EXHIBIT 10.7
Dated 21st September 1992
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GLYCYX PHARMACEUTICALS, LTD (1)
- and -
AB ASTRA (2)
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DISTRIBUTION AGREEMENT
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▇▇▇▇▇▇▇▇ ▇▇▇▇▇ + ▇▇▇▇
▇/▇ ▇▇▇▇▇▇ ▇▇▇▇▇▇
▇▇▇▇▇▇▇▇▇▇▇▇
▇▇▇ ▇▇▇
[*] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS
BEEN REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
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THIS AGREEMENT is made 21st day of September 1992
BETWEEN:
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(1) GLYCYX PHARMACEUTICALS, LTD a company incorporated under the laws of
Bermuda and whose registered office is at ▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇, ▇▇▇▇▇▇▇▇, ▇▇▇▇,
▇▇▇▇▇▇▇("▇▇▇▇▇▇"); and
(2) AB ASTRA a company incorporated under the laws of Sweden whose principal
place of business is at ▇▇▇▇▇▇▇▇▇▇▇▇▇▇▇ ▇▇, ▇-▇▇▇ ▇▇ ▇▇▇▇▇▇▇▇▇▇, ▇▇▇▇▇▇
("Astra").
WHEREAS:
A. Biorex Laboratories Limited ("Biorex") has developed and owns all
intellectual property rights in a therapeutic pharmaceutical product for
treatment and maintenance of colitis based upon the compound Balsalazide
and by an agreement dated 18th March 1992 and made between Biorex and
Glycyx ("the Biorex Agreement") Biorex granted to Glycyx the exclusive
right and licence to manufacture, or have manufactured, use sell or have
sold products incorporating Balsalazide.
B. Glycyx wishes to grant to Astra (who in turn wishes to accept) the
exclusive right to promote market distribute and sell the Product in the
Territory on the terms and subject to the conditions of this Agreement.
NOW IT IS HEREBY AGREED as follows:-
1. DEFINITIONS
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1.1 In this Agreement the following words shall have the following meanings:
"the Applications" means the treatment of Diseases of
Digestive System according to WHO
classification of diseases Class 52
"Astra Associate" means any company which is a holding
company of Astra or a subsidiary of
Astra and any other subsidiary of any
such holding company or subsidiary and
for this purpose:-
- a company shall be deemed to be a
"subsidiary" of another if that other
either:-
(a) is a member of it and controls
the composition of its board of
directors (and for such purpose the
composition of a company's
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board of directors is deemed to be
controlled by another company if that
other company by the exercise of some
power exercisable by it without the
consent or concurrence of any other
person can appoint or remove the
holders of all or a majority of the
directorships); or
(b) holds more than half in
nominal value of its equity share
capital; and
- a company is deemed to be
another's holding company if the other
is its subsidiary
"Balsalazide" means 5- [4 (2- carboxyethyl
carbamoyl)-phenylazo]-salicylic acid
disodium salt dihydrate
"Biorex" shall mean Biorex Laboratories Limited
a company incorporated in England under
Company Registration Number 390233
whose registered office is at ▇
▇▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇, ▇▇▇▇▇▇▇▇ ▇▇▇,
▇▇▇▇▇▇▇, ▇▇▇▇▇▇▇▇▇ ▇▇▇ ▇▇▇
"Biorex Agreement" means the agreement dated 18th March
1992 between Glycyx and Biorex
"Biorex/Astra Agreement" means an agreement of even date
herewith entered into between Biorex
and Astra
"Dossier" shall mean the master regulatory
dossier relating to the Product
prepared under and in accordance with
the terms of the Research Agreement
"Excluded Territory" the United States of America, Italy,
Spain, Portugal and Greece
"Factory Sale Price" means the ex factory sales price of
each Product actually charged by Astra
(or any Astra Associate) for each
shipment of Product on an arms length
open market basis to any third party
(being a person firm or
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company which is not an Astra
Associate) net only of sales and
purchase taxes, customs or import
duties, delivery charges, and returns
and allowances actually charged on each
such shipment
"Filing Date" means the date upon which the Dossier
(completed in accordance with the terms
of the Research Agreement) shall be
submitted by Glycyx for registration
within one of the Principal Markets
under Clause 3.1 of the Research
Agreement
"Force Majeure" means in relation to either party any
circumstances beyond the reasonable
control of that party (including but
not limited to strike, lock out or
other form of industrial action, act of
God, war, riot, accident, breakdown in
plant or machinery, fire, flood,
explosion or government action)
"Launch" means a commercial launch by Astra (or
