e.~., J. Jukic, et al., Life Sciences, 49:1463-1469 (1991); N. Kucharczyk, et al., Journal of Medicinal Chemistry.
36:1654-1661 (1993); N. Rouissi, et al., Biochemical and Biophysical Research Communications. 176:894-901 (1991).
NK-1 Receptor Bindin~ Assay Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan, et al., Journal o~ ImmunoloFy, 133:3260-3265 (1984). In this assay an aliquot of IM9 cells (1 x 106 cells/tube in RPMI 1604 medium supplemented with 10%
fetal calf serum) was incubated with 20 pM l2~I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4~C.
CA 022~910 1998-11-23 The IM9 cell line is a well-characterized cell line which is readily available to the public. See. e.F.. Annals of the New York Academy of Science. 190: 221-234 (1972); Nature (London)~ 251:443-444 (1974); Proceedin~s of the National Academy of Sciences (IJSA)~ 71:84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 ,Lg/ml gent~mi( in sulfate and 10% fetal calf serum.
The reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethyl~nimine. Specific binding of labeled substance 0 P was determined in the presence of 20 nM unlabeled ligand.
Many of the compounds employed in the methods of the present invention are also effective antagonists of the NK-2 receptor.
NK-2 Receptor Bindin~ Assay The CHO-hNK-2R cells, a CHO-derived cell line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per cell, were grown in 75 cm2 flasks or roller bottles in minim~l essential medium (alpha modi~ication) with 10% fetal bovine serum. The gene sequence of the human NK-2 receptor is given in N.P. Gerard, et al., Journal of Biolo~ir.~l Chemistry. 265:20455-20462 (1990).
For preparation of membranes, 30 confluent roller bottle cultures were dissociated by washing each roller bottle with 10 ml of Dulbecco's phosphate buffered saline (PBS) without calcium and magnesium, followed by addition of 10 ml of enzyme-free cell dissor.i~tion solution (PBS-based, from Specialty Media, Inc.). After an additional 15 minutes, the dissociated cells were pooled and centrifuged at 1,000 RPM
for 10 minutes in a ~linir.~l centrifuge. Membranes were prepared by homogeni7.~tion of the cell pellets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar~ homogenizer for 10-15 seconds, followed by centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a Beckm~n JA-14~ rotor. The pellets were washed once using the above procedure. and the final pellets were resuspended in 100-120 ml 50 mM
CA 022~910 1998-11-23 Tris buffer, pH 7.4, and 4 ml aliquots stored frozen at -70~C. The protein concentration of this preparation was 2 mg/ml.
For the receptor binding assay, one 4-ml ali~uot of the CH0-hNK-2R membrane preparation was suspended in 40 ml of assay buffer cont~ining 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02%
bovine serum albumin (BSA) and 4 llg/ml chymostatin. A 200 ~11 volume of the homogenate (40 ,ug protein) was used per sample. The radioactive ligand was 1125I]iodohistidyl-neurokinin A (New F',ngl~nd Nuclear, NEX-252), 2200 Ci/mmol. The ligand was prepared in assay buffer at 20 0 nCi per lO0 ~,11; the final concentration in the assay was 20 pM.
Non-specific binding was determined using 1 ~IM eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration-response curve.
All samples and standards were added to the incubation in 10 ~LI dimethylslllfoxi-l~ (DMSO) for screening (single dose) or in 5 ~1 DMSO for ICso determin~tions. The order of additions for incubation was 190 or 195 ~1 assay buffer, 200 111 homogenate, 10 or 5 ~1 s~ le in DMSO, 100 ~1 radioactive ligand. The samples were incubated 1 hr at room temperature and then filtered on a cell harvester through filters 2 o which had been presoaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12 x 75 mm polysly~ e tubes and counted in a gamma counter.
Upon a showing that a compound has activity as a tachykinin receptor antagonist, assays may be used to demonstrate the ability of such a compound to control or treat hypertension. Typical such assays are described below.
In Vivo Assays Assay 1 The procedure as set out in Farhat, et al., J PET, 261: 686 (1992) (herein incorporated by reference) is carried out. Four to thirty 3 5 rats are sacrificed. The lungs are exsanguinated by perfusion via the CA 022~910 1998-11-23 hepatic pulmonary vein. The pulmonary artery is cannulated as is the trachea to maintain ventilation and the pulmonary cannula is connected to the perfusion line and the whole ventilated lung is removed and suspended in a perfusion chamber. The effects of vasoconstrictor 5 substances on perfusion pressure of the isolated perfused lung is - measured using a Statham pressure transducer. The increase in perfusion pressure (vasoconstriction) induced by thromboxane mimetics in the presence of estradiol is det~rmined and the ability to block the thromboxane effects with a trst compound or the estradiol potentiation of 0 the thromboxane effects will be determined.
Activity of compounds having activity as tachykinin receptor antagonists is illustrated by a reduction in pulmonary perfusion pressure increase following thromboxane mimetic stim~ t.ion 15 Assay 2 Between five and fifty rats are ~rlmini.~tered a single IV dose of monocrotaline pyrrole (3.5 mg/kg) and pulmonary disease is evaluated by histopathology, accumulation of fluorescein conjugated dextran in bronchial alveolar lavage fluid (as a measurement of pulmonary edema), 2 0 and measurements of pulmonary artery pressure using a Standtham P23ID pressure transducer (:Reindel et al., Tox and Applid. Pharm, 106:
179-200 (1990), incorporated herein by reference. A test compound is allmini~tered and the effect on the rats are evaluated.
Activity of compounds having activity as tachykinin receptor 2 5 antagonists is illustrated by a reduction in uptake of fluorescein conjugated dextran from bronchial alveolar lavage fluids of ~nim~
treated with a compound of formula 1, indicating a reduction in pulmonary edema. Rat lungs will also be removed from thorax, perfused with modified Karnovskys fixitive and processed for histopathology. A
3 o reduction in t~irkening of the arterial walls in treated rats is evidence for the protective role of compounds of formula 1 as is a decrease in pulmonary artery pressure.
While it is possible to aflmini.~ter a compound employed in 3 5 the methods of this invention directly without any formulation, the CA 022~910 1998-11-23 compounds are usually ~llmini.qtered in the form of ph~rm~ceutical compositions comprising a ph~rm~ceutically acceptable excipient and at least one active ingredient. These compositions can be a-lmini.~tered by a variety of routes including oral, rectal, trans(lerm~l, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See. e.~., REMINGTON'S PHARMACEUTICAL SCIENCES, (16th 0 ed. 1980).
In m~king the compositions employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition.~ can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments cont~inin~ for 2 o example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a fôrmulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to 2 5 combining with the other ingredients. If the active compound is substantially insoluble, it or-lin~rily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
3 0 Some examples of sllit~hle excipients include lactose, dextrose, sucrose, sorbitol, m~nnitol, starches, gum ~c~ci~, calcium phosphate, ~1gin~tes, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include:
3 5 lubricating agents such as talc, magnesium stearate, and mineral oil;
CA 022~910 1998-11-23 wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so ~ as to provide quick, sustained or delayed release of the active ingredient 5 after a(lmini.~tration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage cont~ining from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient. The term "unit 10 dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other m~mm~ , each unit cont~ining a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable ph~rm~qceutical excipient.
The active compounds are generally effective over a wide dosage range. For examples, dosages per day normally fall within the range of about 0.01 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 0.1 to about 15 mg/kg/day, in single or divided dose, is especially preferred. However, it will be understood that 2 0 the amount of the compound actually ~3(1mini.~tered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of atlmini.~tration, the actual compound or compounds a(lmini~tered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and 2 5 therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into 3 0 several smaller doses for a(lmini~tration throughout the day.
