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Chapter 31. To Market, To Market - 1983
Section V I I . Editor:
Worldwide Market Introductions
Richard C. Allen, Hoechst-Roussel Pharmaceuticals, Inc. Sornerville, New Jersey 08876 Chapter 31.
To Market, To Market
-
1983
Richard C. Allen, Hoechst-Roussel Pharmaceuticals Inc., Somerville, NJ 08876 The ultimate goal of each of us engaged in the multidisciplinary fields of drug discovery and development is the introduction of the fruit of our efforts into the marketplace. Such a milestone may represent the validation of a scientific hypothesis and perhaps an indication of a new era in therapy, or simply, the emergence of an alternative to existing therapy, with or without measurable advantages. In all cases, such a market introduction represents an accomplishment of some magnitude in the face of formidable odds. The new chemical entities (NCEs) recently introduced into the US marketplace are by no means an accurate and timely reflection of these milestones; of the 20 NCEs appearing on the US market in 1983, only four represent first time introductions into the world marketplace-some were introduced 5-10 years ago in other markets and are certainly not an indication of what is new! An attempt has therefore been made to compile information on the first market introductions of NCEs for human therapeutic use in the world as a whole during 1983. It is hoped that this information will be useful to the reader as an accurate reflection of past accomplishments and perhaps future directions. A short summary of the profile, advantages/uniquenes, and utility of each compound is given; several leading references are offered for the reader interested in additional information.
Acetohydmxamic Acid (hypoammonuric)l,2 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
USA Research Organics; Baylor Unk. USA Uro-Research; Mission Pharrnacal LITHOSTAT
Acetohydroxamic acid is a potent, non-competitive and irreversible inhibitor of bacterial urease (Ki zlO-7M). This enzyme, which is widely distributed in plants and bacteria, but not in mammalian cells, catalyzes the decomposition of urea to ammonia. Elevated urinary ammonia levels can reduce the antibacterial effectiveness of a number of agents. Thus, acetohydroxamic acid is useful as adjunctive therapy to decrease urinary ammonia and alkalinity in patients with chronic urea-splitting urinary infection. Such infections are a leading cause of recurring complications and death in paraplegics.
Afloqualone (muscle relaxant)3,4 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Japan Tanabe Japan Tanabe AROFUTO
ANNUAL REPORTS IN MEDICINAL CHEMISTRY-
19
Copyright 0 1984 by Academic Press, Inc. All rights of reproduction in any form reserved ISBN 0-12-040519-9
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Afloqualone is a centrally acting muscle relaxant useful in the management of various spastic conditions, including cerebral palsy, cervical spondylosis, and multiple sclerosis. It is closely related to the hypnotidsedative methaqualone. Alfentanil Hydrochloride (analgesic)5 9 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Belgium Jansseu Netherlands Janssen RAPIFEN
0
CH 20CH 3
CH3CH2~)+H2CH2<*-4>*’ \rcocH2~~3
0-
*4*-\*
‘HC1*H20
‘a=*
/
Alfentanil is a narcotic analgesic with a more rapid onset and shorter duration of action than its structural relative fentanyl. The primary utility of alfentanil is in surgical analgesia/anesthesia, especially for cardiac compromised patients and in procedures of short duration.
Alminoprofen (ana1gesic/antiinflammatory)’7 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
France Labs. Dr. E. Bouchara France Labs. Dr. E. Bouchara MINALFENE
.404\ /*
H3\ p 2 = \
JizOOH
*=a
H2C
Alminoprofen is an arylpropionic acid analgesic/antiinflammatory agent indicated for the short term management of dental, traumatic and postpartum pain.
%.A
Amrinone (cardiotonic)8,9 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
USA Sterling-Winthrop Phillipines Sterling Drug INOCOR
H 2 ( \ * /
I
!
*
\.4 *‘
‘sf
*\.
Amrinone is a positive inotropic agent useful in the management of severe congestive heart failure. It is effective even in unresponsive, fully digitalized patients.
Astemizole (antihistamine)lO,ll Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Belgium Janssen United Kingdom Jaasslen EISMANAL
/*
I
.r\* ;*=/
Astemizole belongs t o the second-generation class of non-sedating, non-anticholinergic antihistamines. Its non-sedating properties appear to result from its poor penetration of the blood brain barrier. As a result it shows no potentiation of CNS depressants, including alcohol. Its long half-life allows once-daily dosing.
Auranofii (chrysotherapeutic)l~~13
YH flCOCH 3
French
/*-rAu+P
First Introduction: W. Germany Introduced by: Smith Kleia & French Trade Name: RIDAURA
cH3oc&\rzf/
CountryOriginator: of Origin: USA Smith Kleiu
(Ir
(C 2H 5 ) 3
~COCH~
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315
Auranofin is the first orally effective gold compound to be marketed for the treatment of severe rheumatoid arthritis. It is better tolerated and more convenient than gold sodium thiomalate, which is administered intramuscularly. Refunolol Hydrochloride (antiglaucoma)l4,15 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Japan Kalcen Japan Kaken BENTOX
Befunolol hydrochloride is the newest of the 8-adrenergic blockers to be introduced for the treatment of glaucoma. It is reportedly devoid of intrinsic sympathomimetic activity, with lower membrane-stabilizing activity than propranolol.
Betaxolol Hydrochloride (8-adrenergic blocker; antihypertensive)16,17
Country of Origin: France First Introduction: France Trade Name: KERLONE
Originator: Synthelabo Introduced by: Robert & Carriere
Betaxolol hydrochloride is a cardioselective 8-adrenergic blocker, reportedly devoid of intrinsic sympathomimetic and membrane stabilizing properties. Its long duration of action permits once-daily dosing in mild to moderate hypertension. It is also being evaluated in glaucoma. Bifonazole (antif ung al)18919 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany Bayer
W. Germany Bayer
MYCOSPOR
Bifonazole represents the first topical broad spectrum antimycotic approved for once daily administration. Its in vitro activity appears equivalent t o its structural relative clotrimazole, being effective against dermatophytes, other filamentous fungi, dimorphic fungi and yeasts. Brotizolam (hypnotic/sedative)20,21 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany
Boehringer Ingelheim Switzerland
Boehrhger Ingelheim LENDORMIN
Brotizolam is a hypnotic/sedative approximately 60-1 00 times more potent than flurazepam. As with other short-acting, annulated benzodiazepines (e.g., triazolam), cited advantages include lack of adverse effects on sleep and performance after arousal. Budralazine (antihypertensive)22,23 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Japan Daiichi Japan Daiichi
BUTERAZINE
IlJI \ ;
i* 7 1
A*P
*\*/
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Budralazine is an antihypertensive agent which is somewhat less potent than structurally related hydralazine, and reportedly produces less tachycardia.
Butyl Flufenamate (topical a n t i i n f l a m r n a t ~ r y ) ~ ~
Japan *A* A* Hokaariku ' I Japan *+*/ Hohnitu; Tokyo Tanabe h02C4HB FENAZOLE; COMBEC Butyl flufenamate is a topical, non-steroidal antiinflammatory agent indicated for the treatment of acute and chronic eczema; contact, seborrheic, and atopic dermatitis; and herpes zoster. Country of Origin: Originator: First Introduction: Introduced by: Trade Names:
i\.8icp3 '
Cadexomer Iodine (wound healing agent)25 Country of Origin: United Kingdom First Introduction: United Kingdom Trade Name: IODOSORB
Originator: Perstorp Introduced by: Stuart
Cadexomer Iodine is a hydrophilic, modified starch polymer containing 0.9% iodine within the helical structure; it is used in the treatment of decubitus and venous leg ulcers. Applied to a wound surface as a powder, it is reported to accelerate healing, stimulate granulation, clean the ulcer surface, relieve pain and reduce bacterial counts.
