ZA906304B - Novel 4,4-disubstituted piperidine derivatives,pharmaceutical compositions containing them and process for preparing same - Google Patents

Novel 4,4-disubstituted piperidine derivatives,pharmaceutical compositions containing them and process for preparing same

Info

Publication number: ZA906304B
Authority: ZA; South Africa
Prior art keywords: alkyl; ethynyl; fluorophenyl; bis; novel
Prior art date: 1989-08-10

Application number

ZA906304A

Other languages

English (en)

Inventor

Edit Toth

Toth Edit

Laszlo Szporny

Szporny Laszlo

Dora Groo

Groo Dora

Ferenc Auth

Auth Ferenc

Jozsef Toerley

Toerley Jozsef

Bela Kiss

Kiss Bela

Istvan Laszlovszky

Laszlovszky Istvan

Laszlo Gaal

Gaal Laszlo

Sandor Goeroeg

Goeroeg Sandor

Eva Palosi

Palosi Eva

Erzsebet Lapis

Lapis Erzsebet

Original Assignee

Richter Gedeon Vegyeszet

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.)

1989-08-10

Filing date

1990-08-09

Publication date

1991-06-26

1990-08-09 Application filed by Richter Gedeon Vegyeszet filed Critical Richter Gedeon Vegyeszet

1991-06-26 Publication of ZA906304B publication Critical patent/ZA906304B/xx

Links

-1 4,4-disubstituted piperidine Chemical class 0.000 title 1
238000004519 manufacturing process Methods 0.000 title 1
239000008194 pharmaceutical composition Substances 0.000 title 1
125000000217 alkyl group Chemical group 0.000 abstract 3
RAPAKELQTSIJRM-UHFFFAOYSA-N 1-[4,4-bis(4-fluorophenyl)but-3-enyl]-4-ethynylpiperidin-4-ol;hydrochloride Chemical compound Cl.C1CC(O)(C#C)CCN1CCC=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 RAPAKELQTSIJRM-UHFFFAOYSA-N 0.000 abstract 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 2
239000002253 acid Substances 0.000 abstract 2
125000003545 alkoxy group Chemical group 0.000 abstract 2
125000003118 aryl group Chemical group 0.000 abstract 2
125000001475 halogen functional group Chemical group 0.000 abstract 2
WYDMNGYRWISCLZ-UHFFFAOYSA-N 1-[3,3-bis(4-fluorophenyl)prop-2-enyl]-4-ethynylpiperidin-4-ol;hydrochloride Chemical compound Cl.C1CC(O)(C#C)CCN1CC=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 WYDMNGYRWISCLZ-UHFFFAOYSA-N 0.000 abstract 1
VLVWUSGOTSWICZ-UHFFFAOYSA-N [1-[4,4-bis(4-fluorophenyl)but-3-enyl]-4-ethynylpiperidin-4-yl] n-benzylcarbamate Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)=CCCN1CCC(C#C)(OC(=O)NCC=2C=CC=CC=2)CC1 VLVWUSGOTSWICZ-UHFFFAOYSA-N 0.000 abstract 1
HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 abstract 1
125000000753 cycloalkyl group Chemical group 0.000 abstract 1
125000002534 ethynyl group Chemical group [H]C#C* 0.000 abstract 1
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
150000003242 quaternary ammonium salts Chemical class 0.000 abstract 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Landscapes

Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Life Sciences & Earth Sciences (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Veterinary Medicine (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
General Chemical & Material Sciences (AREA)
Psychiatry (AREA)
Anesthesiology (AREA)
Pain & Pain Management (AREA)
Hospice & Palliative Care (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Hydrogenated Pyridines (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)

ZA906304A 1989-08-10 1990-08-09 Novel 4,4-disubstituted piperidine derivatives,pharmaceutical compositions containing them and process for preparing same ZA906304B (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
HU894094A HU204276B (en)	1989-08-10	1989-08-10	Process for producing new 1-oxa-2-oxo-4-methylen-8-aza-spiro(4,5)decane derivatives and pharmaceutical compositions containing them