WO 97/44035 PC'rlUS97/09225 Formulation Preparation 1 Hard gelatin capsules cont~ining the following ingredients are prepared:
Quantity In~redient (m ~/capsule) Active Ingredient(s) 30.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin 15 capsules in 340 mg quantities.
Formulation Preparation 2 A tablet formula is prepared using the ingredients below:
Quantity In~redient (m~/tablet) Active Ingredient(s) 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 240 mg.
Formulation Preparation 3 2 o A dry powder inhaler formulation is prepared cont~ining the following components:
Tneredient W~ ht %
Active Ingredient(s) 5 Lactose 95 The active mixture is mixed with the lactose and the mixture is added to a dry powder inh~ling appliance.
Formulation Preparation 4 Tablets, each cont~ining 30 mg of active ingredient, are prepared as follows:
-~~ Quantity Tn~redient (m~/tablet) Active Ingredient(s) 30.0 mg o Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 ~n F
Total 120 mg 2 5 The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60~C and passed through a 16 mesh U.S. sieve. The sodium 3 o carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mi~ing, are compressed on a tablet m~hine to yield tablets each w~i ghin g 120 mg.
3 5 Formulation Preparation 5 CA 022~9l0 l998-ll-23 Capsules, each cont~ining 40 mg of medicament are made as follows:
Quantity Tn~redient (m~/car~sule) Active Ingredient(s) 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mF
Total 150.0 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
Formulation Preparation 6 Suppositories, each cont~ining 25 mg of active ingredient are made as follows:
TT~redient Amount 2 5 Active Ingredient(s) 25 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient(s) is passed through a No. 60 mesh 3 0 U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necess2ry. The mixture is then poured into a suppository mold of nomin~l 2.0 g capacity and allowed to cool.
.
Formulation Preparation 7 Suspensions, each cont~ining 50 mg of medicament per 5.0 5 ml dose are made as follows:
Tn~redient Amount Active Ingredient(s) 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v.
Purified water to 5.0 ml The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a 2 5 previously made solution of the microcrystal~ine cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sllffir.ient water is then added to produce the required volume.
.
Formulation Preparation 8 Capsules, each cont~ining 15 mg of medicament, are made as 5 follows:
Quantity InFredient(mFlcapsule) Active Ingredient(s)15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mF
Total 425.0 mg The active ingredient(s), cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
Formulation Preparation 9 An intravenous form~tion may be prepared as follows:
InFre~ nt Quantity Active Ingredient(s) 250.0 mg Isotonic saline 1000 ml Formulation PreparatioII 10 A topical formulation may be prepared as follows:
Tn Fredient Quantity Active Ingredient(s) 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to 100 g The white soft paraffin is heated until molten. The liquid paraffin and 15 emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
CA 022~9l0 l998-ll-23 W O 97/44035 PCTrUS97109225 FormulationPre~aration 11 Sublingual or buccal tablets, each cont~ining lO mg of active ~ ingredient, may be prepared as follows:
Quantity Tn~redient Per Tablet Active Ingredient(s) 10.0 mg 0 Glycerol 2 10.5 mg Water 143.0 mg Sodium Citrate 4.5 mg Polyvinyl Alcohol 26.5 mg Polyvinylpyrrolidone 15.5 m F
Total 410.0 mg The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maint~ining the temperature at about 9O~C. VVhen the polymers have gone into solution, the solution is cooled to about 50-55~C and the 2 5 medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-cont~ining diffusion matrix having a thickness of about 2-4 mm. This diffusion m~trix is then cut to form individual tablets having the appropriate size.
3 0 Another preferred formulation employed in the methods of the present invention employs transrlerm~l delivery devices ("patches").
Such trans~rm~l patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transd~rm~l patches for 3 5 the delivery of ph ~rm ~ceutical agents is well known in the art. See~ e.~., CA 022~910 1998-11-23 U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on (lem7~nd delivery of ph~rm~reutical agents.
Frequently, it will be desirable or necessary to introduce the 5 ph~rm~ceutical composition to the brain, either directly or indirectly.
Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is described in U.S.
Patent 5,011,472, issued April 30, 1991, which is herein incorporated by reference.
Indirect techniques, which are generally plefelled, usually involve form~ ng the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
15 Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and p~imary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Altematively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which 2 o can transiently open the blood-brain barrier.
The type of formulation employed for the a-lmini.~tration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of 2 5 pharmacokinetic profile desired from the route of a-lmini~tration and the compound(s), and the state of the patient.
Priority Claim This application claims the benefit of United States Provisional Patent application 60/018266, filed May 24, 1996.
B~(~k~round of the Invention Tachykinins are a family of peptides which share a common amidated carboxy termin~l sequence. Substance P was the first peptide of this family to be isolated, although its pllrific~tion and the det~rmin~tion of its primary sequence did not occur until the early 1970's.
Between 1983 and 1984 several groups reported the isol~tion of two novel m~mm~ n tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin a), and neurokinin B (also known as neuromedin K and neurokinin ~). See, J.E. Maggio, Peptides, 6 (Supplement 3):237-243 (1985) for a review of these discoveries.
Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
The m~mm~ n tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
Substance P is believed inter alia to be involved in the neurotr~n.~mi.~.~ion of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as in~qmm~tory bowel disease. Tachykinins CA 022~910 1998-11-23 have also been implicated as playing a role in numerous other maladies, as discussed infra.
Tachykinins play a major role in mediating the s~n.~ion and tr~nsmi.s.~ion of pain or nociception, especially migraine headaches.
see~ e.r., S.L. Shepheard, et al., British Journal of PharmacoloFy. 108 20 (1993); S.M. Moussaoui, et al., European Journal of Ph~rm?,colo~y, 238:421-424 (1993); and W.S. Lee, et al., British Journal of Pharmacolo~y, 112:920-924 (1994).
In view of the wide number of ~linic~l m~l~(lies associated 0 with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these ~linic:~l conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited ph :~rm$l~eutical utility because of their metabolic instability.
Recent public~tionq have described novel classes of non-peptidyl tachykinin receptor antagonists which generally have greater oral bioav~ hility and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in United States Patent 5,491,140, issued February 13, 1996; United States Patent 5,328,927, issued July 12, 1994; United States Patent 5,360,820, issued November 1, 1994; United States Patent 5,344,830, issued September 6, 1994; United States Patent 5,331,089, issued July 19, 1994; European Patent Pllhlic~tion 591,040 A1, published April 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published January 20, 1994; Patent Cooperation Treaty publication WO 94/04494, published March 3, 1994;
Patent Cooperation Treaty publication WO 93/011609, published January 21, 1993; Canadian Patent Application 2154116, published January 23, 1996; European Patent Publication 693,489, published January 24, 1996;
and Canadian Patent Application 2151116, published December 11, 1995.
Patent Cooperation Treaty Patent Publication WO 96/11000, published Ap~il 18, 1996 and European Patent Publication EP 705,600, published April 10, 1996, describe a synergistic effect on the combination of a serotonin agonist and a tachykinin receptor antagonist in treating migraine. United States Patent Application 08/387,056, filed February CA 022~910 1998-11-23 W097/44035 PCT~S97/09225 10, 1995, describes a synergistic effect on the combination of a serotonin agonist and a tachykinin receptor antagonist in treating a variety of psychiatric disorders. United States Patent Application 08/408,238, filed ~ March 22, 1995, describes a synergistic effect on the comhin~tion of a serotonin agonist and a tachykinin receptor antagonist in treating a variety of types of pain and nociception. United States Patent Application 60/000074, filed June 8, 1995, describes a synergistic effect on the comhin?.tion of a serotonin agonist and a tachykinin receptor antagonist in treating the common cold or allergic rhinitis.