.
Cefmenoxime Hydsochldde ( a n t i b i o t i ~ ) ~ ~ , ~ 7 GOOH
CH3
Originator: Takeda Country of Origin: Japan Introduced by: T Nippon Roche First Introduction: Japan Trade Names: TACEF; BESTCALL Cef menoxime hydrochloride is a third generation cephalosporin antibiotic. Structurally, it possesses the (1-methyl-lH-tetrazol-5-y1)thiomethylmoiety in the 3-position; like several other compounds containing this structural element (moxalactam, cefoperazone, cefamandol), bleeding linked to vitamin K interaction has been reported. Cefmenoxime has activity similar to cefotiuime, ceftizoxime and moxalactam against E. C. diversus, Klebsiella, g. Mirabilis, Salmonella, Shigella, Neiseria spp., 5. pyogenes, 5. Pneumoniae, and g. influenzae. It is relatively ineffective against Pseudomonas and Bacteroidea.
e,
Ceftddime ( a n t i b i o t i ~ ) ~ ~ , ~ 9 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
United Kingdom Glaxo United Kingdom Glau, PORTAM
Hz\*/S*
t:2-CH2<
+/*-.\ *,
"*+ '/ e=* ~ - J ~ ~ o m ~ l l l l l ~I 3 , d * OC (CH3) 2CO 2H
Ceftazidime is the latest third generation cephalosporin to reach the market. It has one of the broadest spectrums of the cephalosporins, similar in many regards to that of cefotaxime. It is particularly active against Pseudomonas aeruginosa, being perhaps 4-5 times more potent in vitro than moxalactam and cefotaxime.
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Celiprolol Hydrochloride ( 8-adrenergic blocker)30,31 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Austria Chemie Linz Austria Chemie Linr SELECTOL
(C2H5) 2NCONH-.(
/-\ a=.
).-OCHz 'HC1
Celiprolol hydrochloride is a once-daily, cardioselective padrenergic blocker useful in the management of hypertension, angina pectoris and hyperkinetic heart syndrome. It is also being evaluated in glaucoma.
Chenodiol (anti~holelithogenic)~~,~3 ,COOH
Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
'a
USA Rowell USA Rowell CHEWM
Chenodiol is the first agent to be introduced into the US market for the treatment of radiolucent gallstones. Large scale clinical trials have demonstrated the safety and efficacy of this agent. Chenodiol reduces the biliary concentration of cholesterol relative to that of bile acids and phospholipid, reducing the saturation and thus the lithogenicity of the bile. Success rates in dissolving gallstones are in the range of 50-70% within 4-24 months of treatment. Continuation of the drug after stone dissolution may be required t o prevent reoccurrence. Chenodiol is the 7a-isomer of ursodeoxycholic acid which was introduced into the European market in 1978.
Cyclosporine (ciclosporin) (immunosuppressant)34,35
H3)xfH,.)CH3
C H 2 T p H
H$x 4
5
Country of Origin: Switzerland First Introduction: Switzerland Trade Name: SANDIMMUN
-CO-Abu-MeGly-+leLeu-Val-+leLeu y6
R
7
8
l1
1
Originator: Sandoz Introduced by: Sandoz
Cyclosporine is a cyclic polypeptide with potent, partially selective immunosupressive activity. Isolated from the species Cylindrocarpon lucidium and Trichoderma polysporum, cyclosporine is useful in the prevention and treatment of graft/host disease and the prevention of rejection following organ transplantation. It appears to act by preferentially suppressing T-lymphocytes. Cyclosporine lacks myelotoxicity, although impaired renal and liver function have been observed. Initial administration is via the intravenous route, followed by oral maintenance therapy.
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Ehocitabine (antineoplast ic)36,37
O\
CountryOriginator: of Origin: Japan Asahi First Introduction: Japan Introduced by: Topp Jozo Trade Name: SUNRABIN
""2\0/\/"(:>0*co \ TI
(CH2) 2OCH3
Hb-.
Enocitabine is an antileukemic agent closely related to cytarabine. It appears more resistant to deamination than cytarabine, thus allowing greater in vivo phosphorylation into an active cytotoxic metabolite.
EperisomeHydmchbn'de (muscle r e l a ~ a n t ) 3 ~ , 3 9 Country of Origin: Japan Originator: Eisai First Introduction: Japan
. C2Hg-*'
Introduced Trade Name: by: MYONAL E M
/-*\ 'o=o'
k . 0 HCH2
ZH3
.--.
'0-0':~~~
Eperisone hydrochloride is a centrally acting muscle relaxant useful in the management of various spastic conditions including cervical spondylosis and cerebral palsy. It is structurally related to tolperisone. Epoprostenol sodium (platelet aggregation i n h i b i t ~ r ) ~ O , ~ l Country of Origin: Originator: First Introduction: Introduced by: Trade Names:
United Kingdom Burroughs Wellcome United Kingdom Burroughs Wellcome; Upjohn FtoLAN;CYCLO-PROSTIN
8H
Epoprostenol sodium (prostacyclin) is a naturally occurring prostaglandin indicated for the preservation of platelet function during cardiopulmonary bypass, prevention of platelet aggregation during charcoal hemoperfusion of patients in hepatic failure, and as an alternative to heparin during renal dialysis.
Fenbuprol (choleretic)4&43 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany Klinge Pharma W. Germany Rhom Pharma VALBIL
,.=. l H
,8"8/.-O-CHz
HCliflC4Hg
Fenbuprol produces an increase in the volume of bile secretion. It is useful in patients having symptomatology associated with biliary tract dysfunction. Flutamide (antineoplastic)%45 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
USA
scheting Chile Schering DROGENIL
( CH 3 2
Flutamide is an orally active, non-steroidal antiandrogen indicated for the treatment of prostatic cancer in both castrates and noncastrates.
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Chap. 31
Fluvoxamine Maleate (serontonergic antidepressant)46-48 Country of Origin: Netherlands Originator: First Introduction: Introduced by: Trade Name:
Duphar Switzerland Kali-Duphar FLOXYFRAL
F3C-0,
.=.
p*-*\,
/ 3i-CH2-CH2-CH2-CH2-0-CH3 N-O-CH 2-CH 2-NH 2 ‘C4H404
Fluvoxamine maleate is the most recent of the serotonin-specific antidepressants to reach the market. In vitro and in vivo animal experiments have shown fluvoxamine t o have a marked effect on 5-HT mediated processes and little effect on norepinephrine. Clinical trials suggest similar efficacy t o imipramine and clomipramine with a somewhat lower incidence of side effects, especially anticholinergic effects. Fluvoxamine, in contrast to the tricyclic antidepressants, does not appear to produce heart rate increase, postural hypotension or prolongation of the intraventricular conduction t i m e and QT interval.
Gallopamil Hydrochloride (antianginal)49 Country of Origin: Originator: First Introduction: Introduced by:
W. Germany
Knoll W. Germany Chem. Werke Minden Trade Name: PROCORUM
CH 30
Gallopamil hydrochloride is a somewhat more potent methoxy analog of calcium channel blocker verapamil with a similar profile. It is useful in the treatment of angina and auricular arrhythmia.
Gemeprost ( a b ~ r t i f a c i e n t ) ~ ~ , ~ ~ Country of Origin: Originator: First Introduction: Introduced by:
Japan On0
MalaysiaJSingapore May & Baker
Trade Name: CERVAGEM
*/*\ */’\*/
o\*-.P+*\
CO 2CH 3
/
'a-•
Ho\+’
1.4
\*/
\*/ \*/
dH
Gemeprost, a metabolically stabilized analog of PGE1,has been demonstrated t o reliably induce termination of early pregnancy when administered as a vaginal suppository. Its effect is presumably due to both uterine contraction and rapid decline of steroid hormone levels. Minimal side effects have been reported.
