EP0339071A1 - IMIDAZO(1,2-a)(PYRIDAZINES OR PYRAZINES) FOR TREATMENT OF DISEASES RELATED TO BONE LOSS - Google Patents

IMIDAZO(1,2-a)(PYRIDAZINES OR PYRAZINES) FOR TREATMENT OF DISEASES RELATED TO BONE LOSS

Info

Publication number
EP0339071A1
EP0339071A1 EP88909620A EP88909620A EP0339071A1 EP 0339071 A1 EP0339071 A1 EP 0339071A1 EP 88909620 A EP88909620 A EP 88909620A EP 88909620 A EP88909620 A EP 88909620A EP 0339071 A1 EP0339071 A1 EP 0339071A1
Authority
EP
European Patent Office
Prior art keywords
treatment
compound
formula
pyridine
imidazo
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.)
Withdrawn
Application number
EP88909620A
Other languages
German (de)
English (en)
French (fr)
Inventor
Ingemar Starke
Björn Wallmark
Kalervo Väänänen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hassle AB
Original Assignee
Hassle AB
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hassle AB filed Critical Hassle AB
Publication of EP0339071A1 publication Critical patent/EP0339071A1/en
Withdrawn legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/10Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A61P5/12Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Definitions

  • Imidazo(1,2-a)(pyridazines or pyrazines) for treatment of diseases related to bone loss.
  • the present invention is related to a novel method for the treatment of several bone affecting diseases, especially osteoporosis, which are characterized by loss of bone mass.
  • bone formation which is associated with the number and activity of osteoblasts, that is cells associated with the production of bone in the organism
  • bone loss which is associated with the number and activity of osteoclasts, that is cells associated with the absorption and removal of bone
  • osteoporosis can be mentioned, Paget's disease of bone, hyperparathyroidism and related disorders, and several malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcemia.
  • osteoporosis bone formation as well as bone resorption are disturbed, resulting in decreased bone mass. Osteoporosis predominantly affects the elderly, but also other groups such as postmenopausal women, where an estrogen deficit is believed to be a significant etiological factor, and immobilized patients. At this point it is not possible to clear up the whole picture of the disease mechanism and estimate which is the primary cause of osteoporosis. However, about 25 % of osteoporotic females belong to what is called “rapid bone losers" and at least in those patients the bone resorption rate is probably increased. Landry and Fleisch showed in immobilization induced osteoporosis that bone resorption rate was accelerated, (Landry, M. and Fleisch, H, : The influence of immobilization on bone formation as evaluated the incorporation of tetracyclines. J. Bone Joint Surg. 46B:764, 1964).
  • osteoporosis comprise fractures, especially hip fractures, but also vertebral fractures and fractures of the proximal radius, and complication of such fractures.
  • in Finland it has been estimated that about 10 % of all surgical hospital beds are used for the treatment of osteoporosis related fractures (Luthje, P.: Reisiluunkaulan ja trokantterin murtumapotilaiden hoito ja ennuste seka hiodon kustannukset. Thesis. Helsinki 1983).
  • the present methods for the treatment of osteoporosis include exercise; administration of estrogen, especially for postmenopausal women; and consumption of calcium or calcium containing material such as milk.
  • Calcitonin a hormone associated with calcium metabolism, has also been used in the treatment of osteoporosis. None of these methods of treating osteoporosis results in increase of the bone mass.
  • malignant tumors are known to be associated by hypercalcemia which is due to increased osteoclastic activity. This is a common complication for instance in the case of breast cancer and prostate cancer which are both one of the most common malignant tumors.
  • Hypercalcemia is due to both systemic and local factors.
  • Some malignant cells are known to secrete agents which stimulate bone resorption (Sato, K., Fujii, Y. Kachivehi, T., Kasono, K., Shizume, K.: Production of interleukin 1 alpha (IL-1 ⁇ )-like activity and colony stimulating activity by clonal squanous cell carcinomas derived from patients with hypercalcemia and leucocytosis.
  • IL-1 ⁇ interleukin 1 alpha
  • Pacret's disease (or osteitis deformans) of bone is a disease of unknown etiology where bone resorption and remodelling are increased leading sometimes even to the fractures of affected bone. Bone pain is the main indication of treatment in these patients. In these patients there is highly elevated local osteoclastic bone destruction. The incidence of osteitis deformans is very low in Scandinavian countries. In England it has been estimated to be present in 3-4 % of population on the basis of autopsy studies (Anderson's Textbook of Pathology 1986). It is very rare in patients under 40 years. Calcitonin and diphosphonates are also used in the treatment of Paget's disease.
  • Arylalkoxy-, arylalkylamino- and arylalkylthio-substituted imidazo (1,2-a)pyridines and imidazo (1,2-a)pyrazines are known in the art, e.g. EP-Al-0068378 and EP-A1-0033094, as are methods for using these compound to reduce gastric acid secretion.