0 European Patent Application 0 577 394, published January 5,1994, teaches a series of morpholinyl and thiomorpholinyl tachykinin receptor antagonists. Patent Cooperation Treaty Patent Application WO
95/18124, published July 6,1995, teaches another series of substituted morpholines for use as tachykinin receptor antagonists. None of these references, nor any comhin~tion of them, teach the tachyl~inin receptor antagonists of the present invention.
Pulmonary hypertension represents a serious, life threatening spectrum of diseases of multiple etiology. These include congenital abnormalities of the lung, thorax and diaphragm, congenital or 2 o acquired valvular or myocardial disease, obstructive lung disease, and can be a complication of autoimmune diseases, vasculitis and collagen based diseases (Rubin, Chest. 104: 236,1993). Patients with pulmonary hypertension frequently present with symptoms including dyspnea, fatigue, syncope, and chest pain, and have increased pulmonary artery 2 5 pressure and demonstrate prominence of the main pulmonary artery, hilar vessel enlargement and decreased peripheral vessels on chest radiographs ~ich, Ann. Internal. Med.. 107: 216,1987).
While pulmonary hypertension has multiple etiologies, primary pulmonary hyperten~ion appears to involve an autoimmune 3 0 component and has been reported as a complication in patients with mixed connective tissue disease, rheumatoid arthritis, Sjogren's syndrome, systemic sclerosis and lupus (Sato, Hum. Path., 24: 199,1993).
Primary pulmonary hypertension occurs in females 1.7 times more frequently than males with the greatest pre(lomin~nce between the third 3 5 and fourth decades of life (Rich, Ann. Internal. Med., 107: 216,1987). The . , ,, .. .. ,_ CA 022~910 1998-11-23 W097/44035 PCTrUS97/09225 increased incidence of primary pulmonary hypertension in women of child bearing age as well as the ~linic~l observations that the disease can be exacerbated by pregnancy and oral contraceptives ~ller, Ann. Rheum.
~.46: 159,1987; and cited in Farhat et al., J PET., 261: 686,1992) 5 suggests a role for estrogen in the disease process. To this extent, Farhat et al. have demonstrated that estradiol potentiates the vasopressor response to a thromboxane mimetic in perfused rat lungs (J PET, 261:
686,1992). However, the role of estrogen in pulmonary hypertension is complex and may be dependent on the etiology of the disease process. In 0 a rat model of pulmonary hypertension induced by injection of monocrotaline pyrrole (Reindel, Tox. Ap~l. Pharm., 106: 179,1990) progressive pulmonary hypertension, right ventricular hypertrophy and interstitial edema around the large airways and blood vessels becomes apparent, simil~r to the pathology observed in man. Estradiol treatment 15 decreased right ventricular hypertrophy and prevented interstitial edema in this model (Farhat ~1., Br. J. Pharm., 110: 719,1993) as well as attenuating the hypoxic vasoconstrictive response in isolated sheep lungs (Gordon et al., J. Appl. Physiol., 61: 2116,1986).
Current therapy for pulmonary hypertension is inadequate 2 0 and is largely dependent on the use of vasodilators, diuretics, and anticoagulants ~ubin, DruFs, 43: 37,1992; Palevsky, JAMA. 265:1014, 1991). Vasodilators are effective in only a small subpopulation of patients with primary pulmonary hypertension and is complicated by systemic hypotensive responses. Prostacyclin infusion and high dose calcium 2 5 channel blockers are also being used with limited efficacy. Heart-lung and single lung transplantation have been used on patients which do not respond to vasodilator therapy, however, due to surgical morbidity and mortality, this approach is usually limited to those patients who continue to deteriorate despite aggressive therapy at centers experienced in 3 o mZ~nz~gement of this disease. Patients frequently die of right heart failureand those individuals which have signs of right heart failure have a mean survival of 6-12 months ~ubin, Dru~, 43: 37,1992).
Therefore, pulmonary hypertensive diseases are characterized by inadequate therapies, necessity of organ transplantation 3 5 and poor prognosis, and a need exists for new therapies.
CA 022.7.7910 1998 - 1 1 - 23 W O 97/44035 PCTrUS97/09225 Summary of the Invention This invention provides methods of inhibiting pulmonary 5 hypertensive disease in a m~mm~l which comprise a-lmini.~tering to a m~mm?ll in need thereof an effective amount of a compound having activity as a tachykinin receptor antagonist.
Detailed Description and Plerelled F,mhodiments The terms and abbrevi~tion.~ used in the instant preparations and examples have their normal me~ning.s unless otherwise designated. For example "~C" refers to degrees Celsius; "N" refers to normal or normality; "mmol" refers to millimole or millimoles; "g" refers to 5 gram or grams; "ml" means milliliter or milliliters; "L" means liter or liters; "M" refers to molar or molarity; "MS" refers to mass spectrometry;
"IR" refers to infrared spectroscopy; and "NMR" refers to nuclear magnetic resonance spectroscopy.
The term "inhibit" includes its generally accepted meaning 2 0 which includes prohibiting, preventing, restraining, and slowing, stopping or reversing progression, severity or a resultant symptom. As such, the present method includes both medical therapeutic and/or prophylactic 1mini.~tration, as appropriate.
Pulmonary hypertensive diseases include all conditions 2 5 characterized by an increase in the blood pressure within the blood vessels supplying the lungs and can increase the complications associated with pulmonary embolism, heart failure, valvular disease, chronic lung diseases and autoimmunity.
- The methods of the present invention employ various 3 0 tachykinin receptors. In recent publications many different groups of non-peptidyl tachykinin receptor antagonists have been described. The present invention, however, is not limited to any one of the specific compound or class of compound. The present invention encompasses any compound effective as a tachykinin receptor antagonist.
Patent Cooperation Treaty publication WO 94/01402, published January 20, 1994, rles~ribes a series of compounds best typified by the following compound.
~CF3 H3C~N~ ~NH
~N~J~H~ \CF3 O
European Patent Pllblic~tion 591,040 Al, published April 6, 1994 describes a series of compounds typified by the following compound:
CH
H3 C CH3 ~l C 1 Cl where A iS a ph~rm~(~.eutically acceptable anion.
Patent Cooperation Treaty pllhlic~tion WO 94/04494, published March 3, 1994, describes a series of compounds typified by the 15 following compound.
H3C~-- C ~
WO 97/44035 rCT/US97/09225 Patent Cooperation Treaty publication WO 93/01169, published January 21, 1993, describes a series of compounds typified by the following compound.
--~CF3 H O'~
~ CF3 Another group of tachykinin receptor antagonists is characterized by the compound of the formula:
1 o ~N~OCH 3 having the ~le.cign~tion (~)-CP 96345. These compounds and their syntheses are described in E.J. Warawa, et al., Journal of Me~licinal Chemistry. 18:357 (1975).
Yet another group of tachykinin receptor antagonists is characterized by the compound of the formula:
NH ~
NJ~J
o~ OCH3 H ~=~
having the ~le.cign~tion RP 67580. These compounds and their syntheses are described in C. Garret, et al., Proceedin~s of the National Academy of Sciences (IJSA)~ 88: 10208- 10211 (1991) and the references cited therein.
Patent Cooperation Treaty publication WO 94/07843 describes a series of cyclohexylamine derivatives typified by the following compound ~.~'\~~ ~ CH~
which are useful as tachykinin receptor antagonists.
Another group of compounds useful as tachykinin receptor antagonists is typified by the following compound.
CA 022~910 1998-11-23 ~¢~ NN\>----~
H3 C¦ Br CH3 \~
The synthesis of these compounds is described in European Patent Application Pllhlic~tion 694,535, published January 31, 1996.