any Astra Associate) of the Product in
a Principal Market supported by such
marketing expense and support and
launched in such quantities as may
reasonably be appropriate for the
Product to have a significant effect on
total sales of any similar or
competitive product in such Principal
Market
"the Patents" means the patents and applications
therefor relating to Balsalazide listed
in Schedule 1 to this Agreement
"the Principal Markets" means the United Kingdom, Sweden,
Finland, Norway, Switzerland, Austria,
Denmark, Germany, the Benelux
Countries, France, Eire, South Africa,
Australia, New Zealand and Canada
"Product" means a pharmaceutical preparation in
capsule form containing Balsalazide for
the
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Applications and such other
pharmaceutical preparations containing
Balsalazide for the Applications as may
be developed by Glycyx during the term
of this Agreement
"the Research Agreement" means the research and development
agreement entered into between Astra
and Glycyx on even date herewith in the
approved form
"the Territory" means all the countries in the world
except Italy, Spain, Portugal, Greece,
United States of America, Japan, Taiwan
and Korea
"the Trade ▇▇▇▇" means the trade name "Colazide"
registered as a trademark for use on
pharmaceutical preparations in the
United Kingdom and elsewhere and any
other tradename designated by Glycyx
for use in connection with the Product
in any part of the Territory where use
of the tradename "Colazide" is
inappropriate for such part of the
Territory or where Astra reasonably
considers that the use of another
tradename (in addition to the tradename
"Colazide") may be commercially
advantageous.
1.2 The headings in this Agreement are for convenience only and shall not
affect its interpretation.
1.3 References to documents in the approved form shall be references to
documents in the form agreed between the parties and initialled by both
parties for the purposes of identification.
2. APPOINTMENT OF ASTRA
--------------------
2.1 With effect from the date of this Agreement and in accordance with the
terms and conditions contained in this Agreement Glycyx hereby appoints
Astra as its exclusive distributor for the Product within and throughout
the Territory.
2.2 The rights granted hereunder to Astra shall be in respect of the Product
only. In the event that either party shall become aware of any indications
or applications for Balsalazide other than the Applications it shall
forthwith
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notify the other party and shall supply the other party with such details
of the other indications and applications as may be available to it
Provided Always That:-
2.2.1 Astra shall have a first option to enter into good faith
negotiations with Glycyx during the period six months from the
supply of such details in respect of an agreement concerning the
development of such other indications and applications and the grant
to Astra of the right to exploit the same in the Territory; and
2.2.2 Astra shall have no right whatsoever to use and exploit Balsalazide
in any such other indications and/or applications unless and until
completion of such good faith negotiations and the execution of a
written agreement in respect thereof; and
2.2.3 during such period in which Astra shall continue to negotiate in
good faith Glycyx shall not disclose details of such other
indications and/or applications to any third party or grant any
third party any rights therein in the Territory provided that Glycyx
shall not be prevented or precluded from disclosing the same to any
third party which shall have entered good faith negotiations for the
acquisition of the right to exploit such other indications and/or
applications outside the Territory; and
2.2.4 in respect of any such other applications and indications disclosed
by Astra to Glycyx Glycyx shall not use or exploit the same (either
itself or through any third party) whether in the Territory or
elsewhere without the prior consent of Astra (such consent not to be
unreasonably withheld or delayed); and
2.2.5 in respect of any such other applications and indications disclosed
by Glycyx to Astra, Glycyx shall not use or exploit the same (either
itself or through any third party) in the Territory without the
prior consent of Astra (such consent not to be unreasonably withheld
or delayed).
3. REGULATORY APPROVALS
--------------------
3.1 It is acknowledged and confirmed by Astra and Glycyx that Astra shall not
be able to exercise its rights hereunder unless and until the Dossier (as
defined in the Research Agreement) shall have been completed and is
available for filing with the relevant regulatory authority in the
Territory.