  • compounds of the general formula I as well as pharmaceutically acceptable salts thereof are effective as inhibitors of basal and stimulated bone resorption and are useful as medicals for the treatment of diseases related to bone loss and increased bone resorption, such as osteoporosis, Pagefs disease of bone, hyperparathyroidism, both primary and secondary, malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcemia, immobilization-induced osteoporosis, parodontal diseases and prostetic and implant- related bone losses.
  • diseases related to bone loss and increased bone resorption such as osteoporosis, Pagefs disease of bone, hyperparathyroidism, both primary and secondary, malignant neoplasms where tumor cells are producing osteoclast-activating factors and cause hypercalcemia, immobilization-induced osteoporosis, parodontal diseases and prostetic and implant- related bone losses.
  • the compounds to be used according to th e i nventi on are of the fol lowing formul a I :
  • A is a nonaromatic 5- or 6-membered ring containing O or 1 heteroatom selected from nitrogen, sulfur and oxygen;
  • R x , B y , R z and R u are H, R 9 or R 10 ;
  • R 9 represents H, loweralkyl, halogen, OH, CF 3 or loweralkoxy
  • R 10 is -Z-T-Ar wherein Z represents -O-, -NH-, -SO m - or a single bond; T represents a straight- or branched chain loweralkylene group; when Z is a single bond, T also represents an ethenylene or a propenylene group wherein the unsaturated carbon is at the single bond; when Z is -O-, T also represent an allylene group wherein the saturated carbon is at the oxygen;
  • n zero, one or two
  • n zero, one or two
  • R 4 and R 5 each independently represents H, loweralkyl, loweralkoxyloweralkyl, trifluoromethylloweralkyl, Ar-loweralkyl, Ar, or, when taken together with the nitrogen to which they are attached, form a 4-, 5- or 6-membered cyclic amino group;
  • R 1 represents Ar, loweralkyl, NR 4 R 5 , B-NR 4 R 5 or Ar-loweralkyl;
  • R 6 represents H, C 1 - to C 12 -alkyl, Ar or Ar-loweralkyl
  • R 7 represents H or loweralkyl
  • R 8 represents H, loweralkyl, loweralkoxyloweralkyl, trifluoromethylloweralkyl, Ar-loweralkyl or Ar;
  • salts thereof especially acid addition salts such as hydrochloride and hydrobromide salts,
  • R x is R 9 and R Y is H when G is the group
  • halogen includes fluoro, chloro, bromo and iodo, with fluoro and chloro being preferred;
  • lower when applied to alkyl groups, means straight and branched chain alkyl groups having up to six carbon atoms such as methyl, ethyl, propyl, butyl, t-butyl, isopropyl, neopentyl, dimethylbutyl etc., whereby methyl and ethyl are preferred;
  • pyridyl includes the 2-, 3- and 4-isomers and their halogen- or loweralkyl-substituted analogues;
  • thienyl and “furanyl” include the 2- and 3-isomers and their halogen- and loweralkylsubstituted analogues;
  • imidazolyl included the 2- and 4-isomers and their halogen- and loweralkyl-substituted analogues
  • the loweralkylene group represented by T preferably has 1-6, especially 1-3 carbon atoms as in methylene, ethylene and propylene,
  • Suitable “loweralkenyl” may be the ones having 2 to 6 carbon atoms and may include vinyl, allyl, isopropenyl, 1 (or 2 or 3)-butenyl or 1 (or 2 or 3 or 4)-pentenyl.
  • Suitable “loweralkadienyl” may be the ones having 3 to 6 carbon atoms and may include 1,2-propadienyl, 1,2-butadienyl, 1,3-butadienyl, 2,3-pentadienyl or 1,4-pentadienyl.
  • loweralkenyloxy(lower)alkyl suitable examples may include vinyloxymethyl, allyloxymethyl and 1-allyloxyethyl.
  • loweralkynyloxy(lower)alkyl suitable examples may include ethynyloxymethyl, 2-propynyloxymethyl, 2-(2-propynyloxy)ethyl and 1-(2-butynyloxy)propyl.
  • the invention relates to
  • a preferred group of compounds within the general formula I for use according to the present invention is that wherein G is the group
  • Example 1 The compound 8-benzyloxy-3-cyanomethyl-2-methyl-imidazo- (1,2-a)pyridine (Example 1), 8-benzyloxy-3-hydroxylmethyl- 2-methyl-imidazo(1,2-a)pyridine (Example 2) and Example 3 (mentioned above) were tested. As can be seen from Table 1 the compound was found to significantly inhibit both basal bone resorption and PTH-induced bone resportion.
  • the compounds of the formula I are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration.
  • the pharmaceutical formulation contains a compound of the formula I in combination with a pharmaceutically acceptable carrier.
  • the carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule.
  • These pharmaceutical preparations are a further object of the invention.
  • the amount of active compounds is between 0.1-95 % by weight of the preparation, between 0.2-20 % by weight in preparations for parenteral use and between 1 and 50 % by weight in preparations for oral administration.
  • the typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of active substance.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP88909620A 1987-10-30 1988-10-27 IMIDAZO(1,2-a)(PYRIDAZINES OR PYRAZINES) FOR TREATMENT OF DISEASES RELATED TO BONE LOSS Withdrawn EP0339071A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8704248A SE8704248D0 (sv) 1987-10-30 1987-10-30 Medical use
SE8704248 1987-10-30