The compound (S)-1-(2-methoxybenzyl)-2-[(4-phenyl-1-piperazinyl)methyl]-4-(lH-indol-3-ylmethyl)-2-imidazoline and related compounds are (le.s~rihed in European Patent Pllhlic~t.ion 699,665, published March 6, 1996. This compound has the following structure.
H
N~
The above groups of compounds are only illustrative of the tachykinin receptor antagonists which are currently under development.
This listing of groups of compounds is not meant to be comprehensive, the 15 methods of the present invention may employ any tachykinin receptor antagonist and is not limited to any particular class of compound.
A most preferred class of tachykinin receptor antagonists are those compounds of the following structure ., ,, ........ , .. ~ .. ., .. , .. .. ,.. . . . ,. . ~
H o=<~ CH3 R2 CH2 ~
~/Y
where R1 and R2 are independently selected from the group 5 consisting of hydrogen, methyl, methoxy, chloro, and trifluoromethyl, with the proviso that no more than one of Rl and R2 can be hydrogen; and Yis N--O N--N~ N
CH--N~ CH--O , CH {~
N-Ra, or CH-NRbRC
where Ra, Rb, and Rc are independently selected from the group consisting of hydrogen and C1-C6 alkyl;
or a pharmaceutically acceptable salt or solvate thereo~ The syntheses of these compounds are (lesrrihed in Patent Cooperation Treaty Pllhlic~tions WO 95/14017, published May 26, 1995, and WO 96/01819, published 2 o January 25, 1996. The syntheses of two typical compounds from this class are detailed in~
CA 022~910 1998-11-23 Synthesis of (R)-2-[N-(2-((4-cyclohexyl)piperazin-1-yl)acetyl)amino]-3-(lH-indol- 3 -yl) - 1- [N - (2 -methoxybenzyl) acetylamino]prop ane /=\ OCH3 C~2 N
~ ~N ~O
(a) Preparation of (R)-3-(lH-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid [N-trityltryptophan]
Tritylation ~OH ~ ~~
H H trityl Chlorotrimethylsilane (70.0 ml, 0.527 mol) was added at a moderate rate to a stirred slurry of D-tryptophan (100.0 g, 0.490 mol) in 15 anhydrous methylene chloride (800 ml) under a nitrogen atmosphere.
This mixture was continuously stirred for 4.Z5 hours. Triethylamine - (147.0 ml, 1.055 mol) was added, followed by the arl(lition of a solution of triphenylmethyl chloride (147.0 g, 0.552 mol) in methylene chloride (400 ml) using an adllition funnel. The mixture was stirred at room 2 0 temperature, under a nitrogen atmosphere for at least 20 hours. The reaction was quenched l~y the addition of methanol (500 ml).
The solution was concentrated on a rotary evaporator to near dryness and the mixture was redissolved in methylene chloride and ethyl acetate. An aqueous work-up involving a 5% citric acid solution (2X) and CA 022~910 1998-11-23 brine (2X) was then performed. The organic layer was dried over anhydrous sodium sulfate, f;ltered, and concentrated to dryness on a rotary evaporator. The solid was dissolved in hot diethyl ether followed by the addition of hexanes to promote crystallization. By this process 173.6 g (0.389 mol) of analytically pure (R)-3-(lH-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid was isolated as a white solid in two crops giving a total of 79% yield.
FDMS 446 (M+).
H NMR (DMSO-d6) ~ 2.70 (m, lH), 2.83 (m, 2H), 3.35 (m, lH), 6.92-7.20 0 (mj 12H), 7.30-7.41 (m, 8H), 10.83 (s, lH), 11.73 (br s, lH).
Analysis for C30H26N2o2:
Theory: C, 80.69; H, 5.87; N, 6.27.
Found: C, 80.47; H, 5.92; N, 6.10.
(b) Preparation of (R)-3-(lH-indol-3-yl)-N-(2-methoxybenzyV-2-~-triphenylmethylamino)propanamide Coupling ~ OH ~ ~ H ~C~
H trityl H trityl R
To a stirred solution of (R)-3-(lH-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid (179.8 g, 0.403 mol), 2-methoxybenzylamine (56.0 ml, 0.429 mol), and hydroxybenzot~ole hydrate (67.97 g, 0.429 mol) in anhydrous tetrahydrofuran (1.7 L) and anhydrous N,N-dimethylformamide (500 ml) under a nitrogen atmosphere at 0~C, were added triethylamine (60.0 ml, 0.430 mol) and 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride (82.25 g, 0.429 mol). The mixture was allowed to warm to room temperature under 30 a nitrogen atmosphere for at least 20 hours. The mixture was concentrated on a rotary evaporator and then redissolved in methylene chloride and an aqueous work-up of 5% citric acid solution (2X~, saturated sodium bicarbonate solution (2X), and brine (2X) was performed. The CA 022~9l0 l998-ll-23 organic layer was dried over anhydrous sodium sulfate and concentrated to dryness on a rotary evaporator. The desired product was then recrystallized from hot ethyl acetate to yield 215.8 g (0.381 mol, 95%) of analytically pure material.
5 FDMS 565 ~+).
H NMR (CDCl3) ~ 2.19 (dd, J=6.4 Hz, ~o=14.4 Hz, lH), 2.64 (d, J=6.5 Hz, lH), 3.19 (dd, J=4.3 Hz, ~=14.4 Hz, lH), 3.49 (m, lH), 3.63 (s, 3H), 3.99 (dd, J=5.4 Hz, ~o=14.2 Hz, lH), 4.25 (dd, J=7. 1 Hz, ~v=14.2 Hz, lH), 6.64 (d, J=2.1 Hz, lH), 6.80 (d, J=8.2 Hz, lH), 6.91 (t, J-7.4 Hz, lH), 7.06-7.38 (m, 21 H), 7.49 (d, J=7.9 Hz, lH), 7.75 (s, lH).
Analysis for C38H3sN3O2:
Theory: C, 80.68; H, 6.24; N, 7.43.
Found: C, 80.65; H, 6.46; N, 7.50.
(c) Preparation of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)amino] -2-(N-triphenylmethylamino)propane Reduction of Carbonyl ~ N C~ Rl 2 0 H trityl R2 H trityl R2 RED-AL~ [a 3.4 M, solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahy~ofuian (400 ml) was slowly added using 2 5 an addition funnel to a refluxing solution of the acylation product, (R)-3-(~H-indol-3-yl)-N-(2-methoxybenzyl)-2-(N-triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra, in anhydrous tetrahydrofuran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution. The reaction was quenched 3 0 after at least 20 hours by the slow addition of excess saturated Rochelle's salt solution (potassium sodium tartrate tetrahydrate). The organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No CA 022~9l0 l998-ll-23 further pllrific~tion was done and the product was used directly in the next step.
(d) Preparation of (l?v)-3-(lH-indol-3-yl)- 1-[N-(2-5 methoxybenzyl)-acetylamino]-2-(N-t~iphenylmethylamino)propane Acylation of Secondary Amine N. NH 2 N. ¦ H3 C 2 H trityl R H R
trityl To a stirring solution of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 moV
in anhydrous tetrahydrofuran (1.2 L) under a nitrogen atmosphere at 0~C
was added triethylamine (66.5 ml, 0.477 mol) and acetic anhydride (45.0 ml, 0.477 mol). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2X) and brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of (R)-3-(lH-indol-3-yl)- 1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure m ate~
- Analysis for C4oH3sN3o2:
Theory: C, 80.91; H, 6.62; N, 7.08.
Found: C, 81.00; H, 6.69; N, 6.94.