3.2 Astra undertakes to use all reasonable endeavours to file the Dossier and
to apply for and obtain all relevant regulatory health and price approvals
for the marketing and use of the Product in the Territory as soon as
reasonably
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practicable after the Filing Date.
3.3 Astra undertakes to use its best endeavours to apply for and obtain all
relevant regulatory health and price approvals for the marketing and use of
the Product in each of the Principal Markets and to effect Launch of the
Product in each of the Principal Markets within 90 days of the Filing Date.
3.4 Astra shall be solely responsible for effecting (at its sole cost and
expense) such amendments and translations to the Dossier as may be required
to procure that the Dossier complies with and satisfies the requirements of
any regulatory or approval authority within any particular part of the
Territory and Glycyx shall not be obliged to incur any cost or conduct any
further test or development work or otherwise amend or translate the
Dossier whether before or after the Filing Date.
3.5 In the event that Astra shall fail to effect Launch in any Principal
Market within a period of 180 days after the grant of all necessary
registrations, approvals, price approvals, and reimbursements, then
Glycyx may in its absolute discretion serve written notice on Astra
(within 30 days of the expiry of such period of 180 days) amending the
rights of Astra granted hereunder in respect of any such Principal Market
to those of a non-exclusive distributor for the Product for such
Principal Market only. Thereafter Glycyx for the avoidance of doubt shall
also be entitled to exploit such rights and to market and exploit the
Product in such Principal Market (whether directly or indirectly through
any agent, contractor or licensee) in such manner as it may in its sole
discretion think fit Provided Always that Astra will retain exclusive
rights to use the Trademark.
3.6 In the event that Astra's failure to effect Launch as stated in Clause
3.5 exceeds a period of twelve months from the grant of all necessary
registrations, approvals, price approvals and reimbursements in any
Principal Market Glycyx may at its sole discretion serve written notice
on Astra (within 90 days of the expiry of such period of 180 days)
terminating all rights granted hereunder to Astra in respect of such
Principal Market only and thereafter Glycyx for the avoidance of doubt
shall be entitled to exploit such rights and to market and exploit the
Product in such Principal Market (whether directly or indirectly through
any agent, contractor or licensee) in such manner as it may in its sole
discretion think fit free of any obligation to Astra Provided Always that
Glycyx shall not use or grant any third party the right to use the
Trademark in such Principal Territory either on the Product or otherwise
and the exclusive rights to such Trademark granted hereunder to Astra
shall continue provided that Astra shall not thereafter use the Trademark
in any manner in such Principal Territory.
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4. EFFECTIVE DATE
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4.1 This Agreement shall come into effect forthwith upon the date hereof
Provided Always That the rights to distribute the Product in any part of
the Territory shall become exercisable only as provided in Clause 3 hereof.
5. ASTRA'S UNDERTAKINGS
--------------------
5.1 Astra shall use its best endeavours to promote, market and sell the Product
and maximise sales thereof throughout the Principal Markets.
5.2 Astra shall use all reasonable endeavours to promote market and sell the
Product in such parts of the Territory outside the Principal Markets where
the Product in the reasonable opinion of the parties is deemed to have a
sales potential.
5.3 Without prejudice to the generality of Clauses 5.1 and 5.2 Astra undertakes
to allocate such promotional and sales resources and such technical support
for the promotion, marketing and sales of the Product as may reasonably be
required to maximise sales of the Product in all Principal Markets.
5.4 Astra shall promote market and sell the Product in the Territory entirely
in accordance with the terms of any product licence, price approval (where
applicable), and other restrictions and regulations for the Product as may
be relevant and applicable in each country within the Territory.
