AU4271878A - Compositions containing imidazoisoindoles or imidazoisoquinolines - Google Patents

Description

4 AUSTRALIA PATENTS ACT 1952

APPLICATION FOR A PATENT (CONVENTION OR NON CONVENT.Q

We SIwQl .LTD. of Li1chtstrasse 35, CH-4002 Basle, Switzerland,

hiereby apply for the grant of a Patent for an invention eit4itic

"IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS"

which is described in the accompanying complete specification.

The application is a Convention application 4n based on the application(s) for patent or similar protection made in UNITED STATES OF AMERICA on 20th December, 1977 under No. 862,403 and on 30th January, 1978 under No. 873,131

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COMMONWEALTH OF AUSTRALIA PATENTS ACT 1962-1973 DECLARATION IN SUPPORT OF CONVENTION OR NON-CONVENTION APPLICATION FOR A PATENT 42 7 18 /n OR PATENT OF ADDITION In support of the Application made for a patent for an~ invention Lsaert title of Invention. entitled: ~~~CCM~I4S

Inert full name(s) and address(**) of dosclarant(a) being thr appli- We JEAN KRAMER and PETE7R RASS, of Sandoz Ltd., cant(s) or person(s) suthoized to of Lichtstrasse 35, CH-4002 Basle, Switzerland sign on behalf of an appficant company.

Cross out whichever of paragraphs do solemnly and sincerely declare as follows: I1(a) or I1(b) doe not apply i(a) relates to application Irade We arepant of aA-itiou by individual(s) 1(b) relates o0 appl~cation made or -Mt outhorized by SANDOZ LTD. by sconj~any; insert name of appllftat company.

Caqrt1~t iciever of paragraphs the for the psom~i its behalf. patent of "dition to make this declaation on hi 2 or 2(b) does not apply 2(9) &states to application madl 2. w..M,.the ctuel inventor of the inentin byinveatcl(s) 2(6) relates to application made or 'ULA JOEPH. HOULIHAN, of -15 Raynold Road, by*am W(s) or peron(s) who are, no~ lventor(s); insert full Mountain Lakes, Newi Jersey, and RONALD GLENN name(s) and address(es) of Inven- BABINGTON, of 1.5 Whitman Drive, Denville, tors. New Jersey, both of the United States of America

19the actual inventor.9 of the invention and the facts upon which the applicant is ntitled to make the application are as follows

State #pn&t in which applicant(s) derive title ftom inventor(s) The inventors have assigned the invention to the

3. The basic appliration... 8 1-as defined by Section 141 of the Act made Cross 5out paragraph,, 3 and 4 were for non-cowtention applications. For converition applications, in.. United-States of .America on the 20th December, 1977 Ist accountry(s) followed by dst!(a)ska applicant(s). in o th J by.William Joseph Houlihan and Ronald Glenn Babington

4. The basic application referred to in paragraph 3 of this Declaration W were the first application. made in a Convention country in respect of the invention the subject of the application. Insert place and date of signatusre.

Signature 9i dedariast(s) (no SANDC attestation required)

Note: Initial anl aliemadoac

DAVIES COLLISON, MELSOUlkNE and oflicer

(11) AU-A 42718/78

(12) PATENT SPECIFICATION ADTDArT I 11%aI

(19) AU

(21) 42718/78 (22) 19.12.78 (23) 19.12.78 (24) 20.12.17 (31) 862403 (32) 20.12.77 (33) US 873131 30.1.78 US (43) 28.6.79 (51) A61K 31/415 A61K 31/47 A61K 31/495 (54) COMPOSITIONS CONTAINING 2MIDAZOTSOTNDOLES OR IMIDAZOISOQULNOLINES

(71) SANDOZ LTD. (72) HOULIHAN W.J. AND BABINGT'N R.G. (74) DY (57) A 'twin-pack', and a method of treatment of parkinson's disease are also claimed. CLAIM 1. A pharmaceutical composition for the treat- ment of Parkinson's disease comprising effective amounts

of a compound of formula I, R

(CH2)n OH

N

in which n is 0 or 1, and

R and which may be the same or different,

are hydrogen, fluorine or chlorine,

in free base or pharmaceutically acceptable acid addition

salt form, and a secondary active agent for the treatment

of Parkinson's disease.