(e) Preparation of (R)-2-amino-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino~propane Deprotection CA 022~910 1998-11-23 ~ ? ~ c trityl Formic acid (9.0 ml, 238.540 mmol) was added to a stirring 5 solution of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane (14.11 g, 23.763 mmol) in anhydrous methylene chloride under a nitrogen atmosphere at 0~C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0 N hydrochloric acid. The aqueous 10 layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4X). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound (R)-2-amino-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further p~ c~tion was necessary.
(f) Preparation of (R)-2-amino-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride trityl ~2 HCl - A stirring solution of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane in two 25 volumes of methylene chloride was cooled to between -40~C and -50~C.
Anhydrous hydrogen chloride gas was added at such a rate that the temperature of the reaction mixture did not exceed 0~C. The reaction mixture was stirred for 30 minutes to one hour at 0-10~C.
To this reaction mixture was added two volumes of methyl t-30 butyl ether and the resulting mixture was allowed to stir for 30 minutes CA 022~910 1998-11-23 to one hour at 0- 10~C. The resulting crystalline solid was removed by filtration and then washed with methyl t-butyl ether. The reaction product was dried under vacuum at 50~C. (Yield >98%) Analysis for C21H2sN3O2 ~ 2 HCl:
Theory: C, 59.44; H, 6.41; N, 9.90.
Found: C, 60.40; H, 6.60; N, 9.99.
(g) Preparation of 2-((4-cyclohexyl)piperazin-1-yl)acetic acid potassium salt hydrate Cyclohexylpiperazine (10.0 g, 0.059 mol) was added to ten volumes of methylene chloride at room temperature. To this mixture was added sodium hydroxide (36 ml of a 2N solution, 0.072 mol) and tetrabutylammonium bromide (1.3 g, 0.004 mol). After the addition of the sodium hydroxide and tetrabutylammonium bromide, methyl bromoacetate (7.0 ml, 0.073 mol) was added and the reaction mixture was stirred for four to six hours. The progress of the reaction was monitored by gas chromatography.
The organic fraction was separated and the aqueous phase was back-extracted with methylene chloride. The organic phases were combined and washed twice with deionized water, once with saturated sodium bicarbonate solution, and then with brine. The organic phase was dried over magnesium sulfate and the solvents were removed in vacuo to yield methyl 2-((4-cyclohexyl)piperazin-1-yl)acetate as a yellowish oil.
The title compound was prepared by dissolving the methyl 2-((4-cyclohexyl)piperazin-1-yl)acetate (10.0 g, 0.042 mol) in ten volumes of diethyl ether. This solution was cooled to 15~C and then potassium trimethylsilanoate (5.9 g, 0.044) was added. This mixture was then stirred for four to six hours. The reaction product was removed by filtration, washed twice with five volumes of diethyl ether, then washed twice with five volumes of hexanes, and then dried in a vacuum oven for 12-24 hours at 50~C.
Analysis for Cl2H2lKN202 ~ 1.5 H20:
Theory: C, 49.63; H, 7.98; N, 9.65.
Found: C, 49.54; H, 7.72; N, 9.11.
CA 022~910 1998-11-23 (h) Preparation of (R)-2-[N-(2-((4-cyclohexyl)piperazin-1-yl)acetyl)amino] -3-(lH-indol-3-yl)- 1 - [N-(2-- methoxybenzyl)acetylamino]propane - The title compound was prepared by Iirst cooling 2-((4-cyclohexyl)piperazin-l-yl)acetic acid potassium salt to a temperature between -8~C and -15~C in 5 volumes of anhydrous methylene chloride.
To this mixture was added isobutylchloroformate at a rate such that the o temperature did not exceed -8~C. The resulting reaction mixture was stirred for about 1 hour, the temperature being maintained between -8~C
and - 15~C.
To this mixture was then added (R)-2-amino-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride at such a rate that the temperature did not exceed 0~C. Next added to this mixture was N-methyl morpholine at a rate such that the temperature did not exceed 0~C. This mixture was then stirred for about 1 hour at a temperature between -15~C and -8~C.
The reaction was quenched by the addition of 5 volumes of water. The organic layer was washed once with a saturated sodium bicarbonate solution. The organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent. To the filtrate was then added 2 equivalents of concentrated hydrochloric acid, followed by 1 volume of isopropyl alcohol. The methylene chloride was then çx~h~nged with isopropyl alcohol under vacuum by dist~ on.
The final volume of isopropyl alcohol was then concentrated to three volumes by vacuum. The reaction mixture was cooled to 20~C to 25~C and the product was allowed to crystallize for at least one hour. The desired product was then recovered by filtration and washed with sllffi~ient isopropyl alcohol to give a colorless filtrate. The crystal cake was then dried under vacuum at 50~C. MS 560 (M+l+).
lH NMR (CDCl3) o 1.09-1.28 (m, 5H), 1.64 (d, J=10 Hz, lH), 1.80-1.89 (m, 4H), 2.10 (s, 3H), 2.24-2.52 (m, 9H), 2.90 (s, 2H), 2.95 (d, J=7 Hz, lH), 3.02 (d, J=7 Hz, lH), 3.12 (dd, J=5, 14 Hz, lH), 3.77 (s, 3H), 4.01 (dd, J=10, 14 Hz, lH), 4.49 (ABq, J-17 Hz, 43 Hz, 2H), 4.56 (m, lH), 6.79-6.87 .. ...
CA 022~910 1998-11-23 (m, 3H), 7.05-7.24 (m, 4H), 7.34-7.41 (m, 2H), 7.67 (d, J=8 Hz, lH), 8.22 (s, lH).
Analysis for C33H4~NsO3:
Theory: C, 70.81; H, 8.10; N, 12.51.
Found: C, 70.71; H, 8.21; N, 12.42.
... ..
Synthesis of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin- l-yl)piperidin- l-yl)acetyl)amino]propane /~\ OCH3 ~''X~~
CH
N
\~ N~
(a) Preparation of 2-(4-(piperidin-1-yl)piperidin-1-yl)acetic acid, potassium salt 4-(Piperidin-1-yl)piperidine (1.20 kg, 7.13 mol) was added to methylene chloride (12.0 L) under a nitrogen atmosphere.
Tetrabutylammonium bromide (0.150 kg, 0.47 mol) and sodium hydroxide (1.7 L of a 5 N solution, 8.5 mol) were then added. The reaction mixture was cooled to 10-15~C and methyl bromoacetate (1.17 kg, 7.65 moV was added and the resulting mixture was stirred for a minimum of 16 hours.
Deionized water (1.2 L) was then added to the mixture and the layers separated. The aqueous layer was back-extracted with methylene chloride (2.4 L). The organic fractions were combined and 2 5 washed with deionized water (3 x 1.2 L), a saturated sodium bicarbonate solution (1.1 L) and a saturated sodium chloride solution (1.1 L). The organic fraction was then dried over anhydrous magnesium sulfate and CA 022~910 1998-11-23 concentrated to an oil on a rotary evaporator to yield 1.613 kg (93.5%) of methyl 2-(4-(piperidin-1-yl)piperidin-1-yl)acetate.
A solution of methyl 2-[4-(piperidin- 1-yl)piperidin- 1-yl]acetate (2.395 kg, 9.96 mol) in methanol (2.4 L) was added to a solution of potassium hydroxide (0.662 kg, 10.0 mol ~ 85% purity) in methanol (10.5 L) under a nitrogen atmosphere. The reaction mixture was heated to 45-50~C for a minimum of 16 hours.
A solvent exch~nge from methanol to acetone (15.0 L) was performed on the solution on a rotary evaporator. This solution was 1 o slowly cooled to room temperature over 16 hours. The resulting solids were filtered, rinsed with acetone (5.0 L) and then dried to yield 2.471 kg (93.8%) of 2-(4-(piperidin-1-yl)piperidin-1-yl)acetic acid, potassium salt.