Publications (1)

Publication Number	Publication Date
ZA906304B true ZA906304B (en)	1991-06-26

Family

ID=10966866

Family Applications (3)

Application Number	Title	Priority Date	Filing Date
ZA906299A ZA906299B (en)	1989-08-10	1990-08-09	Novel 4-methylene-2-oxo-8-azaspiro(4,5)decane derivatives,pharmaceutical compositions containing them and process for preparing same
ZA906304A ZA906304B (en)	1989-08-10	1990-08-09	Novel 4,4-disubstituted piperidine derivatives,pharmaceutical compositions containing them and process for preparing same
ZA906300A ZA906300B (en)	1989-08-10	1990-08-09	Novel 2-oxo-3,8-diazaspiro(4,5)decane derivatives,pharmaceutical compositions containing them and process for preparing same

Family Applications Before (1)

Application Number	Title	Priority Date	Filing Date
ZA906299A ZA906299B (en)	1989-08-10	1990-08-09	Novel 4-methylene-2-oxo-8-azaspiro(4,5)decane derivatives,pharmaceutical compositions containing them and process for preparing same

Family Applications After (1)

Application Number	Title	Priority Date	Filing Date
ZA906300A ZA906300B (en)	1989-08-10	1990-08-09	Novel 2-oxo-3,8-diazaspiro(4,5)decane derivatives,pharmaceutical compositions containing them and process for preparing same

Country Status (26)

Country	Link
US (2)	US5132309A (de)
EP (2)	EP0413516B1 (de)
JP (2)	JPH0383985A (de)
KR (2)	KR940000830B1 (de)
CN (1)	CN1025031C (de)
AT (2)	ATE113951T1 (de)
AU (2)	AU621771B2 (de)
CA (2)	CA2023018C (de)
DD (2)	DD299428A5 (de)
DE (2)	DE69014008T2 (de)
DK (1)	DK0413516T3 (de)
ES (2)	ES2063923T3 (de)
FI (1)	FI93456C (de)
HK (1)	HK118295A (de)
HU (2)	HU204276B (de)
IE (1)	IE902885A1 (de)
IL (2)	IL95324A (de)
IN (1)	IN170979B (de)
IS (1)	IS3612A7 (de)
MY (1)	MY107240A (de)
NO (1)	NO903511L (de)
NZ (2)	NZ234843A (de)
PL (2)	PL163899B1 (de)
SG (1)	SG59864G (de)
YU (2)	YU150489A (de)
ZA (3)	ZA906299B (de)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0551963A3 (en) *	1986-12-17	1993-09-01	Glaxo Group Limited	Use of heterocyclic derivatives for the manufacture of medicaments