120 23.3 ND

COMMONWEALTH OF AUSTRALIA

PATENTS ACT 1952

COMPLETE SPECIFICATION

(Original)

FOR OFFICE USE

42718178 aJs T J. L. Class

Application Number: Lodged:

Complete Specification Lodged: Accepted: Published:

Priority:

Related Art: 'L

S S.

Name of Applicant: SANDOZ LTD. 0

S

0 Address of Applicant: Lichtstrasse 35, CH-4002 Basle, Switzerland O

0

Actual Inventor(s): WILLIAM JOSEPH HOULIHAN and RONALD GLENN BABINGTON

Address for Service: DAVIES COLLISON, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000

*Complete specification for the invention entitled:

"IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS" 0960

The following statement is a full description of this invention, including the best method of performing it known to us j Ca-se -600-6799

Thiz invention relates to imidazoisoindoles and-

coo imidazoisoquinolines.

More particularlyp this invention relates to corn-

.qdt pounds of formula It S.. S S S. S R S SOOSSe S 1 OS S.1~ S

55 S SO GO S ~~C2 )n H S OSOS S

N_

5 in which n isO0 or 1, and 0

0* R and Rl, which may be the same or differ- *0

*0 ent, are hydrogen, fluorine or chlorine, GOO S in free base form or in the form of pharmaceutically

acceptable acid addition salts.

2 600-6799

The compounds of formula I and processes for their

production are known [for example J. Org. Chem. 33(7),

2874-2877 (1968)]. It is also that the compounds of

formula I may exist in various tautomeric forms, for

example when in acid addition salt form. For the sake

Sof simplicity, reference is herein made only to the form

OO of formula I, but it is to be understood that the inven-

t4 tion is not intended to be limited to any particular form

of the compounds.

It has now been found that the compounds of

formula I are useful, as indicated in standard clinical

studies, in enhancing the anti-Parkinson activity of other

active agents known or found to be useful in treating

Parkinson's disease, such other active agents hereinafter

15 being referred to as "secondary active agents". Such

secondary active agents include ergocryptines, such as

2-bromo-a-ergocryptine, ergolines, such as lergotrile,

lisuride, 8a-cyanomethyl-6-methylergoline, and 6-methyl-

8a-(N,N-dimethylsulphamoylamino)-ergoline, apomorphines,

20 such as apomorphine and N-propyl apomorphine, and

S* amantadine. e

o*o The present invention accordingly provides a

pharmaceutical composition for the treatment of

Parkinsor's Disease comprising effective amounts of a

compound of formula I, in free base or pharmaceutically

acceptable acid addition salt form, and a secondary

-3 '600-6799'

active agent.

The in-.ention also provides a miethod for the treatment of- Parkinson's disease which comprises admnini-

stering to a subject in need of such treatment effactive

amounts of a compound of formula I, in free base or

pharmaceutically acceptable acid addition salt form, and COa secondary active agent, in combination or as co-medic-

t~ation.

The invention also provides r.twin-pack compris-

ing separately a plurality of dosage units of each of a compound of formula I, in free base or pharmaceutically

acceptable acid addition salt form, and a secondary

active agent, together with instructions on the co-administration of the compound of formula I and the

15 secondary active agent in the treatment of Parkinson's disease.

For use in accordance with the invention, the

dosage of the compound of formula I will of course vary

depending on the severity of the condition being treated,

20 and the particular compound of formula I and secondary ad-lye agent being used. However, an indicated, suitable

total daily dosage of the compound of formula I is from

0.1 to 5 mg, in particular 0.2 to zi mg, more particularly,

to 5 mg, suitably administered in divided dosages of

from 0.025 to 2.5 mg, in particular 0.05 to 2.5 mg, more

particularly 0.125 2.5 mng, two to four times daily, or

4 600-6799

in retard form.

