AU4409797A - Novel methods - Google Patents
Novel methodsInfo
- Publication number
- AU4409797A AU4409797A AU44097/97A AU4409797A AU4409797A AU 4409797 A AU4409797 A AU 4409797A AU 44097/97 A AU44097/97 A AU 44097/97A AU 4409797 A AU4409797 A AU 4409797A AU 4409797 A AU4409797 A AU 4409797A
- Authority
- AU
- Australia
- Prior art keywords
- cardiovascular disease
- compound
- formula
- effects
- compounds
- 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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
NOVEL METHODS
Field of the Invention
The present invention relates to therapeutic agents that are tissue selective estrogen agonist/antagonist compounds that have been found to be useful in the treatment and prevention of cardiovascular disease in postmenopausal women.
Background of the Invention
The decrease in estrogen that occurs at the menopause is an important etiological factor in the increased incidence of cardiovascular disease in postmenopausal women. Estrogen therapy after the menopause has been shown to have beneficial effects on a number of independent risk factors for cardiovascular disease including serum levels of LDL-cholesterol and poprotein (a) (lp(a)) and plasma levels of fibnnogen. For references please see Levenson J et al, ( 1995), Artenoscler Thromb Vase Biol, 15, 1263-1268. Kroon et al ( 1994), Thomb Hemost, 71, 420-423. Ettinger B ( 1990) Obstet Gynecol Clinics of North America, 17, 741- 757 Mendoza S et al ( 1994) J Lab Chn Med 123, 837-841. These effects may explain in part the epideiruological observations that estrogen therapy causes a reduction in the incidence of cardiovascular disease. However unopposed estrogen given alone increases the risk of endometnal cancer and may also be associated with an increased risk of breast cancer. For these reasons and because of troublesome side effects (pπncipally breast tenderness and vaginal bleeding) few women continue HRT for long enough to benefit from the cardioprotective effects. An ideal therapy would retain the desirable cardiovascular effects of estrogen without having the unwanted effects on reproductive tissues. Consequently, efforts have been made to identify compounds that have tissue-selective estrogen agonist or antagonist properties. Such tissue selective effects could produce the beneficial effects of estrogen on risk factors for cardiovascular disease without the unwanted effects in breast and uteπne tissue.
Summary of the Invention
This invention provides a method for the prevention and treatment of cardiovascular disease in postmenopausal women without having an overt uterotrophic effect, or promoting an increased risk of breast cancer or causing an increased incidence of vaginal bleeding and breast tenderness The method comprises administering to a human in need thereof an effective amount of a compound of formula I
wherein X represents 3- or 4- lodo or bromo and the R-* and Rr symbols, which may be the same or different, represent Cj-3 alkyl, especially methyl or ethyl, groups or R1- represents a hydrogen atom and R2 a C1.3 alkyl group or R-- and R2 together with the nitrogen atom to which they are attached represent a saturated heterocyclic group, typically having 5 or 6 ring atoms, especially a pyrrolidmo, pipendino, 4- methylpipeπdino or morpholino group, and their pharmaceutically acceptable acid addition salts
Detailed Description of the Invention
The present invention is a therapeutic method for preventing and treating cardiovascular disease in postmenopausal women with a group of compounds that have been previously prepared and evaluated as effective in the treatment of estrogen receptor-positive breast cancer These compounds are described in formula I above and in U S. patent 4,839,155
The preferred compound for the described method of treatment is
(E)- l-[2-[4-[ l-(4-lodophenyl)-2-phenyl- l-butenyl]phenoxy]pyrrolιdιne
Such compounds are known to bind to the estrogen receptor and to cause either estrogen agonist or antagonist effects depending on the tissue bemg studied A beneficial effect on cardiovascular disease would be produced by estrogen agonist
effects on the liver ( to alter the hpid profile and levels of fibinogen) However estrogen agonist effects on the arterial wall may also contribute to a reduction in the risk of cardiovascular disease.
The term "cardiovascular disease" refers to atherosclerotic cardiovascular diseases such as myocardial infarction, stroke, angina, intermittent claudication transient blindness, transient lschemic attacks (TIA) and peripheral vascular disease. The method of this invention is useful in producing a plasma lipid profile that is associated with a reduced risk of atherosclerosis and a reduction of raised LDL cholesterol levels Additionally this method is useful in producing a reduction of other independent cardiovascular risk factors such as plasma fibnnogen levels and serum levels of lp(a).
The ability to reduce the risk of cardiovascular disease is assessed by studies of the effect of idoxifene a number of different risk factors for cardiovascular disease in postmenopausal women. These include different parameters of the pid profile and levels of coagulation and fibπnolysis markers.