Publications (1)

Publication Number Publication Date
EP0339071A1 true EP0339071A1 (en) 1989-11-02

Family

ID=20370069

Family Applications (1)

Application Number Title Priority Date Filing Date
EP88909620A Withdrawn EP0339071A1 (en) 1987-10-30 1988-10-27 IMIDAZO(1,2-a)(PYRIDAZINES OR PYRAZINES) FOR TREATMENT OF DISEASES RELATED TO BONE LOSS

Country Status (9)

Country Link
EP (1) EP0339071A1 (xx)
JP (1) JPH02501929A (xx)
KR (1) KR890701587A (xx)
AU (1) AU2620388A (xx)
DK (1) DK322189A (xx)
HU (1) HU203663B (xx)
IL (1) IL88205A0 (xx)
SE (1) SE8704248D0 (xx)
WO (1) WO1989003833A1 (xx)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
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CA1327796C (en) * 1987-07-16 1994-03-15 Jorg Senn-Bilfinger Diazoles
US5081253A (en) * 1989-12-21 1992-01-14 American Home Products Corporation Imidazo(4,5-c)pyridines as antiosteoporotic agents
US5464843A (en) * 1992-06-23 1995-11-07 G.D. Searle & Co. Imidazo[1,2-a]pyridinyldiacid compounds for cognitive enhancement and for treatment of cognitive disorders and neutrotoxic injury
JPH11505524A (ja) * 1995-05-01 1999-05-21 藤沢薬品工業株式会社 イミダゾ1,2−aピリジンおよびイミダゾ1,2−aピリデジン誘導体、および骨吸収阻害剤としてのその用途
GB9518552D0 (en) * 1995-09-11 1995-11-08 Fujisawa Pharmaceutical Co New heterocyclic compounds
US7709468B2 (en) 2005-09-02 2010-05-04 Abbott Laboratories Imidazo based heterocycles
WO2012087833A1 (en) 2010-12-22 2012-06-28 Abbott Laboratories Hepatitis c inhibitors and uses thereof
DE102012200349A1 (de) 2012-01-11 2013-07-11 Bayer Intellectual Property Gmbh Substituierte annellierte Pyrimidine und Triazine und ihre Verwendung
US9624214B2 (en) 2012-11-05 2017-04-18 Bayer Pharma Aktiengesellschaft Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
US8796305B2 (en) 2012-11-05 2014-08-05 Bayer Pharma Aktiengesellschaft Carboxy-substituted imidazo[1,2-a]pyridinecarboxamides and their use
US9126998B2 (en) 2012-11-05 2015-09-08 Bayer Pharma AG Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
US8778964B2 (en) 2012-11-05 2014-07-15 Bayer Pharma Aktiengesellschaft Hydroxy-substituted imidazo[1,2-a]-pyridinecarboxamides and their use
CA2914100A1 (en) 2013-06-04 2014-12-11 Bayer Pharma Aktiengesellschaft 3-aryl-substituted imidazo[1,2-a]pyridines and the use thereof
JP2016523944A (ja) 2013-07-10 2016-08-12 バイエル・ファルマ・アクティエンゲゼルシャフト ベンジル−1H−ピラゾロ[3,4−b]ピリジンおよびその使用
CN106459090A (zh) 2014-02-19 2017-02-22 拜耳制药股份公司 3‑(嘧啶‑2‑基)咪唑并[1,2‑a]吡啶
EP3119777A1 (de) 2014-03-21 2017-01-25 Bayer Pharma Aktiengesellschaft Cyano-substituierte imidazo[1,2-a]pyridincarboxamide und ihre verwendung