Guanadrel Sulfate (antihypert ensive)%53 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
USA Cutter USA Penuwalt WLOREL
Guanadrel sulfate is an antihypertensive belonging t o the class of adrenergic neuron blocking drugs. It diminishes sympathetic vasoconstriction by inhibiting norepinephrine storage and release from neuronal storage sites. It appears similar in effectiveness and side effect profile to its structural relative guanethidine.
319
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a
Halometasone (topical antiinflammatory)%55 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Allen, Ed.
Switzerland Ciba-igy Switzerland Ciba-Geigy SICORTEN
Halometasone is a Dotent,. topical - steroid useful in a variety of acute and chronic eczematous dermaioses and psoriasis. It is reportedly devoid of skin toxicity and systemic effects. Hydrocortisone Butyrate Propionate (topical antiinflammat0ry)5~ GH flCOCH 2CH 3 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Japan Taiaho Japan Taisho
PANDEL
Hydrocortisone butyrate propionate is a potent, topical steroid reported to possess minimal systemic side effects. It is indicated in the treatment of various acute and chronic contact, eczematous, and atopic dermatoses and psoriasis. Jndalpine (serotonergic a n t i d e p r e ~ s a n t ) ~ ~ - ~ g
Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
France Pharmuka France Labs. Fournier Freres UPSTENE
.’! /.B c r ‘0-.
\*/
yH
Indalpine is a non-tricyclic antidepressant with a serotonin selective profile. It is 6-7 times more potent than fluoxetine and clomipramine in inhibiting serotonin reuptake in vitro in rat brain synaptosomes. Statistically significant clinical effects within one week of onset of treatment have been reported. An anxiolytic effect may accompany the antidepressant effect. Indalpine appears devoid of anticholinergic and cardiovascular side effects and does not promote weight gain or affect appetite. sox xi cam (antiinflammatory)6&62 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
USA
Warner-Lambert W. Germany Warner-Lambert
PAC=
Isoxicam is a non-steroidal antiinflammatory agent useful in the treatment of various forms of rheumatoid arthritis, osteoarthritis and musculoskeletal disorders. It is about one-tenth as potent as its structural relative sudoxicam; its similar long TQ (>30hrs.) allows once-daily dosing.
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Loprazolam Mesylate (hypnotic/sedative)63,64 Country of Origin: United Kingdom Originator: R o w e l First Introduction: United Kingdom Introduced by: Roussel Trade Name: DORMONOCT
p<
*-a
*-a
)NCH3
‘a
’ ‘
a’
‘a
02daaa/
Loprazolam mesylate is a potent hypnotic/sedative belonging t o the second generation of annulated-l,4benzodiazepines. The T + of loprazolam (-6 hr.) is longer than those of triazolam and midazolam, but shorter than the “effective” T% of flurazepam.
/.
*CH3S03H
*/ ‘*/C‘
! U a/
Meglutol ( h y p ~ l i p i d e r n i c ) ~ ~ , ~ ~ Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
India Aligarh Muslim Univ.
Italy Ausonia LIPOGLUTAREN
p:“
HO2CCH2 CH2C02H
Meglutol (B-hydroxy- 6-methylglutaric acid; HMG) is a hypolipidemic agent that acts via the inhibition of cholesterol synthesis a t the stage of HMG-CoAreductase, blocking the conversion of HMG-CoA to mevalonate. This conversion is the rate-limiting step in cholesterol biosynthesis and is the point of physiological feedback control; as such, it appears to be the ideal locus of action for a hypolipidemic agent. Investigational compounds that act by this mechanism include the natural products compactin and mevinolin. Meptazinol Hydrochloride
r3
/ \
Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
United Kingdom Wyeth United Kingdom Wyeth MEPTID
1
i/C2H5 a
\
\a-a/
*HC1
*Aa ‘ I ‘OH
Meptazinol hydrochloride is an injectable narcotic analgesic with antagonist properties; it is similar in potency to meperidine. Meptazinol appears to have a low propensity toward respiratory depression and other opiate-like side effects, possibly due to selective interaction with the mu-1 receptor. Also somewhat unique for an analgesic, it interacts with central cholinergic receptors. An oral form of meptazinol is under development. Muzolimine (diuretic)70-72 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany Bayer Italy Bayer EDRUL
321
g-*/ 3
H 2 ‘ a v
I
a -.
/*-a\
/c \a<]
\a=./
b
Muzolimine is a structurally novel, pyrazolone diuretic with a high-ceiling profile. It is somewhat slower in onset than furosemide, but has a more prolonged effect, similar t o the thiazides. Muzolimine has been shown to be effective in edema of cardiac, hepatic and renal origin. It also appears to be effective as an antihypertensive agent.
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Nitrefazole (alcohol deterrent)73,74 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany E. Merck W. Germany E. Merck ALTIMOL
Nitrefazole is an inhibitor of aldehyde dehydrogenase useful in the management of alcoholism. Cited advantages over disulfiram include longer duration of action, higher specificity (no inhibition of dopamine 8-hydroxylase) and fewer side effects. It is generally recognized that the efficacy of such agents with respect to permanent abstinence is low. However, temporary abstinence and/or controlled drinking may facilitate supportive psychotherapy and/or delay the onset of severe alcoholic diseases. Norfloxacin (antibact erialI7597 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Japan Kyorin Italy Merck NOROXIN
Norfloxacin is the first of the third generation nalidixic acid analogs to reach the marketplace. It exhibits potent in vitro and in vivo activity against Pseudomonas, enteric gram-negative rods and gram-positive cocci. Norfloxacin is orally effective in the treatment of urinary tract infections, including those due to organisms refractory to many other agents. ~ x a p r o z i n(antiinflammatory)77,78 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
United Kingdom
Wyeth Fbrtugal
Wyeth DURAPROX
H C ~ H ~ oCOA 2 o~o\o/
1-4
c 6 d
Oxaprozin is a non-steroidal antiinflammatory agent indicated for use in various forms of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. A long T$ allows once/twice daily dosing. Structurally it is somewhat unique, being a 3substituted, rather than a 2-substituted propionic acid. Oxiconazole Nitrate (antifungal)79 Country of Origin: Originator: First Introduction: Introduced by: Trade Names:
Switzerland Siegfried Switzerland Sauter; Siegfried OCERAL; MYFUNGAR
c1
Oxiconazole nitrate is a broad-spectrum antifungal agent indicated for the treatment of skin infections due to yeasts, dermatophytes, yeast-like fungi and molds, and gram positive organisms.
Allen
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Chap. 31
Oxitropium Bromide (bronchodilat or)80-8 2 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany Boehringer Ingelheim W. Germany Dieclcmann
TERSIGAT
Oxitropium bromide is an analog of the anticholinergics methscopolamine bromide and ipratropium bromide, useful in the treatment of bronchial asthma. Cited advantages include a long duration of action and lack of cardiovascular effects.
Promegestone (progestogen)83,84 France Roussel France Labs. Cassenne Trade Name: SURGESTONE
Country of Origin: Originator: First Introduction: Introduced by:
a’
‘.’