5.5 Astra further undertakes:-
5.5.1 to promote, market and sell the Product in the Territory under the
Trade ▇▇▇▇ only and not to use any other trade name, trademark or
logo for or on the Product (Provided That the name "Balsalazide" may
be used but only as a generic name for the Product in accordance
with and as required by applicable laws and regulations); and
5.5.2 to enter into Trade ▇▇▇▇ user agreements and such other agreements
(whether relating to the Trade ▇▇▇▇, Technical Standards or
otherwise) as may reasonably be required by Glycyx or is required by
applicable regulations in any part of the Territory in connection
with the exploitation by Astra of the Product and/or the use by
Astra of the Trade ▇▇▇▇; and
5.5.3 to notify Glycyx immediately of any improper or wrongful use of the
Trade ▇▇▇▇, the Patents or otherwise any proprietary or confidential
information of Glycyx or Biorex relating to the Product coming to
Astra's knowledge; and
5.5.4 forthwith to refer to Glycyx all enquiries
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received for the supply of the Product outside the Territory; and
5.5.5 not actively to seek customers for the Product outside the
Territory; and
5.5.6 to develop and design packaging for the Product in each part of the
Territory at its sole cost and expense Provided Always That the
general quality design and content of such packaging and any
information supplied with the Product by Astra shall be subject to
prior approval by Glycyx; and
5.5.7 not to use any misleading statements or misrepresentations on the
Product packaging or use any defective packaging materials and to
comply in all respects with all local regulations and laws in
connection with the Product packaging and the information provided
thereon; and
5.5.8 in the sale and use of the Product in each part of the Territory to
comply with all relevant regulatory health and pricing regulations
and approvals in such part of the Territory. For the avoidance of
doubt Glycyx shall not be responsible or liable in any manner
whatsoever for compliance with any such regulations and approvals
(whether or not it shall have assisted Astra in or approved the sale
or use of the Product in such part of the Territory); and
5.5.9 not to use any packaging which may adversely affect the Product in
any way whatsoever including but without limitation the Product's
approved shelf-life; and
5.5.10 not to incur any liability on behalf of Glycyx or in any manner
pledge or purport to pledge Glycyx's credit or accept any order or
make any contract binding on Glycyx or give or make any
representation, warranties or conditions or quantities with
reference to the Product on behalf of Glycyx. Astra is not and shall
not be deemed to be the agent of Glycyx and in all correspondence
and dealings with third parties shall clearly indicate that it is
acting as principal; and
5.5.11 to be solely responsible for the acts and omissions of its
employees and representatives in connection with the performance of
its rights and obligations hereunder.
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5.6 Astra shall be entirely responsible for the collection of debts due to it
and shall bear all losses owing to its failure so to do.
6. PRODUCT DATABASE AND ADVERSE REACTIONS REPORTING
------------------------------------------------
6.1 Glycyx shall maintain a database of all adverse and other reactions or
events occurring in connection with the Product in any part of the
Territory or the Excluded Territory and shall use reasonable endeavours to
procure that any such adverse and other reactions are notified to it in a
timely manner by any sub-licensee and/or distributor of the Product in the
Territory and the Excluded Territory.
6.2 Astra undertakes to notify Glycyx:-
6.2.1 forthwith in the event that it becomes aware of any serious or
previously unknown adverse reaction or contra indications to the
Product; and
6.2.2 within three months, on a quarterly basis of other adverse reactions
or contra indications to the Product other than stated under 6.2.1.
6.3 Glycyx undertakes to notify Astra:-
6.3.1 forthwith in the event that it becomes aware of any serious or
previously unknown adverse reaction or contra indications to the
Product in any part of the Territory and the Excluded Territory; and
6.3.2 within three months, on a quarterly basis of other adverse reactions
or contra indications to the Product other than stated under 6.2.1.
6.4 In the event that Glycyx or any third party shall conduct clinical studies
in support of any promotional or marketing activities of Glycyx or such
third party within the Territory or the Excluded Territory, Glycyx shall
use reasonable endeavours to grant or procure the grant to Astra of full
unrestricted access to the results of such trials so that Astra shall be
entitled to use such results in connection with the marketing, sale and use
of the Product in the Territory.
7. CONSIDERATION
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7.1 In consideration of the rights hereby granted by Glycyx to Astra Astra
hereby agrees to pay to Glycyx a sum of [*] such sum to be payable to
Glycyx as follows:-
7.1.1 [*]
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THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
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7.1.2 [*]
7.2 Glycyx hereby agrees that it shall reimburse to Astra the sum of
[*] paid by Astra under the terms of the Research Agreement by way of (and
not otherwise in any manner whatsoever) a retention by Astra of either:-
7.2.1 [*] of the price charged by Glycyx under Clause 10 to Astra on each
of Astra's orders for bulk quantities of capsules containing the
Product (net of all sales taxes, discounts, credits, insurance and
delivery charges); or
7.2.2 in the event that Astra shall have commenced manufacture of the
Product under the provisions of Clause 13.2, [*] of all fees due to
Glycyx from Astra under paragraph 6 of Schedule 2
until the said sum shall have been reimbursed in full to Astra whereupon
all such retentions shall cease forthwith.