YU150489A (sh) *	1989-08-10	1992-12-21	W.L. Gore & Co. Gmbh.	Uređaj za ispitivanje odevnih predmeta na nepromočivost
HU204529B (en) *	1989-08-10	1992-01-28	Richter Gedeon Vegyeszet	Process for producing new 1-oxa-2-oxo-8-aza-spiro(4,5)decane derivatives and pharmaceutical compositions containing them
US5534520A (en) *	1990-04-10	1996-07-09	Fisher; Abraham	Spiro compounds containing five-membered rings
US5852029A (en) *	1990-04-10	1998-12-22	Israel Institute For Biological Research	Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity
EP0492020A1 (de) *	1990-12-21	1992-07-01	Merrell Dow Pharmaceuticals Inc.	Verwendung von bestimmten Estern von Hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-on und verwandter Verbindungen zur Behandlung von kognitiven Erkrankungen
GB9206989D0 (en) *	1992-03-31	1992-05-13	Glaxo Group Ltd	Chemical compounds
US5756743A (en)	1996-04-10	1998-05-26	Hoechst Marion Roussel Inc.	Spiro cyclopent b!indole-piperidines!
US6100256A (en) *	1996-12-02	2000-08-08	Merck Sharp & Dohme Ltd.	Use of NK-1 receptors antagonists for treating schizophrenic disorders
US6974825B1 (en)	1996-12-20	2005-12-13	Astrazeneca Canada Inc.	Compounds with analgesic effect
SE9604786D0 (sv)	1996-12-20	1996-12-20	Astra Pharma Inc	New compounds
SE9904675D0 (sv)	1999-12-20	1999-12-20	Astra Pharma Inc	Novel compounds
SE0101770D0 (sv) *	2001-05-18	2001-05-18	Astrazeneca Ab	Novel compounds
SE0101773D0 (sv) *	2001-05-18	2001-05-18	Astrazeneca Ab	Novel compounds
SE0101771D0 (sv)	2001-05-18	2001-05-18	Astrazeneca Ab	Novel compounds
SE0101769D0 (sv)	2001-05-18	2001-05-18	Astrazeneca Ab	Novel compounds
KR20030087248A (ko) *	2002-05-08	2003-11-14	(주)씨엔아이	온라인을 통한 상거래 기초항목의 설정기능을 갖는 상거래관리장치
CA2765415A1 (en) *	2009-06-16	2010-12-23	Merck Sharp & Dohme Corp.	Substituted -1,3,8-triazaspiro[4.5]decane-2,4-diones
GB201416346D0 (en) *	2014-09-16	2014-10-29	Shire Internat Gmbh	Spirocyclic derivatives
GB201416352D0 (en) *	2014-09-16	2014-10-29	Shire Internat Gmbh	Spirocyclic derivatives