H3C FOCH2CH3 a I am*CH3
I
l
\a
l
a/ag\a/ I
/\*/
!
a-a
! La/
Promegestone is a potent progesterone-like agent devoid of androgenic properties, and thus masculinizing side effects. It is useful in the treatment of various gynecological conditions due to luteal insufficiency, such as premenopausal disorders, dysmenorrhea, and premenstrual syndrome. sodium Cellulose Phosphate (hypocalciuric)85
Country of Origin: USA First Introduction: USA Trade Name: CALCIBIND
Originator: University of Texas Introduced by: Mission Pharmacal
Sodium cellulose phosphate (SCP)is an insoluble, non-absorbable ester of cellulose containing 34% inorganic phosphate and 11% sodium. It is capable of binding calcium in the intestinal tract, reducing absorption of this ion, as well as magnesium. SCP is indicated only for the treatment of absorptive hypercalciuria type I with recurrent calcium oxalate or calcium phosphate nephrolithiasis. ~ u f e ~ t a n(analgesic)86,87 il
Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Belgium Jaassen Netherlands Janssen SUFENTA
a-a
1
\d
E(~-)~,CHZOCH 3 1-CH2CH2 *-a )COCH~CR~
Sufentanil is a narcotic analgesic with a greater potency and therapeutic ratio than its structural relative fentanyl. It appears t o produce fewer cardiac effects and less respiratory depression than fentanyl, and thus is especially useful as an analgesic/anesthetic in open heart surgery.
323
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Suprofen (analgesic/an t iinflam mat ory)88-90
Belgium .Ao/ 2H Janssen I 1 Switzerland \s/ Cilag MALDOCIL Suprofen is an arylpropionic acid analgesic/antiinflammatory agent with close structural resemblance to ketoprofen. It is more potent in many assays than indomethacin and ketoprofen and appears better tolerated. Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Terconazole (antifungal)gl Country of Origin: Belgium Originator: First Introduction: introduced by: Trade Name:
\./ \./. 8
I;-!
\.A/
Janssen Switzerland
Cilag FUNGISTAT
Terconazole is an antifungal agent somewhat more potent than clotrimazole and useful in the topical treatment of vaginal dermatophytosis and candidiasis.
Tianeptine Sodium (serotonergic antidepressant)9&93 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
France Sci. Union et Cie France Servier STABLON
‘ L 1 I\./. ’ .\./ Lo/
h ( C H 2 ) &O 2 N a
Tianeptine sodium is a structurally novel, serotonin specific antidepressant. It is useful in the treatment of neurotic and reactive depressions, as well as depressive states accompanied by anxiety.
Tioconazole (antifungal)g4
/.‘7 71
Country of Origin: United Kiugdom fo)?-CH2[HDCH2T’ Originator: Pfieer 0-0 - - 0 First Introduction: Switzerland / Introduced by: Pfizer i i Trade Name: TROSYL Tioconazole is an antifungal agent, closely related to A1 miconazole. Tioconazole is effective in the topical treatment of superficial fungal infections and appears t o be more potent than miconazole against Candida and Trichophyton species.
\p
.\./
Tiropramide Hydrochloride (antispasmodic)95-97 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Italy (C 2H5 2N( CH2 ) 2 0 4 ’ Rotta Research Italy Rotta ResearCa; Rarer MAIORAD; ALFOSPAS
‘.+Xi2
.HC1
€ICON( C LCOC&
Tiropramide hydrochloride is a smooth muscle relaxant indicated for the treatment of spastic conditions of the gastrointestinal and urogenital systems. It appears to act by increasing intracellular levels of c-AMP.
2
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References G. R. Gale, Drugs Fut., 5, 599 (1980). J. R. Prous, ed., Annu. Drug Dat a Rep., 3, 2 (1981). J. R. Prous, ed., Annu. Drug Dat a Rep., 2,4 (1983). A. J. Sweetman, Drugs Fut., 1,539 (1982). J. R. Prous, ed., Annu. Drug Dat a Rep., 3, 8 (1981). R. T. Owen, Drugs Today, 20, 10 (1984). J. R. Prous, ed., Annu. Drug Dat a Rep., 4,10 (1982). K. Hillier, Drugs Fut., 5, 245 (1979). J. R. Prous, ed., Annu. Drug Dat a Rep., 2, 14 (1981). K. Hillier, Drugs Fut., 1,10 (1982). 11. J. R. Prous, ed., Annu. Drug Dat a Rep., 2, 12 (1983). 12. J. A. Bogan, Drugs Fut., 1,451 (1976). 13. J. R. Prous, ed., Annu. Drug Dat a Rep., 2, 13 (1983). 14. J. R. Prous, ed., Annu. Drug Dat a Rep., 3, 27 (1981). 15. M. Takase, Jpn. J. Ophthalmol., 26, 88 (1982). 16. K. Hillier, Drugs Fut., 4, 867 (1979). 17. J. R. Prous, ed., Annu. Drug Dat a Rep., 3, 31 (1981). 18. Drugs Fut., 1,87 (1982). 19. J. R. Prous, ed., Annu. Drug Dat a Rep., 4,24 (1982). 20. H. Koch, Drugs Fut., 4,85 (1979). 21. J. R. Prous, ed., Annu. Drug Dat a Rep., 2,36 (1981). 22. K. Hillier, Drugs Fut., 2,788 (1977). 23. J. R. Prous, ed., Annu. Drug Dat a Rep., 5, 26 (1983). 24. J. R. Prous, ed., Annu. Drug Dat a Rep., 2, 120 (1981). 25. Drugs Today, 19,426 (1983). 26. Drugs Today, 9 , 4 2 9 (1983). 27. J. R. Prous, ed., Annu. Drug Dat a Rep., 2, 33 (1983). 28. A. J. Sweetman, Drugs Fut., 612 (1981). 29. J. R. Prous, ed., Annu. Drug Dat a Rep., 4,44(1982). 30. H. Koch, Drugs Today, g,632 (1982). 31. J. R. Prous, ed., Annu. Drug Dat a Rep., 2, 37 (1983). 32. A. C. Sullivan, L. Cheng and J. C. Hamilton, Annu. Rep. Med. Chem., l2,196 (1977). 33. M. N. Cayen, Annu. Rep. Med. Chem., l4, 205 (1979). 34. J. R. Prous, ed., Annu. Drug Dat a Rep., 2, 42 (1983). 35. Drugs Today, 2,665 (1983). 36. F. Cabanillas, Drugs Fut., 2, 603 (1980). 37. J. R. Prous, ed., Annu. Drug Dat a Rep., 2,28 (1981). 38. Drugs Fut., 1,105 (1982). 39. J. R. Prous, ed., Annu. Drug Dat a Rep., 4,84 (1982). 40. K. Hillier, Drugs Fut., 4, 688 (1977). 41. J. R. Row, ed., AMU. Drug Dat a Rep., 5, 68 (1983). 42. P. S t Ja n i a k, Drugs Fut., 3, 191 (1978). 43. U. R i t t e r and H. J. Kyrein, Arzneim. Forsch., 33, 891 (1983). 44. P. Thorpe, Drugs Fut., 1,108 (1976). 45. J. R. Prous, ed., Annu. Drug Dat a Rep., 4, 105 (1979/1980). 46. P. Thorpe, Drugs Fut., 2,288 (1978). 47 J. R. Prous, ed., Annu. Drug DataRep., 2, 107 (1979/1980). 48 F. H. Geukes-Foppen, S. J. Papworth and A. W. Peck, eds., Br. J. Clin. Pharmacol., 15 (Suppl. 31, 347S-450S (1983). 49. K R . Prous, ed., Annu. Drug Dat a Rep., 5, 85 (1983). 50. P. Leeson, Drugs Fut., 4,38 (1979). 51. J. R. Prous, ed., Annu. Drug Dat a Rep., 5, 85 (1983). 52. D. M. Paton, Drugs Today, l6,140 (1980). 53. J. R. Prous, ed., Annu. Drug Dat a Rep., 4,100 (1982). 54. K. J. Schwarz, M. Konzelmann, S. J. Yawalkar and P. M. Schoenenberger, Br. J. Clin. Pract., 36, 192 (1982). 55. J. E. Murphy, ed., J. Int. Med. Res., 11 (Suppl. l), 1-57 (1983). 56. J. R. Prous, ed., Annu. Drug Dat a Rep., 2, 200 (1983). 57. R. T. Owen, Drugs Fut., 4,873 (1979). 58. J. R. Prous, ed., Annu. Drug Dat a Rep., 5, 95 (1983). 59. B. Shopsin, C. Lefebvre, and C. Maulet, Curr. Ther. Res., 34,239 (1983).