The dosage of the secondary active agent for use

in accordance with the invention will also of course vary

depending on the condition being treated, and the partic-

ular secondary active agent and compound of formula I being

r being used. In general, however, in view of the activity 00 Senhancing effect of the compounds of formula I, dosages

lower than the standard anti-Parkinson dosages of the

secondary active agents may be employed to obtain the

same level of effect. Alternatively, the standard dosages

a may be employed to obtain an enhanced effect. In the case

of the preferred secondary active agent in accordance with

the invention, namely 2-bromo-a-ergocryptine, the indic-

ated suitable total daily dosage for use in accordance a *:so S 15 with the invention is from 0.5 to 10 mg, suitably admini-

s\:ered ir divided dosages of from 0.125 to 5 mg, two to

four times daily, or in retard form.

The preferred compounds of formula I are imidazo- isoindoles compounds in which n is 0) and the most 0

S\ 20 preferred compound is 5-(p-chlorophenyl)-5-hydroxy-2,3-

dihydro-5H-imidazo[2,1-alisoindole (Mazindol). As indic-

ated, the compounds of formula I may be employed in free

base form or in the form of pharmaceutically acceptable

acid addition salts, which salt forms have the same order

5 600-6799

of activity as the free base forms. Suitable acid add-

ition salt forms include mineral acid salt forms, e.g. the

hydrochloride, hydrobromide, sulphate or phosphate, and

organic acid salt forms, e.g. the succinate, maleate,

fumarate, acetate or p-toluenesulphonate.

cj The compositions of the invention may be admini-

Sstered as such or admixed with conventional, pharmaceutic- C1 ally acceptable diluents or carriers. They may be admini-

stered parenterally or, preferably, orally. They may be

administered orally in such forms as integral solid dosage forms, e.g. tablets or capsules, dispersible powders or

granules, or as oral liquids, oral liquid suspensions,

syrups, and elixirs, and parenterally in such forms as sol-

utions, suspensions, dispersions and emulsions, in partic- 15 ular a sterile injectable aqueous suspension, and as

suppositories, etc. The compositions for oral use may

contain one or more conventional adjuvants, such as sweet- ening agents, flavouring agents, colouring agents and preserving agents, in order to provide an elegant and

20 palatable preparation. Tablets may contain the active

ingredient in admixture with conventional pharmaceutically

acceptable excipients, e.g. inert diluents, such as calcium

S* carbonate, sodium carbonate, lactose and talc, granulating

and disintegrating agents, e.g. starch and alginic acid,

6 600-6799

binding agents, e.g. starch, gelatin and acacia, and li.b- ricating agents, e.g. magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques or be otherwise prepared so as to delay dis-

integration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. ,0 Similarly, suspensions, syrups and elixirs may contain the

active ingredient in admixture with any of the conventional

excipients utilised for the preparation of such compos-

itions, e.g. suspending agents (methyl-cellulose, traga- canth and sodium alginate), wetting agents (lecithin, poly-

oxyethylene stearate and polyoxyethylene sorbitan mono- e oleate) and preservatives (ethyl-p-hydroxybenzoate).

Capsules may contain the active ingredient alone or admixed

15 with an inert solid diluent, e.g. calcium carbonate, cal- cium phosphate and kaolin. The injectable compositions are formulated as known in the art and may contain appro-

priate dispersing or wetting agents; and suspending agents

identical or similar to those mentioned above. These 20 pharmacputical preparations may contain up to about

of the active ingredient in combination with the carrier

or adjuvant. oo00o*

-7 600-6799

The preferred pharmaceutical compositions from

the standpoint of ease of preparation and administration

are integral solid unit dosage forms, e.g. tablets and

capsules.

The following Examples illustrate the invention.