8. CLINICAL TRIALS AND DEVELOPMENTS
--------------------------------
8.1 Astra is authorised by Glycyx to undertake clinical studies after the
Filing Date in support of Astra's regulatory, promotional and marketing
activities and to enhance the Product's approval and/or use within the
Applications Provided Always That:-
8.1.1 such trials are conducted solely for such purposes and not for any
other purpose whatsoever; and
8.1.2 prior to the conduct of such trials the trial objectives and
protocols are approved by Glycyx (such approval not to be
unreasonably withheld or delayed and Provided Always That such
approval
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shall be deemed given by Glycyx in the event that no response is
received by Astra from Glycyx within 20 working days of receipt by
Glycyx of any request for approval); and
8.1.3 Astra shall keep Glycyx fully informed as to the conduct progress
and results of such trials; and
8.1.4 Glycyx shall have full unrestricted access to the results of such
trials and shall be entitled to disclose the same to third parties
for use in connection with the registration marketing sale and use
of the Product in the Excluded Territory only; and
8.1.5 save as provided in Clause 10.6 Astra shall bear all the costs and
expenses associated with such trials (including but without
limitation the costs of documentation and administrative payments to
trialists); and
8.1.6 such trials shall be conducted only in accordance with any
regulatory permissions and/or approvals granted for the Product in
such part of the Territory in which the trials are conducted.
8.2 It is anticipated that Astra shall support any symposia organised, arranged
or sponsored by Glycyx involving areas of medicine relating to diseases of
the gastrointestinal tract and similar conditions and shall nominate and
sponsor key physicians in the said field of medicine to attend at those
symposia (and in particular shall sponsor those physicians presenting the
results of clinical research studies relating to the Product).
9. SUPPLY OF PRODUCT
-----------------
9.1 Astra shall notify Glycyx in writing of its forecast requirements for
quantities of the Product (in the form of bulk filled capsules) and details
of its proposals for Launch in each of the Principal Markets on or before
June 30th 1993. With such forecast Astra shall deliver a detailed forecast
of its requirements for the Product during 1994 and in January, April, July
and October in each year shall deliver to Glycyx revised forecasts for the
subsequent 12 month period commencing on the subsequent April 1st, July
1st, October 1st and January 1st respectively.
9.2 Glycyx shall fulfill all written orders placed on it by Astra for the
Product in the form of bulk filled capsules.
9.3 Whilst the forecasts delivered by Astra to Glycyx under Clause 9.1 shall be
non-binding and will not place any obligation on either Astra to order such
quantities or Glycyx to deliver such quantities:-
9.3.1 Astra shall use all reasonable endeavours to
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estimate accurately in such forecasts its requirements for the
Product; and
9.3.2 Astra shall ensure that all written orders are placed permitting a
lead time for manufacturing of the Product of not less than 16
weeks; and
9.3.3 Astra acknowledges that Glycyx shall not be obliged to fulfill any
firm written orders placed on it that may be in excess of [*] of
the last forecast quantities (in accordance with Clause 9.1) for
such period; and
9.3.4 Astra undertakes to place written orders and accept delivery of
quantities of the Product that are not less than [*] of the last
forecast quantities (in accordance with Clause 9.1) for such period.
9.4 During the term of the Research Agreement Glycyx shall supply Astra with
such quantities of the Product as Astra may reasonably require (in bulk
filled capsule form) for clinical trials undertaken by Astra under the
terms of the Research Agreement. Astra shall endeavour to provide Glycyx
with the maximum period of notice of such requirements and in any event
shall place firm written orders on Glycyx therefor not less than 90 days
before any requested delivery date.