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
i,
326 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97.
Sect. V I I
- Worldwide
Market I n t r o d u c t i o n s
A l l e n , Ed.
E. Arrigoni-Martelli, Drugs Fut., 1,123 (1976). J. R. Prous, ed., Annu. Drug Data Rep., 5, 99 (1983). G. DiPasquale, Drugs Today, 3, 119 (1983). P. J. Thorpe, Drugs Fut., 2, 144 (1980). J. R. Prous, ed., Annu. Drug Data Rep., 2, 143 (1981). 2. H. Beg and M. Siddiqi, Experiemtia, 2,380 (1967). P. J. Lupien, S. Moorjani, D. Brun, and P. Bielmann, J. Clin. Pharmacol., l9, 120 (1979). M. Thorpe, Drugs Fut., 1,68 (1976). J. R. Prous, ed., Annu. Drug Data Rep., 2,141 (1979/1980). 0.W. Lever, Jr., K.-J. Chang and J. D. McDermed, Annu. Rep. Med. Chem., 9, 52 (1983). K. Hillier, Drugs Fut., 2, 387 (1977). J. R. Prow, ed., Annu. Drug Data Rep., 5, 129 (1983). L. deAngelis, Drugs Today, 19,267 (1983). J. R. Prous, ed., Annu. Drug Data Rep., 4, 146 (1982). D. E. McMillan, Drug Dev. Res., 2,193 (1983). J. R. Prous, ed., Annu. Drug Data Rep., 3, 12 (1981). J. R. Prow and N. E. Mealy, Drugs Today, 2, 341 (1983). E. Arrigoni-Martelli, Drugs Fut., 2,539 (1978). J. R. Prous, ed., Annu. Drug Data Rep., 2,144 (1983). J. R. Prow, ed., Annu. Drug Data Rep., 2, 184 (1981). A. P. Dharma, Drugs Fut., 4, 117 (1979). H. Koch, Drugs Today, 2,444 (1983). J. R. Prous, ed., Annu. Drug Data Rep., 5, 145 (1983). P. J. Roberts, Drugs Fut., 2,469 (1978). J. R. Row, ed., Annu. Drug Data Rep., 5, 156 (1983). C. P. Robinson, Drugs Today, l9,372 (1983). E. Arrigoni-Martelli, Drugs Fut., 2,334 (1977). J. R. Prous, ed., Annu. Drug Data Rep., i,206 (1979/1980). S. S. Chatterjee, Drugs Fut., 1,148 (1976). J. R. Prous, ed., Annu. Drug Data Rep., 2,211 (1979/1980). S. S. Chu, Drugs Today, l9, 675 (1983). J. R. Prow, ed., Annu. Drug Data Rep., 2, 190 (1983). J. R. Prous, ed., Annu. Drug Data Rep., 2, 193 (1983). M. Neuman, Drugs Today, 2, 306 (1983). J. R. Prow, ed., Annu. Drug Data Rep., 2, 226 (1979/1980). L. deAngelis, Drugs Fut., 413 (1982). J. R. Prous, ed., Annu. Drug Data Rep., 5, 195 (1983). L. deAngelis, Drugs Today, 3, 271 (1983).
z,
Worldwide Market Introductions
Richard C. Allen, Hoechst-Roussel Pharmaceuticals, Inc. Sornerville, New Jersey 08876 Chapter 31.
To Market, To Market
-
1983
Richard C. Allen, Hoechst-Roussel Pharmaceuticals Inc., Somerville, NJ 08876 The ultimate goal of each of us engaged in the multidisciplinary fields of drug discovery and development is the introduction of the fruit of our efforts into the marketplace. Such a milestone may represent the validation of a scientific hypothesis and perhaps an indication of a new era in therapy, or simply, the emergence of an alternative to existing therapy, with or without measurable advantages. In all cases, such a market introduction represents an accomplishment of some magnitude in the face of formidable odds. The new chemical entities (NCEs) recently introduced into the US marketplace are by no means an accurate and timely reflection of these milestones; of the 20 NCEs appearing on the US market in 1983, only four represent first time introductions into the world marketplace-some were introduced 5-10 years ago in other markets and are certainly not an indication of what is new! An attempt has therefore been made to compile information on the first market introductions of NCEs for human therapeutic use in the world as a whole during 1983. It is hoped that this information will be useful to the reader as an accurate reflection of past accomplishments and perhaps future directions. A short summary of the profile, advantages/uniquenes, and utility of each compound is given; several leading references are offered for the reader interested in additional information.
Acetohydmxamic Acid (hypoammonuric)l,2 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
USA Research Organics; Baylor Unk. USA Uro-Research; Mission Pharrnacal LITHOSTAT
Acetohydroxamic acid is a potent, non-competitive and irreversible inhibitor of bacterial urease (Ki zlO-7M). This enzyme, which is widely distributed in plants and bacteria, but not in mammalian cells, catalyzes the decomposition of urea to ammonia. Elevated urinary ammonia levels can reduce the antibacterial effectiveness of a number of agents. Thus, acetohydroxamic acid is useful as adjunctive therapy to decrease urinary ammonia and alkalinity in patients with chronic urea-splitting urinary infection. Such infections are a leading cause of recurring complications and death in paraplegics.
Afloqualone (muscle relaxant)3,4 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Japan Tanabe Japan Tanabe AROFUTO
ANNUAL REPORTS IN MEDICINAL CHEMISTRY-
19
Copyright 0 1984 by Academic Press, Inc. All rights of reproduction in any form reserved ISBN 0-12-040519-9
314
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A l l e n , Ed.
Afloqualone is a centrally acting muscle relaxant useful in the management of various spastic conditions, including cerebral palsy, cervical spondylosis, and multiple sclerosis. It is closely related to the hypnotidsedative methaqualone. Alfentanil Hydrochloride (analgesic)5 9 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Belgium Jansseu Netherlands Janssen RAPIFEN
0
CH 20CH 3
CH3CH2~)+H2CH2<*-4>*’ \rcocH2~~3
0-
*4*-\*
‘HC1*H20
‘a=*
/
Alfentanil is a narcotic analgesic with a more rapid onset and shorter duration of action than its structural relative fentanyl. The primary utility of alfentanil is in surgical analgesia/anesthesia, especially for cardiac compromised patients and in procedures of short duration.
Alminoprofen (ana1gesic/antiinflammatory)’7 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
France Labs. Dr. E. Bouchara France Labs. Dr. E. Bouchara MINALFENE
.404\ /*
H3\ p 2 = \
JizOOH
*=a
H2C
Alminoprofen is an arylpropionic acid analgesic/antiinflammatory agent indicated for the short term management of dental, traumatic and postpartum pain.
%.A
Amrinone (cardiotonic)8,9 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
USA Sterling-Winthrop Phillipines Sterling Drug INOCOR
H 2 ( \ * /
I
!
*
\.4 *‘
‘sf
*\.
Amrinone is a positive inotropic agent useful in the management of severe congestive heart failure. It is effective even in unresponsive, fully digitalized patients.