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
NL127065C (de) *	1964-04-22
CH601304A5 (de) *	1974-02-12	1978-07-14	Buskine Sa
BE790675A (fr) *	1971-10-29	1973-04-27	Science Union & Cie	Nouveaux derives de l'oxa-1 diaza-3,8 spiro (4,5) decane
FR2615515B1 (fr) *	1987-05-22	1989-06-30	Adir	Nouveaux derives du spiro 4, 5 decane, leur procede de preparation et les compositions pharmaceutiques les renfermant
HU204529B (en) *	1989-08-10	1992-01-28	Richter Gedeon Vegyeszet	Process for producing new 1-oxa-2-oxo-8-aza-spiro(4,5)decane derivatives and pharmaceutical compositions containing them
YU150489A (sh) *	1989-08-10	1992-12-21	W.L. Gore & Co. Gmbh.	Uređaj za ispitivanje odevnih predmeta na nepromočivost
HU204530B (en) *	1989-08-10	1992-01-28	Richter Gedeon Vegyeszet	Process for producing new 1-oxa-2-oxo-8-aza-spiro(4,5)decane derivatives and pharmaceutical compositions containing them

1989
- 1989-07-27 YU YU150489A patent/YU150489A/sh unknown
- 1989-08-10 HU HU894094A patent/HU204276B/hu not_active IP Right Cessation
- 1989-08-10 HU HU903233A patent/HU206677B/hu not_active IP Right Cessation
1990
- 1990-08-08 KR KR1019900012169A patent/KR940000830B1/ko not_active Expired - Fee Related
- 1990-08-08 KR KR1019900012168A patent/KR940002826B1/ko not_active Expired - Fee Related
- 1990-08-09 DE DE69014008T patent/DE69014008T2/de not_active Expired - Fee Related
- 1990-08-09 ES ES90308779T patent/ES2063923T3/es not_active Expired - Lifetime
- 1990-08-09 AT AT90308779T patent/ATE113951T1/de not_active IP Right Cessation
- 1990-08-09 YU YU154090A patent/YU154090A/sh unknown
- 1990-08-09 NZ NZ234843A patent/NZ234843A/en unknown
- 1990-08-09 NZ NZ234846A patent/NZ234846A/en unknown
- 1990-08-09 JP JP2209363A patent/JPH0383985A/ja active Pending
- 1990-08-09 DD DD90343354A patent/DD299428A5/de not_active IP Right Cessation
- 1990-08-09 AU AU60803/90A patent/AU621771B2/en not_active Ceased
- 1990-08-09 IL IL9532490A patent/IL95324A/en not_active IP Right Cessation
- 1990-08-09 DD DD90343359A patent/DD299431A5/de not_active IP Right Cessation
- 1990-08-09 AU AU60804/90A patent/AU621238B2/en not_active Ceased
- 1990-08-09 ZA ZA906299A patent/ZA906299B/xx unknown
- 1990-08-09 CA CA002023018A patent/CA2023018C/en not_active Expired - Fee Related
- 1990-08-09 IN IN687/CAL/90A patent/IN170979B/en unknown
- 1990-08-09 JP JP2209362A patent/JPH0381277A/ja active Pending
- 1990-08-09 ES ES90308783T patent/ES2052179T3/es not_active Expired - Lifetime
- 1990-08-09 NO NO90903511A patent/NO903511L/no unknown
- 1990-08-09 EP EP90308783A patent/EP0413516B1/de not_active Expired - Lifetime
- 1990-08-09 EP EP90308779A patent/EP0412821B1/de not_active Expired - Lifetime
- 1990-08-09 IS IS3612A patent/IS3612A7/is unknown
- 1990-08-09 IL IL9532590A patent/IL95325A/en not_active IP Right Cessation
- 1990-08-09 DK DK90308783.1T patent/DK0413516T3/da active
- 1990-08-09 CA CA002023015A patent/CA2023015A1/en not_active Abandoned
- 1990-08-09 IE IE288590A patent/IE902885A1/en unknown
- 1990-08-09 AT AT9090308783T patent/ATE104671T1/de not_active IP Right Cessation
- 1990-08-09 ZA ZA906304A patent/ZA906304B/xx unknown
- 1990-08-09 DE DE69008275T patent/DE69008275T2/de not_active Expired - Fee Related
- 1990-08-09 SG SG1995903969A patent/SG59864G/en unknown
- 1990-08-09 ZA ZA906300A patent/ZA906300B/xx unknown
- 1990-08-10 MY MYPI90001343A patent/MY107240A/en unknown
- 1990-08-10 CN CN90106974A patent/CN1025031C/zh not_active Expired - Fee Related
- 1990-08-10 PL PL90286443A patent/PL163899B1/pl unknown
- 1990-08-10 US US07/566,279 patent/US5132309A/en not_active Expired - Fee Related
- 1990-08-10 FI FI903974A patent/FI93456C/fi not_active IP Right Cessation
- 1990-08-10 PL PL90291648A patent/PL164662B1/pl unknown
- 1990-08-10 US US07/566,278 patent/US5132303A/en not_active Expired - Fee Related
1995
- 1995-07-20 HK HK118295A patent/HK118295A/en not_active IP Right Cessation