MS 265 (M+1) (b) Preparation of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin- l-yl)piperidin- 1-yl)acetyl)amino]propane The title compound was prepared by first a-lmixing (R)-2-amino-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride (50.0 g, 0.118 mol) with 100 ml of methylene chloride under a nitrogen atmosphere.
In a second flask, under a nitrogen atmosphere, 2-(4-(piperidin-1-yl)piperidin-1-yl)acetic acid potassium salt (62.3 g, 0.236 mol) was added to 600 ml of methylene chloride. This mixture was cooled to about -10~C and stirring was continued. To this mixture isobutylchloroformate (23 ml, 0.177 mol) was added dropwise such that the temperature of the 2-(4-(piperidin-1-yl)piperidin-1-yl)acetic acid potassium salt mixture never rose appreciably.
This reaction mixture was stirred at about - 10~C for about 1.5 hours at which time the (R)-2-amino-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride/methylene chloride mixture prepared sul~ra was slowly added to the 2-(4-(piperidin-1-yl)piperidin-1-yl)acetic acidpotassium salt/isobutylchloroformate/methylene chloride solution. The resulting CA 022~5910 1998-11-23 W O 97/44035 PCTrUS97/09225 mixture was then stirred for about 1 hour at a temperature between -15~C
and -8~C.
The reaction mixture was removed from the ice bath and allowed to warm to 15-20~C and the reaction was quenched by the addition of 200 ml of water. The pH of the solution was adjusted to 2.3-2.7 by the additon of lN sulfuric acid. The layers were separated and the aqueous layer was washed with 100 ml of methylene chloride.
The organic fractions were combined and washed with water (100 ml). The water wash was back extracted with methylene chloride (50 0 ml) and combined with the aqueous fraction from above. Methylene chloride (500 ml) was added to the combined aqueous layers and the mixture was stirred at room temperature for 15 minutes as basification with 2N sodium hydroxide to a final pH of 9.8 to 10.2 was achieved.
The organic and aqueous fractions were separated. The aqueous fraction was washed with methylene chloride and the methylene chloride was added to the organic fraction. The organic fraction was then washed with a mixture of saturated sodium bicarbonate solution (100 ml) and water (50 ml). The bicarbonate wash was separated from the organic fraction and back extracted with methylene chloride (50 ml). The back 2 o extraction was combined with the methylene chloride fraction and the combined fractions were dried over magnesium sulfate. The m~gn~.~ium sulfate was removed by filtration and the volatiles were removed by vacuum distillation to yield the title product as a foam. (72.5 g, >g8%
yield). MS 559(M+1) NMR (DMSO-d6 3:2 mixture of amide rotamers) ~ 1.25-1.70 (m, lOH), 1.77-2.00 (m, 2H), 1.95 (s, 3/5-3H), 2.04 (s, 2/5-3H), 2.10-2.97 (m, 9H), 3.10-3.65 (m, 3H), 3.72 (s, 2/5-3H), 3.74 (s, 3/5-3H), 4.26-4.68 (m, 3H), 6.76-7.12 (m, 6H), 7.13-7.35 (m, 2H), 7.42-7.66 (m, 2H), 10.80 (br s, lH).
Analysis for C33H4sNsO3:
Theory: C, 70.81; H, 8.10; N, 12.51.
Found: C, 70.57; H, 8.05; N, 12.39.
CA 022~910 1998-11-23 Preparation of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin- l-yl)piperidin- l-yl)acetyl)amino]propane dihydrochloride trihydrate oCH3 ~ I
~N~ C=~3 + > H o=~
N~--N
~ N~N- CH2 ~ CO2 K+ 2 HCl Under a nitrogen atmosphere 2-(4-(piperidin-1-yl)piperidin-l-yl)acetic acid, potassium salt (0.75 kg, 2.84 mol) was added to methylene chloride (7.5 L). The resulting mixture was cooled to -15 to -8~C and isobutyl chloroformate (0.29 kg, 2.12 mol) was added at such a rate so as to maintain the temperature of the reaction mixture below -8~C.
After the addition the resulting reaction mixture was stirred for 90 minutes between -15 and -8~C.
The reaction mixture was then cooled to -35~C and solid (R)-2-amino-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyVamino]propane dihydrochloride (0.60 kg, 1.14 mol) was added at such a rate that the reaction temperature was maintained at less than -20~C. After the addition, the reaction mixture was stirred for about one hour with the temperature being maintained between -37~C and -20~C. The reaction 2 0 was quenched by the addition of (i~icmi7ed water (7.5 L). The reaction mixture was basified to pH 12.8-13.2 by the addition of 5 N sodium hydroxide. The aqueous fraction was removed and retained. Additional deionized water (3.75 L) was added to the organic fraction as was sufficient 5 N sodium hydroxide to re-adjust the pH to 12.8-13.2.
2 5 The two aqueous fractions were combined, back-extracted with methylene chloride (1.5 L) and then discarded. The organic fractions were combined and washed with deionized water (4 x 3.5 L). These CA 022~910 1998-11-23 WO 97/44035 PCTtUS97/09225 extracts were comhined, back-extracted with methylene chloride (1.5 L), and then discarded. The two organic layers were combined and washed with a saturated sodium chloride solution (3.7 L).
The organic fraction was dried over anhydrous magnesium 5 sulfate, filtered, and solvent exchanged from methylene chloride to acetone (3.75 L) on a rotary evaporator. An aqueous solution of hydrochloric acid (0.48 L of 6 N solution, 2.88 mol) and seed crystals (2 g) were added and mixture was stirred for 30-90 minutes. Acetone (13.2 L) was then added and the slurry stirred for one hour. The resulting solid was then filtered, washed with acetone (2 x 1.4 L), and dried to yield 633 g (90%) of (R)-3-(lH-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin- 1-yl)piperidin- 1 -yl)acetyl)amino]propane dihydrochloride trihydrate.
The biological efficacy of a compound believed to be effective as a tachykinin receptor antagonist may be confirmed by employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK- 1 and NK-2 receptor sites.
2 o Assays useful for evaluating tachykinin receptor antagonists are we~l known in the art. See~ e.~., J. Jukic, et al., Life Sciences, 49:1463-1469 (1991); N. Kucharczyk, et al., Journal of Medicinal Chemistry.
36:1654-1661 (1993); N. Rouissi, et al., Biochemical and Biophysical Research Communications. 176:894-901 (1991).
NK-1 Receptor Bindin~ Assay Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan, et al., Journal o~ ImmunoloFy, 133:3260-3265 (1984). In this assay an aliquot of IM9 cells (1 x 106 cells/tube in RPMI 1604 medium supplemented with 10%
fetal calf serum) was incubated with 20 pM l2~I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4~C.
CA 022~910 1998-11-23 The IM9 cell line is a well-characterized cell line which is readily available to the public. See. e.F.. Annals of the New York Academy of Science. 190: 221-234 (1972); Nature (London)~ 251:443-444 (1974); Proceedin~s of the National Academy of Sciences (IJSA)~ 71:84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 ,Lg/ml gent~mi( in sulfate and 10% fetal calf serum.
The reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethyl~nimine. Specific binding of labeled substance 0 P was determined in the presence of 20 nM unlabeled ligand.
Many of the compounds employed in the methods of the present invention are also effective antagonists of the NK-2 receptor.