Astemizole (antihistamine)lO,ll Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Belgium Janssen United Kingdom Jaasslen EISMANAL
/*
I
.r\* ;*=/
Astemizole belongs t o the second-generation class of non-sedating, non-anticholinergic antihistamines. Its non-sedating properties appear to result from its poor penetration of the blood brain barrier. As a result it shows no potentiation of CNS depressants, including alcohol. Its long half-life allows once-daily dosing.
Auranofii (chrysotherapeutic)l~~13
YH flCOCH 3
French
/*-rAu+P
First Introduction: W. Germany Introduced by: Smith Kleia & French Trade Name: RIDAURA
cH3oc&\rzf/
CountryOriginator: of Origin: USA Smith Kleiu
(Ir
(C 2H 5 ) 3
~COCH~
To Market, To Market
Chap. 31
Allen
315
Auranofin is the first orally effective gold compound to be marketed for the treatment of severe rheumatoid arthritis. It is better tolerated and more convenient than gold sodium thiomalate, which is administered intramuscularly. Refunolol Hydrochloride (antiglaucoma)l4,15 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Japan Kalcen Japan Kaken BENTOX
Befunolol hydrochloride is the newest of the 8-adrenergic blockers to be introduced for the treatment of glaucoma. It is reportedly devoid of intrinsic sympathomimetic activity, with lower membrane-stabilizing activity than propranolol.
Betaxolol Hydrochloride (8-adrenergic blocker; antihypertensive)16,17
Country of Origin: France First Introduction: France Trade Name: KERLONE
Originator: Synthelabo Introduced by: Robert & Carriere
Betaxolol hydrochloride is a cardioselective 8-adrenergic blocker, reportedly devoid of intrinsic sympathomimetic and membrane stabilizing properties. Its long duration of action permits once-daily dosing in mild to moderate hypertension. It is also being evaluated in glaucoma. Bifonazole (antif ung al)18919 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany Bayer
W. Germany Bayer
MYCOSPOR
Bifonazole represents the first topical broad spectrum antimycotic approved for once daily administration. Its in vitro activity appears equivalent t o its structural relative clotrimazole, being effective against dermatophytes, other filamentous fungi, dimorphic fungi and yeasts. Brotizolam (hypnotic/sedative)20,21 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany
Boehringer Ingelheim Switzerland
Boehrhger Ingelheim LENDORMIN
Brotizolam is a hypnotic/sedative approximately 60-1 00 times more potent than flurazepam. As with other short-acting, annulated benzodiazepines (e.g., triazolam), cited advantages include lack of adverse effects on sleep and performance after arousal. Budralazine (antihypertensive)22,23 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Japan Daiichi Japan Daiichi
BUTERAZINE
IlJI \ ;
i* 7 1
A*P
*\*/
316
Sect. V I I
- Worldwide Market
Introductions
Allen, Ed.
Budralazine is an antihypertensive agent which is somewhat less potent than structurally related hydralazine, and reportedly produces less tachycardia.
Butyl Flufenamate (topical a n t i i n f l a m r n a t ~ r y ) ~ ~
Japan *A* A* Hokaariku ' I Japan *+*/ Hohnitu; Tokyo Tanabe h02C4HB FENAZOLE; COMBEC Butyl flufenamate is a topical, non-steroidal antiinflammatory agent indicated for the treatment of acute and chronic eczema; contact, seborrheic, and atopic dermatitis; and herpes zoster. Country of Origin: Originator: First Introduction: Introduced by: Trade Names:
i\.8icp3 '
Cadexomer Iodine (wound healing agent)25 Country of Origin: United Kingdom First Introduction: United Kingdom Trade Name: IODOSORB
Originator: Perstorp Introduced by: Stuart
Cadexomer Iodine is a hydrophilic, modified starch polymer containing 0.9% iodine within the helical structure; it is used in the treatment of decubitus and venous leg ulcers. Applied to a wound surface as a powder, it is reported to accelerate healing, stimulate granulation, clean the ulcer surface, relieve pain and reduce bacterial counts.
.
Cefmenoxime Hydsochldde ( a n t i b i o t i ~ ) ~ ~ , ~ 7 GOOH
CH3
Originator: Takeda Country of Origin: Japan Introduced by: T Nippon Roche First Introduction: Japan Trade Names: TACEF; BESTCALL Cef menoxime hydrochloride is a third generation cephalosporin antibiotic. Structurally, it possesses the (1-methyl-lH-tetrazol-5-y1)thiomethylmoiety in the 3-position; like several other compounds containing this structural element (moxalactam, cefoperazone, cefamandol), bleeding linked to vitamin K interaction has been reported. Cefmenoxime has activity similar to cefotiuime, ceftizoxime and moxalactam against E. C. diversus, Klebsiella, g. Mirabilis, Salmonella, Shigella, Neiseria spp., 5. pyogenes, 5. Pneumoniae, and g. influenzae. It is relatively ineffective against Pseudomonas and Bacteroidea.
e,
Ceftddime ( a n t i b i o t i ~ ) ~ ~ , ~ 9 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
United Kingdom Glaxo United Kingdom Glau, PORTAM
Hz\*/S*
t:2-CH2<
+/*-.\ *,
"*+ '/ e=* ~ - J ~ ~ o m ~ l l l l l ~I 3 , d * OC (CH3) 2CO 2H
Ceftazidime is the latest third generation cephalosporin to reach the market. It has one of the broadest spectrums of the cephalosporins, similar in many regards to that of cefotaxime. It is particularly active against Pseudomonas aeruginosa, being perhaps 4-5 times more potent in vitro than moxalactam and cefotaxime.
Chap. 31
Allen
To Market, To Market
317
Celiprolol Hydrochloride ( 8-adrenergic blocker)30,31 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Austria Chemie Linz Austria Chemie Linr SELECTOL
(C2H5) 2NCONH-.(
/-\ a=.
).-OCHz 'HC1
Celiprolol hydrochloride is a once-daily, cardioselective padrenergic blocker useful in the management of hypertension, angina pectoris and hyperkinetic heart syndrome. It is also being evaluated in glaucoma.
Chenodiol (anti~holelithogenic)~~,~3 ,COOH
Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
'a
USA Rowell USA Rowell CHEWM
Chenodiol is the first agent to be introduced into the US market for the treatment of radiolucent gallstones. Large scale clinical trials have demonstrated the safety and efficacy of this agent. Chenodiol reduces the biliary concentration of cholesterol relative to that of bile acids and phospholipid, reducing the saturation and thus the lithogenicity of the bile. Success rates in dissolving gallstones are in the range of 50-70% within 4-24 months of treatment. Continuation of the drug after stone dissolution may be required t o prevent reoccurrence. Chenodiol is the 7a-isomer of ursodeoxycholic acid which was introduced into the European market in 1978.
Cyclosporine (ciclosporin) (immunosuppressant)34,35
H3)xfH,.)CH3
C H 2 T p H
H$x 4
5
Country of Origin: Switzerland First Introduction: Switzerland Trade Name: SANDIMMUN
-CO-Abu-MeGly-+leLeu-Val-+leLeu y6
R
7
8
l1
1
Originator: Sandoz Introduced by: Sandoz
Cyclosporine is a cyclic polypeptide with potent, partially selective immunosupressive activity. Isolated from the species Cylindrocarpon lucidium and Trichoderma polysporum, cyclosporine is useful in the prevention and treatment of graft/host disease and the prevention of rejection following organ transplantation. It appears to act by preferentially suppressing T-lymphocytes. Cyclosporine lacks myelotoxicity, although impaired renal and liver function have been observed. Initial administration is via the intravenous route, followed by oral maintenance therapy.