Three different doses of idoxifene (2.5, 5 and lOmg/day) were compared with placebo in a study of three months duration m postmenopausal women. Changes in the levels of different lipid parameters, fibnnogen and other coagulation/fibπnolysis parameters were measured before and after treatment. The results of this study are described below All changes are descnbed as percentage change from the baseline value. Statistically significant differences from placebo are designated by the following notation: *=p<0.01 , **=p<0.001.
Placebo 2.5 5.0 10.0
Total chol 0.5(1.1) -0.9(1.1) -4.2(1.2)* -98(1.1)**
LDL-chol 1.3(1.5) -1.3(2.0) -4.7(1.7)* -15.2(1.6)**
HDL-chol 2.4(1.4) 2.7(1.5) -1.4(1.5) 0.8(1.7)
HDLLDL ratio 2.2(1.6) 7.1 (2.6) 5.2(2.1) 21.7(3.1)** lipoprotein (a) 5.0(3.0) -2.0 (6.0) 1.0(4.0) -6.0 (4.0) triεlvcendes 1.3(3.8) 1.8(3.9) -3.2 (3.6) 3.8(3.8)
Fibnnogen 5.8 (3.0) -17(2.4) -83(3 n* -16.9(2.4)**
D-dimer 00(31) 47(43) -21 (2.7) -71 (2.7)
Factor VII 54(2.4) -10.1 (24)** -96(21)** -111 (16)**
In the same study the incidence of vaginal bleeding and breast tenderness was reduced compared to placebo and there were no cases of histologically defined endometnal hyperplasia in idoxifene treated patients as compared to one case in the placebo cohort
These results show that in humans idoxifene is able to produce the desired beneficial effects of estrogen on cardiovascular risk factors without the undesirable effects on reproductive tissues. The compounds of the instant invention and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carner(s) for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or colonng agent A composition in the form of a tablet can be prepared using any suitable pharmaceutical carπer(s) routinely used for prepaπng solid formulations Examples of such earners include magnesium stearate, starch, lactose, sucrose and cellulose A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule: alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carner(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
The compounds of the instant invention and their pharmaceutically acceptable salts which are active when administered parenterally (i.e by injection of infusion) can be formulated as solutions or suspensions.
A composition for parenteral administration will generally consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrro done, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophi sed and then reconstituted with a suitable solvent just prior to administration
A typical suppository composition comprises a compound of the instant invention or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric
glycols, gelatins or coca butter or other low melting vegetable or synthetic waxes or fats
A typical transdermal formulation comprises a conventional aqueous or non- aqueous vehicle, for example, a cream, ointment lotion or paste or in the form of a medicated plaster, patch or membrane
For topical administration, the pharmaceutical compositions adapted include solutions, suspensions, ointments, and solid inserts Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, and water soluble ophthalmologically acceptable non-toxic polymers, for example, cellulose derivatives such as methyl cellulose The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting and bodying agents, as for example, polyethylene glycols, antibacterial components such as quaternary ammonium compounds; buffering ingredients such as alkali metal chloride, antioxidants such as sodium metabisulfite, and other conventional ingredients such as sorbitan monolaurate
Preferably the composition is in unit dose form. Doses of the compounds of the instant invention in a pharmaceutical dosage unit will be an efficacious, non- toxic quantity selected from the range of 01 - 200 mg/kg of active compound, preferably 1 - 100 mg/kg. The selected dose is administered to a human patient in need of treatment or prevention of cardiovascular disease is or in the lowering of plasma cholesterol from 1-6 times daily, orally, rectally, topically, by injection, or continuously by infusion Oral dosage units for human administration preferably contain from 10 to 500 mg of active compound Lower dosages are used generally for parenteral administration Oral administration is used when safe, effective, and convenient for the patient
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention
Example 1
An oral dosage form for administering orally active Formula (I) compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below
Ingredients Amounts (E)- 1 -[2-[4-[ I -(4-lodophenyl)-2-phenyl- 1 -butenyl] phenoxyjpyrrolidine 100 mg magnesium stearate 10 mg lactose 100 mg
Example 2 The sucrose calcium sulfate dihydrate and orally active Formula (I) compounds are mixed and granulated with a 10% gelatmg solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
ingredients Amounts
(E)- l-[2-[4-[l-(4-lodophenyl)-2-phenyl- 1 -butenyl] phenoxylpyrrolidine 75 mg calcium sulfate dihydrate 100 mg sucrose 15 mg starch 8 mg talc 4 mg stearic acid 2 mg
Eχι ample 3
(E)-l-[2-[4-[ l-(4-lodophenyl)-2-phenyl-l-butenyl]phenoxy]pyrrolidme, 50 mg, is dispersedin 25 ml of normal saline to prepare an injectable preparation.