9.5 After the termination of the Research Agreement Glycyx shall supply Astra
with such quantities of the Product in bulk filled capsule form as Astra
shall reasonably require for use as product samples and clinical trial
samples and as shall have been forecast and ordered by Astra in accordance
with Clauses 9.1 to 9.3.
9.6 Glycyx hereby warrants and undertakes that all quantities of the Product
(in bulk filled capsule form) supplied by it to Astra under the terms of
this Agreement shall as at the date of delivery be supplied fully in
accordance with the Bulk Product Specification and the Finished Product
Specification contained in Schedule 3 and shall have been manufactured in
accordance with European Community Good Manufacturing Practice and the Drug
Master File for the Product.
9.7 Upon the receipt of any delivery of the Product from Glycyx Astra shall
test such Product (in accordance with the Quality Test Procedures to be
agreed and incorporated into Schedule 4 to this Agreement after execution
of this Agreement) and in the event that such Quality Test Procedures
reveal any breach of the warranty given in Clause 9.6 Astra shall be
entitled to reject the full shipment of the Product within 45 days of
receipt of such shipment by notice in writing to Glycyx.
9.8 In the event of any dispute between the parties concerning any allegation
of breach of the warranty contained in clause 9.6 or concerning any
rejection or purported rejection of
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any shipment of the Product a sample quantity of the Product in question
shall (at the joint cost and expense of the parties) be delivered to an
independent laboratory (nominated by the agreement of the parties or in the
absence of agreement on the application of either party by the President
for the time being of the Royal Pharmaceutical Society of Great Britain)
which shall be supplied with copies of the Bulk Product Specification, the
Finished Product Specification and the Drug Master File and shall carry out
testing in accordance with the Quality Test Procedures and whose decision
as to the quality of such Product and as to any breach of warranty by such
Product, shall in the absence of manifest error be final and binding on the
parties.
9.9 The terms and conditions relating to the supply of the Product by Glycyx to
Astra shall be as set out in this Agreement and each written order placed
on Glycyx by Astra shall form a separate contract for the supply of the
Product.
9.10 The parties undertake to execute an agreement relating to the manufacture
and supply of Product for the purpose of disclosure to the relevant
regulatory authorities in the Territory substantially in the form contained
in Schedule 4 on or before the Filing Date. In the event that such
agreement is entered into by any Astra Associate in place of Astra Astra
undertakes to guarantee and procure the proper performance by such Astra
Associate of all its obligations under such agreement.
10. PRICE
-----
10.1 The price charged for the Product by Glycyx to Astra shall (save as
provided in Clause 10.6 and 10.7) be established in Sterling Pounds as
follows:
10.1.1 the price for the Product shall be finally determined by the end of
March and September of each calendar half-year for the preceding
July-December and January-June and shall (subject to Clause 10.1.5)
equal [*] for the Product in the Territory during the calendar
half-year in question;
10.1.2 for the conversion of the relevant currencies into Sterling Pounds
under Article 10.1.1 the official average exchange rates for the
sale and purchase of foreign currency at the SE-Banken, Stockholm on
the last banking day of the calendar half-year in question shall be
applied. With respect to currencies not quoted by the SE-Banken the
average rate for purchasing Sterling Pounds in the respective
country as published by any leading London Bank shall apply;
10.1.3 until the price can be finally determined in accordance with
Article 10.1.1 the Product will be
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THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
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supplied at provisional prices fixed by Glycyx and Astra based on
historical figures, forecasts and best estimates;
10.1.4 any balance resulting from differences between the provisional and
the final prices shall be settled by April 15 and October 15 of the
calendar half-year in which the final prices are established;
10.1.5 in the event that the [*] of all Product sold by Astra (and any
Astra Associate) in Germany after Launch in Germany shall exceed [*]
the price charged by Glycyx to Astra for supplies of the Product
(for Germany and elsewhere) after the month in which said sales
level for any such [*] is achieved shall be permanently increased
thereafter to equal [*] under Article 10.1.1 above.
10.2 In order to calculate the price charged by Glycyx to Astra pursuant to
Clause 10.1 Astra shall notify Glycyx for a six month period of its best
available estimate of the Factory Sales Prices (calculated by reference to
estimated sales in the Principal Markets and weighted by reference to
estimated quantities to be sold at such prices) which it reasonably
considers will be obtained for total sales of the Product by Astra in the
Territory.