318
Sect. VII
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Allen, Ed.
Ehocitabine (antineoplast ic)36,37
O\
CountryOriginator: of Origin: Japan Asahi First Introduction: Japan Introduced by: Topp Jozo Trade Name: SUNRABIN
""2\0/\/"(:>0*co \ TI
(CH2) 2OCH3
Hb-.
Enocitabine is an antileukemic agent closely related to cytarabine. It appears more resistant to deamination than cytarabine, thus allowing greater in vivo phosphorylation into an active cytotoxic metabolite.
EperisomeHydmchbn'de (muscle r e l a ~ a n t ) 3 ~ , 3 9 Country of Origin: Japan Originator: Eisai First Introduction: Japan
. C2Hg-*'
Introduced Trade Name: by: MYONAL E M
/-*\ 'o=o'
k . 0 HCH2
ZH3
.--.
'0-0':~~~
Eperisone hydrochloride is a centrally acting muscle relaxant useful in the management of various spastic conditions including cervical spondylosis and cerebral palsy. It is structurally related to tolperisone. Epoprostenol sodium (platelet aggregation i n h i b i t ~ r ) ~ O , ~ l Country of Origin: Originator: First Introduction: Introduced by: Trade Names:
United Kingdom Burroughs Wellcome United Kingdom Burroughs Wellcome; Upjohn FtoLAN;CYCLO-PROSTIN
8H
Epoprostenol sodium (prostacyclin) is a naturally occurring prostaglandin indicated for the preservation of platelet function during cardiopulmonary bypass, prevention of platelet aggregation during charcoal hemoperfusion of patients in hepatic failure, and as an alternative to heparin during renal dialysis.
Fenbuprol (choleretic)4&43 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany Klinge Pharma W. Germany Rhom Pharma VALBIL
,.=. l H
,8"8/.-O-CHz
HCliflC4Hg
Fenbuprol produces an increase in the volume of bile secretion. It is useful in patients having symptomatology associated with biliary tract dysfunction. Flutamide (antineoplastic)%45 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
USA
scheting Chile Schering DROGENIL
( CH 3 2
Flutamide is an orally active, non-steroidal antiandrogen indicated for the treatment of prostatic cancer in both castrates and noncastrates.
Allen
To Market, To Market
Chap. 31
Fluvoxamine Maleate (serontonergic antidepressant)46-48 Country of Origin: Netherlands Originator: First Introduction: Introduced by: Trade Name:
Duphar Switzerland Kali-Duphar FLOXYFRAL
F3C-0,
.=.
p*-*\,
/ 3i-CH2-CH2-CH2-CH2-0-CH3 N-O-CH 2-CH 2-NH 2 ‘C4H404
Fluvoxamine maleate is the most recent of the serotonin-specific antidepressants to reach the market. In vitro and in vivo animal experiments have shown fluvoxamine t o have a marked effect on 5-HT mediated processes and little effect on norepinephrine. Clinical trials suggest similar efficacy t o imipramine and clomipramine with a somewhat lower incidence of side effects, especially anticholinergic effects. Fluvoxamine, in contrast to the tricyclic antidepressants, does not appear to produce heart rate increase, postural hypotension or prolongation of the intraventricular conduction t i m e and QT interval.
Gallopamil Hydrochloride (antianginal)49 Country of Origin: Originator: First Introduction: Introduced by:
W. Germany
Knoll W. Germany Chem. Werke Minden Trade Name: PROCORUM
CH 30
Gallopamil hydrochloride is a somewhat more potent methoxy analog of calcium channel blocker verapamil with a similar profile. It is useful in the treatment of angina and auricular arrhythmia.
Gemeprost ( a b ~ r t i f a c i e n t ) ~ ~ , ~ ~ Country of Origin: Originator: First Introduction: Introduced by:
Japan On0
MalaysiaJSingapore May & Baker
Trade Name: CERVAGEM
*/*\ */’\*/
o\*-.P+*\
CO 2CH 3
/
'a-•
Ho\+’
1.4
\*/
\*/ \*/
dH
Gemeprost, a metabolically stabilized analog of PGE1,has been demonstrated t o reliably induce termination of early pregnancy when administered as a vaginal suppository. Its effect is presumably due to both uterine contraction and rapid decline of steroid hormone levels. Minimal side effects have been reported.
Guanadrel Sulfate (antihypert ensive)%53 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
USA Cutter USA Penuwalt WLOREL
Guanadrel sulfate is an antihypertensive belonging t o the class of adrenergic neuron blocking drugs. It diminishes sympathetic vasoconstriction by inhibiting norepinephrine storage and release from neuronal storage sites. It appears similar in effectiveness and side effect profile to its structural relative guanethidine.
319
320
Sect. VII
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Introductions
a
Halometasone (topical antiinflammatory)%55 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Allen, Ed.
Switzerland Ciba-igy Switzerland Ciba-Geigy SICORTEN
Halometasone is a Dotent,. topical - steroid useful in a variety of acute and chronic eczematous dermaioses and psoriasis. It is reportedly devoid of skin toxicity and systemic effects. Hydrocortisone Butyrate Propionate (topical antiinflammat0ry)5~ GH flCOCH 2CH 3 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Japan Taiaho Japan Taisho
PANDEL
Hydrocortisone butyrate propionate is a potent, topical steroid reported to possess minimal systemic side effects. It is indicated in the treatment of various acute and chronic contact, eczematous, and atopic dermatoses and psoriasis. Jndalpine (serotonergic a n t i d e p r e ~ s a n t ) ~ ~ - ~ g
Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
France Pharmuka France Labs. Fournier Freres UPSTENE
.’! /.B c r ‘0-.
\*/
yH
Indalpine is a non-tricyclic antidepressant with a serotonin selective profile. It is 6-7 times more potent than fluoxetine and clomipramine in inhibiting serotonin reuptake in vitro in rat brain synaptosomes. Statistically significant clinical effects within one week of onset of treatment have been reported. An anxiolytic effect may accompany the antidepressant effect. Indalpine appears devoid of anticholinergic and cardiovascular side effects and does not promote weight gain or affect appetite. sox xi cam (antiinflammatory)6&62 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
USA
Warner-Lambert W. Germany Warner-Lambert
PAC=
Isoxicam is a non-steroidal antiinflammatory agent useful in the treatment of various forms of rheumatoid arthritis, osteoarthritis and musculoskeletal disorders. It is about one-tenth as potent as its structural relative sudoxicam; its similar long TQ (>30hrs.) allows once-daily dosing.
Chap. 31
To Market, To Market
Allen
Loprazolam Mesylate (hypnotic/sedative)63,64 Country of Origin: United Kingdom Originator: R o w e l First Introduction: United Kingdom Introduced by: Roussel Trade Name: DORMONOCT
p<
*-a
*-a
)NCH3
‘a
’ ‘
a’
‘a
02daaa/
Loprazolam mesylate is a potent hypnotic/sedative belonging t o the second generation of annulated-l,4benzodiazepines. The T + of loprazolam (-6 hr.) is longer than those of triazolam and midazolam, but shorter than the “effective” T% of flurazepam.
/.
*CH3S03H
*/ ‘*/C‘
! U a/
Meglutol ( h y p ~ l i p i d e r n i c ) ~ ~ , ~ ~ Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
India Aligarh Muslim Univ.