Claims (6)
- What is claimed is1 A method of treating and preventing postmenopausal cardiovascular disease in women which compnses administering to a subject in need thereof an effective amount of a compound of formula I
- 2 A method according to Claim 1 wherein the compound of formula I is (E)-l-[2-[4-[ 1 -(4-lodophenyl)-2-phenyl- 1 -butenyl]phenoxy ]pyrrolιdιne
- 3 A method according to Claim 1 wherein the postmenopausal cardiovascular disease is myocardial infarction or stroke
- 4 The use of a compound of formula I in the manufacture of a medicament for use in the treatment of cardiovascular disease in women.
- 5 A use according to Claim 4 wherein the compound of formula I is (E)-l-[2-[4-[ 1 -(4-lodophenyl)-2-phenyl- 1 -buteπyl]phenoxy]pyrrolιdme.
- 6. A use according to Claim 4 wherein the disease is myocardial or stroke.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2543996P | 1996-09-06 | 1996-09-06 | |
| US60025439 | 1996-09-06 | ||
| US5066697P | 1997-06-24 | 1997-06-24 | |
| US60050666 | 1997-06-24 | ||
| PCT/US1997/015475 WO1998009619A1 (en) | 1996-09-06 | 1997-09-03 | Novel methods |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU4409797A true AU4409797A (en) | 1998-03-26 |
Family
ID=26699738
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU42473/97A Abandoned AU4247397A (en) | 1996-09-06 | 1997-09-03 | Method of treating post menopausal diseases, including osteoporosis |
| AU44097/97A Abandoned AU4409797A (en) | 1996-09-06 | 1997-09-03 | Novel methods |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU42473/97A Abandoned AU4247397A (en) | 1996-09-06 | 1997-09-03 | Method of treating post menopausal diseases, including osteoporosis |
Country Status (16)
| Country | Link |
|---|---|
| EP (2) | EP0927029A4 (en) |
| JP (2) | JP2002515047A (en) |
| KR (2) | KR20000068472A (en) |
| CN (2) | CN1236299A (en) |
| AR (1) | AR008155A1 (en) |
| AU (2) | AU4247397A (en) |
| BR (2) | BR9711681A (en) |
| CA (2) | CA2264943A1 (en) |
| CO (2) | CO5070658A1 (en) |
| CZ (1) | CZ76699A3 (en) |
| IL (1) | IL128645A0 (en) |
| NO (2) | NO991097D0 (en) |
| PL (2) | PL332038A1 (en) |
| TR (2) | TR199900506T2 (en) |
| TW (1) | TW411273B (en) |
| WO (2) | WO1998009619A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998034608A1 (en) * | 1997-02-11 | 1998-08-13 | Novo Nordisk A/S | Methods for treatment or prophylaxis of menopausal symptoms |
| GB9827121D0 (en) * | 1998-12-09 | 1999-02-03 | Orion Corp | Agent for lowering endothelin levels |
| DE19905961A1 (en) * | 1999-02-12 | 2000-08-17 | Stefan Neubauer | Use of estrogens to treat cardiac insufficiency and left ventricular dysfunction following myocardial infarction |
| US6528681B2 (en) * | 2000-04-05 | 2003-03-04 | Bristol-Meyers Squibb Pharma Company | Halogenated triphenylethylene derivatives as selective estrogen receptor modulators |
| IL145876A0 (en) | 2000-10-17 | 2002-07-25 | Pfizer Prod Inc | Methods and kits for improving vascular health |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2196003A (en) * | 1986-09-11 | 1988-04-20 | Nat Res Dev | Iodo-and bromo-tamoxifen derivatives |
| KR100326962B1 (en) * | 1992-09-15 | 2002-12-02 | 메렐 파마슈티칼스 인크. | Tamoxifen-Non Metabolic Clomiphene Analog for Treatment of Tolerant Tumor |
| US6197789B1 (en) * | 1995-06-07 | 2001-03-06 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies with tamoxifen analogues |
| US5681835A (en) * | 1994-04-25 | 1997-10-28 | Glaxo Wellcome Inc. | Non-steroidal ligands for the estrogen receptor |
| US5604248A (en) * | 1994-05-05 | 1997-02-18 | Eli Lilly And Company | Method for minimizing the uterotrophic effect of tamoxifen and tamoxifen analogs |