NK-2 Receptor Bindin~ Assay The CHO-hNK-2R cells, a CHO-derived cell line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per cell, were grown in 75 cm2 flasks or roller bottles in minim~l essential medium (alpha modi~ication) with 10% fetal bovine serum. The gene sequence of the human NK-2 receptor is given in N.P. Gerard, et al., Journal of Biolo~ir.~l Chemistry. 265:20455-20462 (1990).
For preparation of membranes, 30 confluent roller bottle cultures were dissociated by washing each roller bottle with 10 ml of Dulbecco's phosphate buffered saline (PBS) without calcium and magnesium, followed by addition of 10 ml of enzyme-free cell dissor.i~tion solution (PBS-based, from Specialty Media, Inc.). After an additional 15 minutes, the dissociated cells were pooled and centrifuged at 1,000 RPM
for 10 minutes in a ~linir.~l centrifuge. Membranes were prepared by homogeni7.~tion of the cell pellets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar~ homogenizer for 10-15 seconds, followed by centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a Beckm~n JA-14~ rotor. The pellets were washed once using the above procedure. and the final pellets were resuspended in 100-120 ml 50 mM
CA 022~910 1998-11-23 Tris buffer, pH 7.4, and 4 ml aliquots stored frozen at -70~C. The protein concentration of this preparation was 2 mg/ml.
For the receptor binding assay, one 4-ml ali~uot of the CH0-hNK-2R membrane preparation was suspended in 40 ml of assay buffer cont~ining 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02%
bovine serum albumin (BSA) and 4 llg/ml chymostatin. A 200 ~11 volume of the homogenate (40 ,ug protein) was used per sample. The radioactive ligand was 1125I]iodohistidyl-neurokinin A (New F',ngl~nd Nuclear, NEX-252), 2200 Ci/mmol. The ligand was prepared in assay buffer at 20 0 nCi per lO0 ~,11; the final concentration in the assay was 20 pM.
Non-specific binding was determined using 1 ~IM eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration-response curve.
All samples and standards were added to the incubation in 10 ~LI dimethylslllfoxi-l~ (DMSO) for screening (single dose) or in 5 ~1 DMSO for ICso determin~tions. The order of additions for incubation was 190 or 195 ~1 assay buffer, 200 111 homogenate, 10 or 5 ~1 s~ le in DMSO, 100 ~1 radioactive ligand. The samples were incubated 1 hr at room temperature and then filtered on a cell harvester through filters 2 o which had been presoaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12 x 75 mm polysly~ e tubes and counted in a gamma counter.
Upon a showing that a compound has activity as a tachykinin receptor antagonist, assays may be used to demonstrate the ability of such a compound to control or treat hypertension. Typical such assays are described below.
In Vivo Assays Assay 1 The procedure as set out in Farhat, et al., J PET, 261: 686 (1992) (herein incorporated by reference) is carried out. Four to thirty 3 5 rats are sacrificed. The lungs are exsanguinated by perfusion via the CA 022~910 1998-11-23 hepatic pulmonary vein. The pulmonary artery is cannulated as is the trachea to maintain ventilation and the pulmonary cannula is connected to the perfusion line and the whole ventilated lung is removed and suspended in a perfusion chamber. The effects of vasoconstrictor 5 substances on perfusion pressure of the isolated perfused lung is - measured using a Statham pressure transducer. The increase in perfusion pressure (vasoconstriction) induced by thromboxane mimetics in the presence of estradiol is det~rmined and the ability to block the thromboxane effects with a trst compound or the estradiol potentiation of 0 the thromboxane effects will be determined.
Activity of compounds having activity as tachykinin receptor antagonists is illustrated by a reduction in pulmonary perfusion pressure increase following thromboxane mimetic stim~ t.ion 15 Assay 2 Between five and fifty rats are ~rlmini.~tered a single IV dose of monocrotaline pyrrole (3.5 mg/kg) and pulmonary disease is evaluated by histopathology, accumulation of fluorescein conjugated dextran in bronchial alveolar lavage fluid (as a measurement of pulmonary edema), 2 0 and measurements of pulmonary artery pressure using a Standtham P23ID pressure transducer (:Reindel et al., Tox and Applid. Pharm, 106:
179-200 (1990), incorporated herein by reference. A test compound is allmini~tered and the effect on the rats are evaluated.
Activity of compounds having activity as tachykinin receptor 2 5 antagonists is illustrated by a reduction in uptake of fluorescein conjugated dextran from bronchial alveolar lavage fluids of ~nim~
treated with a compound of formula 1, indicating a reduction in pulmonary edema. Rat lungs will also be removed from thorax, perfused with modified Karnovskys fixitive and processed for histopathology. A
3 o reduction in t~irkening of the arterial walls in treated rats is evidence for the protective role of compounds of formula 1 as is a decrease in pulmonary artery pressure.
While it is possible to aflmini.~ter a compound employed in 3 5 the methods of this invention directly without any formulation, the CA 022~910 1998-11-23 compounds are usually ~llmini.qtered in the form of ph~rm~ceutical compositions comprising a ph~rm~ceutically acceptable excipient and at least one active ingredient. These compositions can be a-lmini.~tered by a variety of routes including oral, rectal, trans(lerm~l, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See. e.~., REMINGTON'S PHARMACEUTICAL SCIENCES, (16th 0 ed. 1980).
In m~king the compositions employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition.~ can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments cont~inin~ for 2 o example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a fôrmulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to 2 5 combining with the other ingredients. If the active compound is substantially insoluble, it or-lin~rily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
3 0 Some examples of sllit~hle excipients include lactose, dextrose, sucrose, sorbitol, m~nnitol, starches, gum ~c~ci~, calcium phosphate, ~1gin~tes, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include:
3 5 lubricating agents such as talc, magnesium stearate, and mineral oil;
CA 022~910 1998-11-23 wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so ~ as to provide quick, sustained or delayed release of the active ingredient 5 after a(lmini.~tration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage cont~ining from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient. The term "unit 10 dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other m~mm~ , each unit cont~ining a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable ph~rm~qceutical excipient.
The active compounds are generally effective over a wide dosage range. For examples, dosages per day normally fall within the range of about 0.01 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 0.1 to about 15 mg/kg/day, in single or divided dose, is especially preferred. However, it will be understood that 2 0 the amount of the compound actually ~3(1mini.~tered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of atlmini.~tration, the actual compound or compounds a(lmini~tered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and 2 5 therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into 3 0 several smaller doses for a(lmini~tration throughout the day.
WO 97/44035 PC'rlUS97/09225 Formulation Preparation 1 Hard gelatin capsules cont~ining the following ingredients are prepared:
Quantity In~redient (m ~/capsule) Active Ingredient(s) 30.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin 15 capsules in 340 mg quantities.
Formulation Preparation 2 A tablet formula is prepared using the ingredients below:
Quantity In~redient (m~/tablet) Active Ingredient(s) 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 240 mg.
Formulation Preparation 3 2 o A dry powder inhaler formulation is prepared cont~ining the following components:
Tneredient W~ ht %
Active Ingredient(s) 5 Lactose 95 The active mixture is mixed with the lactose and the mixture is added to a dry powder inh~ling appliance.
Formulation Preparation 4 Tablets, each cont~ining 30 mg of active ingredient, are prepared as follows:
-~~ Quantity Tn~redient (m~/tablet) Active Ingredient(s) 30.0 mg o Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 ~n F
Total 120 mg 2 5 The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60~C and passed through a 16 mesh U.S. sieve. The sodium 3 o carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mi~ing, are compressed on a tablet m~hine to yield tablets each w~i ghin g 120 mg.