Italy Ausonia LIPOGLUTAREN
p:“
HO2CCH2 CH2C02H
Meglutol (B-hydroxy- 6-methylglutaric acid; HMG) is a hypolipidemic agent that acts via the inhibition of cholesterol synthesis a t the stage of HMG-CoAreductase, blocking the conversion of HMG-CoA to mevalonate. This conversion is the rate-limiting step in cholesterol biosynthesis and is the point of physiological feedback control; as such, it appears to be the ideal locus of action for a hypolipidemic agent. Investigational compounds that act by this mechanism include the natural products compactin and mevinolin. Meptazinol Hydrochloride
r3
/ \
Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
United Kingdom Wyeth United Kingdom Wyeth MEPTID
1
i/C2H5 a
\
\a-a/
*HC1
*Aa ‘ I ‘OH
Meptazinol hydrochloride is an injectable narcotic analgesic with antagonist properties; it is similar in potency to meperidine. Meptazinol appears to have a low propensity toward respiratory depression and other opiate-like side effects, possibly due to selective interaction with the mu-1 receptor. Also somewhat unique for an analgesic, it interacts with central cholinergic receptors. An oral form of meptazinol is under development. Muzolimine (diuretic)70-72 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany Bayer Italy Bayer EDRUL
321
g-*/ 3
H 2 ‘ a v
I
a -.
/*-a\
/c \a<]
\a=./
b
Muzolimine is a structurally novel, pyrazolone diuretic with a high-ceiling profile. It is somewhat slower in onset than furosemide, but has a more prolonged effect, similar t o the thiazides. Muzolimine has been shown to be effective in edema of cardiac, hepatic and renal origin. It also appears to be effective as an antihypertensive agent.
322 -
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Allen, Ed.
Nitrefazole (alcohol deterrent)73,74 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany E. Merck W. Germany E. Merck ALTIMOL
Nitrefazole is an inhibitor of aldehyde dehydrogenase useful in the management of alcoholism. Cited advantages over disulfiram include longer duration of action, higher specificity (no inhibition of dopamine 8-hydroxylase) and fewer side effects. It is generally recognized that the efficacy of such agents with respect to permanent abstinence is low. However, temporary abstinence and/or controlled drinking may facilitate supportive psychotherapy and/or delay the onset of severe alcoholic diseases. Norfloxacin (antibact erialI7597 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Japan Kyorin Italy Merck NOROXIN
Norfloxacin is the first of the third generation nalidixic acid analogs to reach the marketplace. It exhibits potent in vitro and in vivo activity against Pseudomonas, enteric gram-negative rods and gram-positive cocci. Norfloxacin is orally effective in the treatment of urinary tract infections, including those due to organisms refractory to many other agents. ~ x a p r o z i n(antiinflammatory)77,78 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
United Kingdom
Wyeth Fbrtugal
Wyeth DURAPROX
H C ~ H ~ oCOA 2 o~o\o/
1-4
c 6 d
Oxaprozin is a non-steroidal antiinflammatory agent indicated for use in various forms of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. A long T$ allows once/twice daily dosing. Structurally it is somewhat unique, being a 3substituted, rather than a 2-substituted propionic acid. Oxiconazole Nitrate (antifungal)79 Country of Origin: Originator: First Introduction: Introduced by: Trade Names:
Switzerland Siegfried Switzerland Sauter; Siegfried OCERAL; MYFUNGAR
c1
Oxiconazole nitrate is a broad-spectrum antifungal agent indicated for the treatment of skin infections due to yeasts, dermatophytes, yeast-like fungi and molds, and gram positive organisms.
Allen
To Market, To Market
Chap. 31
Oxitropium Bromide (bronchodilat or)80-8 2 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
W. Germany Boehringer Ingelheim W. Germany Dieclcmann
TERSIGAT
Oxitropium bromide is an analog of the anticholinergics methscopolamine bromide and ipratropium bromide, useful in the treatment of bronchial asthma. Cited advantages include a long duration of action and lack of cardiovascular effects.
Promegestone (progestogen)83,84 France Roussel France Labs. Cassenne Trade Name: SURGESTONE
Country of Origin: Originator: First Introduction: Introduced by:
a’
‘.’
H3C FOCH2CH3 a I am*CH3
I
l
\a
l
a/ag\a/ I
/\*/
!
a-a
! La/
Promegestone is a potent progesterone-like agent devoid of androgenic properties, and thus masculinizing side effects. It is useful in the treatment of various gynecological conditions due to luteal insufficiency, such as premenopausal disorders, dysmenorrhea, and premenstrual syndrome. sodium Cellulose Phosphate (hypocalciuric)85
Country of Origin: USA First Introduction: USA Trade Name: CALCIBIND
Originator: University of Texas Introduced by: Mission Pharmacal
Sodium cellulose phosphate (SCP)is an insoluble, non-absorbable ester of cellulose containing 34% inorganic phosphate and 11% sodium. It is capable of binding calcium in the intestinal tract, reducing absorption of this ion, as well as magnesium. SCP is indicated only for the treatment of absorptive hypercalciuria type I with recurrent calcium oxalate or calcium phosphate nephrolithiasis. ~ u f e ~ t a n(analgesic)86,87 il
Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Belgium Jaassen Netherlands Janssen SUFENTA
a-a
1
\d
E(~-)~,CHZOCH 3 1-CH2CH2 *-a )COCH~CR~
Sufentanil is a narcotic analgesic with a greater potency and therapeutic ratio than its structural relative fentanyl. It appears t o produce fewer cardiac effects and less respiratory depression than fentanyl, and thus is especially useful as an analgesic/anesthetic in open heart surgery.
323
324
Sect. VII
- Worldwide Market Introductions
Allen, Ed.
Suprofen (analgesic/an t iinflam mat ory)88-90
Belgium .Ao/ 2H Janssen I 1 Switzerland \s/ Cilag MALDOCIL Suprofen is an arylpropionic acid analgesic/antiinflammatory agent with close structural resemblance to ketoprofen. It is more potent in many assays than indomethacin and ketoprofen and appears better tolerated. Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Terconazole (antifungal)gl Country of Origin: Belgium Originator: First Introduction: introduced by: Trade Name:
\./ \./. 8
I;-!
\.A/
Janssen Switzerland
Cilag FUNGISTAT
Terconazole is an antifungal agent somewhat more potent than clotrimazole and useful in the topical treatment of vaginal dermatophytosis and candidiasis.
Tianeptine Sodium (serotonergic antidepressant)9&93 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
France Sci. Union et Cie France Servier STABLON
‘ L 1 I\./. ’ .\./ Lo/
h ( C H 2 ) &O 2 N a
Tianeptine sodium is a structurally novel, serotonin specific antidepressant. It is useful in the treatment of neurotic and reactive depressions, as well as depressive states accompanied by anxiety.
Tioconazole (antifungal)g4
/.‘7 71
Country of Origin: United Kiugdom fo)?-CH2[HDCH2T’ Originator: Pfieer 0-0 - - 0 First Introduction: Switzerland / Introduced by: Pfizer i i Trade Name: TROSYL Tioconazole is an antifungal agent, closely related to A1 miconazole. Tioconazole is effective in the topical treatment of superficial fungal infections and appears t o be more potent than miconazole against Candida and Trichophyton species.
\p
.\./
Tiropramide Hydrochloride (antispasmodic)95-97 Country of Origin: Originator: First Introduction: Introduced by: Trade Name:
Italy (C 2H5 2N( CH2 ) 2 0 4 ’ Rotta Research Italy Rotta ResearCa; Rarer MAIORAD; ALFOSPAS
‘.+Xi2
.HC1
€ICON( C LCOC&
Tiropramide hydrochloride is a smooth muscle relaxant indicated for the treatment of spastic conditions of the gastrointestinal and urogenital systems. It appears to act by increasing intracellular levels of c-AMP.
2
Chap. 31
To Market, To Market
Allen
325
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Sect. V I I
- Worldwide
Market I n t r o d u c t i o n s
A l l e n , Ed.
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