| US5470883A (en) * | 1994-05-23 | 1995-11-28 | Stromberg; Brent V. | Method of treating peripheral vasoconstriction with tamoxifen citrate |
| HN1996000101A (en) * | 1996-02-28 | 1997-06-26 | Inc Pfizer | COMBINED THERAPY FOR OSTEOPOROSIS |
| US6069175A (en) * | 1996-11-15 | 2000-05-30 | Pfizer Inc. | Estrogen agonist/antagonists treatment of atherosclerosis |
-
1997
- 1997-08-29 AR ARP970103968A patent/AR008155A1/en unknown
- 1997-09-03 TR TR1999/00506T patent/TR199900506T2/en unknown
- 1997-09-03 CA CA002264943A patent/CA2264943A1/en not_active Abandoned
- 1997-09-03 BR BR9711681A patent/BR9711681A/en not_active Application Discontinuation
- 1997-09-03 PL PL97332038A patent/PL332038A1/en unknown
- 1997-09-03 IL IL12864597A patent/IL128645A0/en unknown
- 1997-09-03 JP JP51283898A patent/JP2002515047A/en active Pending
- 1997-09-03 WO PCT/US1997/015475 patent/WO1998009619A1/en not_active Application Discontinuation
- 1997-09-03 TR TR1999/00504T patent/TR199900504T2/en unknown
- 1997-09-03 AU AU42473/97A patent/AU4247397A/en not_active Abandoned
- 1997-09-03 KR KR1019997001860A patent/KR20000068472A/en not_active Application Discontinuation
- 1997-09-03 AU AU44097/97A patent/AU4409797A/en not_active Abandoned
- 1997-09-03 EP EP97942388A patent/EP0927029A4/en not_active Withdrawn
- 1997-09-03 CZ CZ99766A patent/CZ76699A3/en unknown
- 1997-09-03 KR KR1019997001861A patent/KR20000068473A/en not_active Application Discontinuation
- 1997-09-03 CN CN97199492A patent/CN1236299A/en active Pending
- 1997-09-03 CN CN97199493A patent/CN1236313A/en active Pending
- 1997-09-03 WO PCT/US1997/015474 patent/WO1998009519A1/en not_active Application Discontinuation
- 1997-09-03 PL PL97332278A patent/PL332278A1/en unknown
- 1997-09-03 BR BR9711676A patent/BR9711676A/en not_active Application Discontinuation
- 1997-09-03 EP EP97940773A patent/EP0929216A4/en not_active Withdrawn
- 1997-09-03 JP JP51283798A patent/JP2002515046A/en active Pending
- 1997-09-03 CA CA002264775A patent/CA2264775A1/en not_active Abandoned
- 1997-09-04 CO CO97051289A patent/CO5070658A1/en unknown
- 1997-09-04 CO CO97051287A patent/CO4920218A1/en unknown
- 1997-12-11 TW TW086112930A patent/TW411273B/en active
-
1999
- 1999-03-05 NO NO991097A patent/NO991097D0/en not_active Application Discontinuation
- 1999-03-05 NO NO991096A patent/NO991096L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| BR9711681A (en) | 1999-08-24 |
| EP0929216A1 (en) | 1999-07-21 |
| NO991097L (en) | 1999-03-05 |
| WO1998009519A1 (en) | 1998-03-12 |
| TW411273B (en) | 2000-11-11 |
| CO4920218A1 (en) | 2000-05-29 |
| NO991096D0 (en) | 1999-03-05 |
| AU4247397A (en) | 1998-03-26 |
| EP0929216A4 (en) | 2001-04-04 |
| BR9711676A (en) | 1999-08-24 |
| JP2002515046A (en) | 2002-05-21 |
| CN1236299A (en) | 1999-11-24 |
| CA2264775A1 (en) | 1998-03-12 |
| IL128645A0 (en) | 2000-01-31 |
| CZ76699A3 (en) | 1999-08-11 |
| PL332278A1 (en) | 1999-08-30 |
| PL332038A1 (en) | 1999-08-16 |
| AR008155A1 (en) | 1999-12-09 |
| EP0927029A1 (en) | 1999-07-07 |
| CA2264943A1 (en) | 1998-03-12 |
| CN1236313A (en) | 1999-11-24 |
| TR199900506T2 (en) | 1999-07-21 |
| KR20000068473A (en) | 2000-11-25 |
| JP2002515047A (en) | 2002-05-21 |
| EP0927029A4 (en) | 2001-06-13 |
| KR20000068472A (en) | 2000-11-25 |
| WO1998009619A1 (en) | 1998-03-12 |
| CO5070658A1 (en) | 2001-08-28 |
| NO991097D0 (en) | 1999-03-05 |
| TR199900504T2 (en) | 1999-06-21 |
| NO991096L (en) | 1999-03-05 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK5 | Application lapsed section 142(2)(e) - patent request and compl. specification not accepted |