0 S 6

S 0OSS0@ 0

S. 6 OOS

0 SO SS 6

0

0 SOS.

0 0 5.

S. 00 060

0 50 S 50 00

0

0

S

0SOS ~0 00 0

0 000000

-8 600-6799 I EXAMPLES* I and 2: *Tablets' and, Capsules Suitable for Oral

Administrcation

Tablets and.capsules containing the ingredients

indicated below may be prepared by conventional techniques

and are indicated for use in treating Parkinson's disease

at a dose of one tablet or capsule 2 to 4 times a day.

Ingredient Weight (mg) Tablet Capsule

(p-chlorophenyl) 2,3-dihydro-5H-imidazo [2,1-al 0.5 isoindole

2-bromo-a-ergocryptine 2 4

tragacanth O0 lactose 247 295.5 00

corn starch

talcum

magnesium stearate 0

@@00 a s The compounds 5- 4-dichlorophenyl) 0

2, 3-dihydro-5H-imidazo[2 ,1-al isoindole, 5- (3-fluorophenyl) 0 0 5-hydroxy-2 ,3-dihydro-5H-imidazo [2,,1-al isoindole, 0000:

(E-fluoi-ophenyl) -5-hydroxy-2, 3,4,

fe *fee 9 l-alisoquinoline, or 5-hydroxy-5-phenyl-2, 3-dihydro-Sil-

imidazoll2,l-alisoindole may be used in place of

chlorophenyl) -5--hydroxy--2, 3-dihydro-5H-imidazo[2

isoindole in the formulations .of Examples 1 and 2.

Claims (1)

1. 60-6799

   51IA WECL(PM[

   The claims defining the invention are as follows:-

   1. A pharmaceutical composition for the treat-

   ment of Pakno's disease comprising effective amounts

   of a compound of formula I, '-0 R

   (CH) O

   inwh 0 ai or1In

   inndRl which is 0h 1,ffandtma or sm

   sal Rnascndr whciv mayet samte orediffeent,

   ~acpal di re hydcargefurnro.hoie

   C AUSTRALIA 10 600-6799.

   3. A pharmaceutical composition according to Claim 1 or 2, in which the compound of formula I is

   chlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo[2,1-a]iso-

   indole.

   4. A pharmaceutical composition according to

   any one of Claims 1 to 3, in which the secondary active 00 agent is 2-bromo-a-ergocryptine.

   A pharmaceutical composition comprising a compound of formula I, stated in Claim 1, in free base or

   pharmaceutically acceptable acid addition salt form, for

   co-administration with a secondary active agent in the

   treatment of Parkinson's disease.

   5S A pharmaceutical composition comprising an

   S agent for the treatment of Parkinson's disease, for co-

   0* 15 administration with a compound of formula I, stated in *o o

   S° Claim 1, in free base or pharmaceutically acceptable acid 4

   *o addition salt form.

   7. A twin-pack comprising separately a plural- 00*0

   ity of dosage units of each of a compound of formula I,

   00 20 stated in Claim 1, in free base or pharmaceutically accept- S

   able acid addition salt form, and a secondary active agent, S S together with instructions for the co-administration of 0000 _the compound of formula I and the secondary active agent 00 S S

   S

   T60-6799R 11 600-6799

   in the treatment of Parkinson's disease.

   9. A method of treating Parkinson's disease

   comprising administering, in combination or as co-medic-

   ation, effective amounts'of a compound of formula I,

   stated in Claim 1, in free base or pharmaceutically

   Sacceptable acid addition salt form, and a secondary

   OO active agent.

   1> 9. The steps, features, compositions and com-

   pounds referred to or indicated in the specification

   and/or claims of this application, individually or col-

   lectively, and any and all combinations or any two or

   more.of said steps or features.

   Dated this 18th day of December, 1978 5* SANDOZ LTD. 3700/MO/HD by its Patent Attorneys *r 0

   S DAVIES COLLISON. e. 0

   0O

   0

   Se

   S