EP3137463A1 (de) * 2014-05-02 2017-03-08 Bayer Pharma Aktiengesellschaft Enantiomere des n-(2-amino-5-fluor-2-methylpentyl)-8-[(2,6-difluorbenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-carboxamids sowie der di- and tri-fluor-derivate zur behandlung von kardiovaskulären erkrankungen
EP3137465A1 (de) * 2014-05-02 2017-03-08 Bayer Pharma Aktiengesellschaft 6-chlor-substituierte imidazo[1,2-a]pyridincarboxamide und ihre verwendung als stimulatoren der löslichen guanylatcyclase
JP2017514899A (ja) * 2014-05-02 2017-06-08 バイエル・ファルマ・アクティエンゲゼルシャフト ヘテロシクリル−およびヘテロアリール−置換イミダゾ[1,2−a]ピリジンおよびその使用
CN107001361A (zh) 2014-12-02 2017-08-01 拜耳医药股份有限公司 杂芳基取代的咪唑并[1,2‑a]吡啶及其用途
EP3227286B1 (de) 2014-12-02 2018-12-26 Bayer Pharma Aktiengesellschaft Substituierte pyrazolo[1,5-a]pyridine und imidazo[1,2-a]pyrazine und ihre verwendung
JP2018505885A (ja) 2015-02-05 2018-03-01 バイエル・ファルマ・アクティエンゲゼルシャフト 置換ピラゾロ[1,5−a]−ピリジン−3−カルボキサミドおよびその使用
WO2016124564A1 (de) 2015-02-05 2016-08-11 Bayer Pharma Aktiengesellschaft N-substituierte 8-[(2,6-difluorbenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyrazin-3-carboxamid-derivate als stimulatoren der löslichen guanylatcyclase (sgc) zur behandlung von kardiovaskulären erkrankungen
WO2018184976A1 (de) 2017-04-05 2018-10-11 Bayer Pharma Aktiengesellschaft Substituierte imidazo[1,2-a]pyridincarboxamide und ihre verwendung

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US4468400A (en) * 1982-12-20 1984-08-28 Schering Corporation Antiulcer tricyclic imidazo [1,2-a]pyridines
DE3446778A1 (de) * 1984-12-21 1986-07-03 Dr. Karl Thomae Gmbh, 7950 Biberach Neue imidazoderivate, ihre herstellung und diese verbindungen enthaltende arzneimittel
US4725601A (en) * 1985-06-04 1988-02-16 Fujisawa Pharmaceutical Co., Ltd. Certain imidazo[1,2-a]pyridines useful in the treatment of ulcers
EP0228006A1 (en) * 1985-12-16 1987-07-08 Fujisawa Pharmaceutical Co., Ltd. Imidazopyridine compounds and processes for preparation thereof

Non-Patent Citations (1)

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Title
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Also Published As

Publication number Publication date
DK322189D0 (da) 1989-06-28
AU2620388A (en) 1989-05-23
SE8704248D0 (sv) 1987-10-30
WO1989003833A1 (en) 1989-05-05
IL88205A0 (en) 1989-06-30
DK322189A (da) 1989-06-28
JPH02501929A (ja) 1990-06-28
KR890701587A (ko) 1989-12-21
HU203663B (en) 1991-09-30
HUT51138A (en) 1990-04-28

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