3 5 Formulation Preparation 5 CA 022~9l0 l998-ll-23 Capsules, each cont~ining 40 mg of medicament are made as follows:
Quantity Tn~redient (m~/car~sule) Active Ingredient(s) 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mF
Total 150.0 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
Formulation Preparation 6 Suppositories, each cont~ining 25 mg of active ingredient are made as follows:
TT~redient Amount 2 5 Active Ingredient(s) 25 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient(s) is passed through a No. 60 mesh 3 0 U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necess2ry. The mixture is then poured into a suppository mold of nomin~l 2.0 g capacity and allowed to cool.
.
Formulation Preparation 7 Suspensions, each cont~ining 50 mg of medicament per 5.0 5 ml dose are made as follows:
Tn~redient Amount Active Ingredient(s) 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v.
Purified water to 5.0 ml The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a 2 5 previously made solution of the microcrystal~ine cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sllffir.ient water is then added to produce the required volume.
.
Formulation Preparation 8 Capsules, each cont~ining 15 mg of medicament, are made as 5 follows:
Quantity InFredient(mFlcapsule) Active Ingredient(s)15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mF
Total 425.0 mg The active ingredient(s), cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
Formulation Preparation 9 An intravenous form~tion may be prepared as follows:
InFre~ nt Quantity Active Ingredient(s) 250.0 mg Isotonic saline 1000 ml Formulation PreparatioII 10 A topical formulation may be prepared as follows:
Tn Fredient Quantity Active Ingredient(s) 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to 100 g The white soft paraffin is heated until molten. The liquid paraffin and 15 emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
CA 022~9l0 l998-ll-23 W O 97/44035 PCTrUS97109225 FormulationPre~aration 11 Sublingual or buccal tablets, each cont~ining lO mg of active ~ ingredient, may be prepared as follows:
Quantity Tn~redient Per Tablet Active Ingredient(s) 10.0 mg 0 Glycerol 2 10.5 mg Water 143.0 mg Sodium Citrate 4.5 mg Polyvinyl Alcohol 26.5 mg Polyvinylpyrrolidone 15.5 m F
Total 410.0 mg The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maint~ining the temperature at about 9O~C. VVhen the polymers have gone into solution, the solution is cooled to about 50-55~C and the 2 5 medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-cont~ining diffusion matrix having a thickness of about 2-4 mm. This diffusion m~trix is then cut to form individual tablets having the appropriate size.
3 0 Another preferred formulation employed in the methods of the present invention employs transrlerm~l delivery devices ("patches").
Such trans~rm~l patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transd~rm~l patches for 3 5 the delivery of ph ~rm ~ceutical agents is well known in the art. See~ e.~., CA 022~910 1998-11-23 U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on (lem7~nd delivery of ph~rm~reutical agents.
Frequently, it will be desirable or necessary to introduce the 5 ph~rm~ceutical composition to the brain, either directly or indirectly.
Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is described in U.S.
Patent 5,011,472, issued April 30, 1991, which is herein incorporated by reference.
Indirect techniques, which are generally plefelled, usually involve form~ ng the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
15 Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and p~imary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Altematively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which 2 o can transiently open the blood-brain barrier.
The type of formulation employed for the a-lmini.~tration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of 2 5 pharmacokinetic profile desired from the route of a-lmini~tration and the compound(s), and the state of the patient.
Claims (4)
1. A method of inhibiting pulmonary hypertensive disease in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound or composition having activity as a tachykinin receptor antagonist.
2. A method as claimed in Claim 1 wherein the compound having activity as a tachykinin receptor antagonist is (R)-2-[N-(2-((4-cyclohexyl)piperazin-1-yl)acetyl)amino]-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane, (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane, (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-[N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane dihydrochloride trihydrate, 1-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole, RP
67580, (~)CP 96345, 5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-2-((4-methylpiperazin-1-yl)acetamido)-3-pentanone, (4-methylphenyl)methyl [R-(R*,S*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]carbamate, or 1-(3,5-dimethylbenzyloxy)-2-amino-2-phenylcyclohexane, or a salt or solvate thereof.
67580, (~)CP 96345, 5-(3,5-bistrifluoromethylphenyl)-1-(3-indolyl)-2-((4-methylpiperazin-1-yl)acetamido)-3-pentanone, (4-methylphenyl)methyl [R-(R*,S*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]carbamate, or 1-(3,5-dimethylbenzyloxy)-2-amino-2-phenylcyclohexane, or a salt or solvate thereof.
3. A pharmaceutical formulation adapted for inhibiting pulmonary hypertensive disease containing as an active ingredient a tachykinin receptor antagonist as claims in any one of Claims 1 to 2.
4. The use of a tachykinin receptor antagonist as claimed in Claim 1 or Claim 2 for the manufacture of a medicament for the inhibition of pulmonary hypertensive disease.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1826696P | 1996-05-24 | 1996-05-24 | |
US60/018,266 | 1996-05-24 | ||
PCT/US1997/009225 WO1997044035A1 (en) | 1996-05-24 | 1997-05-23 | Methods of treating hypertension |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2255910A1 true CA2255910A1 (en) | 1997-11-27 |
Family
ID=21787068
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002255910A Abandoned CA2255910A1 (en) | 1996-05-24 | 1997-05-23 | Methods of treating hypertension |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0912178A4 (en) |
JP (1) | JP2000511193A (en) |
AU (1) | AU3149297A (en) |
CA (1) | CA2255910A1 (en) |
WO (1) | WO1997044035A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9927125D0 (en) * | 1999-11-16 | 2000-01-12 | Univ Reading The | Placental human neurokinin B precursor |
WO2008090114A1 (en) | 2007-01-24 | 2008-07-31 | Glaxo Group Limited | Pharmaceutical compositions comprising 2-methoxy-5- (5-trifluoromethyl-tetrazol-i-yl-benzyl) - (2s-phenyl-piperidin-3s-yl-) |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5612336A (en) * | 1992-07-13 | 1997-03-18 | Merck, Sharp & Dohme Ltd. | Heterocyclic amide derivatives as tachykinin antagonists |
GB9220286D0 (en) * | 1992-09-25 | 1992-11-11 | Merck Sharp & Dohme | Therapeutic agents |
FR2696178B1 (en) * | 1992-09-30 | 1994-12-30 | Sanofi Elf | Quaternary basic amides, process for their preparation and pharmaceutical compositions containing them. |
US5344830A (en) * | 1992-12-10 | 1994-09-06 | Merck & Co., Inc. | N,N-diacylpiperazine tachykinin antagonists |
US6175013B1 (en) * | 1994-06-10 | 2001-01-16 | Eli Lilly And Company | Imidazolinyl tachykinin receptor antagonists |
DE69602087T2 (en) * | 1995-02-22 | 1999-09-09 | Novartis Ag | 1-ARYL-2-ACYLAMINO-ETHAN COMPOUNDS AND THEIR USE AS A NEUROKININE, IN PARTICULAR AS A NEUROKININ-1 ANTAGONIST |
RU2156250C2 (en) * | 1995-04-24 | 2000-09-20 | Новартис Аг | Derivatives of chromone, method of their synthesis and pharmaceutical composition |
-
1997
- 1997-05-23 CA CA002255910A patent/CA2255910A1/en not_active Abandoned
- 1997-05-23 JP JP09542963A patent/JP2000511193A/en active Pending
- 1997-05-23 EP EP97926817A patent/EP0912178A4/en not_active Withdrawn
- 1997-05-23 WO PCT/US1997/009225 patent/WO1997044035A1/en not_active Application Discontinuation
- 1997-05-23 AU AU31492/97A patent/AU3149297A/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
EP0912178A1 (en) | 1999-05-06 |
WO1997044035A1 (en) | 1997-11-27 |
AU3149297A (en) | 1997-12-09 |
EP0912178A4 (en) | 2000-08-16 |
JP2000511193A (en) | 2000-08-29 |
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