Also Published As

Publication number	Publication date
JPH0381277A (ja)	1991-04-05
EP0412821A2 (de)	1991-02-13
HU903233D0 (en)	1990-10-28
AU6080390A (en)	1991-02-14
JPH0383985A (ja)	1991-04-09
ZA906300B (en)	1991-05-29
AU6080490A (en)	1991-02-14
US5132303A (en)	1992-07-21
ES2063923T3 (es)	1995-01-16
PL164662B1 (pl)	1994-09-30
DD299428A5 (de)	1992-04-16
SG59864G (en)	1995-09-01
ES2052179T3 (es)	1994-07-01
NO903511D0 (no)	1990-08-09
KR910004630A (ko)	1991-03-29
CN1049349A (zh)	1991-02-20
FI93456B (fi)	1994-12-30
CA2023015A1 (en)	1991-02-11
IL95324A (en)	1994-02-27
CA2023018A1 (en)	1991-02-11
HUT59375A (en)	1992-05-28
YU154090A (sh)	1992-12-21
CN1025031C (zh)	1994-06-15
EP0412821B1 (de)	1994-11-09
IN170979B (de)	1992-06-27
HUT55785A (en)	1991-06-28
ZA906299B (en)	1991-06-26
DD299431A5 (de)	1992-04-16
IL95324A0 (en)	1991-06-30
NZ234846A (en)	1992-03-26
AU621238B2 (en)	1992-03-05
IL95325A0 (en)	1991-06-30
HU204276B (en)	1991-12-30
IE902885A1 (en)	1991-02-27
AU621771B2 (en)	1992-03-19
PL291648A1 (en)	1992-06-01
DK0413516T3 (da)	1994-05-24
FI93456C (fi)	1995-04-10
MY107240A (en)	1995-10-31
IS3612A7 (is)	1991-02-11
DE69014008D1 (de)	1994-12-15
EP0412821A3 (en)	1991-11-27
HK118295A (en)	1995-07-28
EP0413516A2 (de)	1991-02-20
CA2023018C (en)	1995-11-28
PL286443A1 (en)	1992-01-13
ATE113951T1 (de)	1994-11-15
KR940000830B1 (ko)	1994-02-02
IL95325A (en)	1994-06-24
DE69008275T2 (de)	1994-08-04
NZ234843A (en)	1992-03-26
ATE104671T1 (de)	1994-05-15
YU150489A (sh)	1992-12-21
KR910004631A (ko)	1991-03-29
DE69014008T2 (de)	1995-03-23
PL163899B1 (pl)	1994-05-31
DE69008275D1 (de)	1994-05-26
US5132309A (en)	1992-07-21
HU206677B (en)	1992-12-28
NO903511L (no)	1991-02-11
EP0413516A3 (en)	1991-11-27
FI903974A0 (fi)	1990-08-10
KR940002826B1 (ko)	1994-04-04
EP0413516B1 (de)	1994-04-20

Publication	Publication Date	Title
HUT59375A (en)	1992-05-28	Process for producing new 4,4-disubstituted piperidine derivatives and pharmaceutical compositions comprising such compounds
ZA958895B (en)	1996-05-23	Piperidine compounds process for their preparation and the pharmaceutical compositions which contain them
ATE136885T1 (de)	1996-05-15	Azacyclische verbindungen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische zubereitungen
ES8601978A1 (es)	1985-11-16	Procedimiento para preparar derivados de isoquinoleina
DE58901510D1 (de)	1992-07-02	6-phenyldihydro-3(2h)-pyridazinone, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel.
CA2178302A1 (fr)	1996-12-08	Nouveaux derives de l'indole, de l'indazole et du benzisoxazole,leur pr ocede de preparation et les compositions pharmaceutiques qui les contiennent
ES8605269A1 (es)	1986-03-16	Procedimiento para la fabricacion de derivados de tiadiazol activos sobre el sistema nervioso central
ZA200003035B (en)	2001-01-11	Compounds of 7-oxo-2,3,7,14-tetrahydro-1H-benzo[B]-pyrano[3,2-H] acridin carboxylate, a process for their preparation and pharmaceutical compositions containing them.
HU9302260D0 (en)	1993-10-28	Tetrahydro-naphtaline derivatives and methods for producing these compounds and for preparing pharmaceutical preparatives containing them
IL115028A0 (en)	1995-12-08	Cyclohexadiene derivatives their pharmaceutical compositions containing them
ES8604150A1 (es)	1986-01-16	Un procedimiento para la preparacion de medicamentos a base de derivados de la 1,4-dihidropiridina
HUT47906A (en)	1989-04-28	Process for producing heterocyclic urea derivatives and pharmaceutical compositions containing them
HUT61293A (en)	1992-12-28	Process for producing 6-member heteroaromatic compounds comprising 1-3 nitrogen atoms and pharmaceutical compositions comprising same