10.3 Astra shall keep Glycyx informed of any material movement in the Factory
Sales Prices for the Product achieved on sales into any Principal Market
during any six month period.
10.4 Astra shall keep full proper and up-to-date books of account and records
showing clearly all transactions relating to the calculation of the Factory
Sales Price.
10.5 Astra shall allow Glycyx or its auditors or representative reasonable
access during normal business hours to inspect the books of account of
Astra (or any Astra Associate) in order to verify the Factory Sales Prices
and the prices changed by Glycyx to Astra under this Clause 10 Provided
That such verification shall be at the sole cost and expense of Glycyx.
10.6 Glycyx shall at its own cost and expense provide such supplies of the
Product to Astra as Astra may reasonably require for the conduct of
clinical trials.
10.7 In each country within the Territory Astra shall use all reasonable
endeavours to obtain the most favourable Factory Sales Price which is
consistent with competitive market characteristics and the demonstrated
advantages of the Product and presenting the Product as a new chemical
entity within such country.
10.8 The Product supplied by Glycyx to Astra in respect of any
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THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
-▇▇-
▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇ for the purpose of Product samples shall be supplied to
Astra [*] for a period of [*] from the date of Launch in each such
Principal Market Provided That:-
10.8.1 the quantities so delivered in any one year shall not exceed [*] of
the total aggregate Product sold by Astra in such Principal Market
in such year; and
10.8.2 for the purpose of determining [*] it is understood that this shall
include direct costs of material, labour and interest and direct
manufacturing overhead but shall not in any circumstances exceed [*]
of such Product in such Principal Market; and
10.8.3 Clauses 10.4 and 10.5 shall apply mutatis mutandis with respect to
Glycyx for the purpose of verifying [*] prices charged
Provided Further That for the avoidance of doubt Glycyx shall be entitled
to charge and receive the price calculated in accordance with Clause 10.1
in respect of any supplies of Product samples for any Principal Market made
after such [*] period or made during such [*] period which are in excess of
such [*] figure.
11. TERMS OF PAYMENT
----------------
11.1 Payment is strictly net cash to be paid to Glycyx within thirty (30) days
from the date of invoice in pounds sterling. Such payment shall be made by
express payment through the banking system into such bank account as Glycyx
shall designate for such purpose.
11.2 If payment is not made as set out in Clause 11.1 for any bulk delivery of
the Product to Astra Glycyx reserves the right;
11.2.1 to charge interest to Astra at the rate of 2% (two per cent) per
annum above the base rate for the time being of Barclays Bank plc on
the unpaid balance (such interest to accrue on a day-to-day basis
from the date of payment (as well after as before any judgment));
and
11.2.2 to require payment in advance for any delivery of the Product made
prior to receipt of such payment in full.
12. DELIVERY
--------
12.1 Delivery of the Product to Astra by Glycyx shall be Ex-Works any of the
European manufacturing plants designated by Glycyx (Incoterms 1990) and
otherwise as specified in the agreement entered into pursuant to Clause
9.10.
12.2 The Product shall be shipped to Astra by such method of
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
-16-
transport as Astra shall nominate and such transport shall be arranged and
paid for by Astra. Glycyx does not accept any liability for loss of or
damage to the Product after delivery and whilst in transit.
12.3 Risk in the Product shall pass to Astra on delivery and Astra shall be
responsible for insuring the Product from the date of delivery and in
transit at its own cost and expense.
13. LICENCE TO MANUFACTURE
----------------------
13.1 Save only in the circumstances set out below, Glycyx shall manufacture the
Product and shall supply Astra with such quantities of the Product as it
shall require and (save as expressly provided in this Clause 13) Astra
shall have no right title or interest in any of the Patents or proprietary
rights relating to the Product and is entitled to use the same only under
the terms of this Agreement.
13.2 In the event that Glycyx shall
13.2.1 be in breach of its obligations to supply the Product in the form
and manner specified in Clause 9 or otherwise in accordance with
forecast schedules and written orders placed on it by Astra and
shall fail to remedy such breach within 90 days of written notice
from Astra requiring remedy; or
13.2.2 give Astra 180 days notice in writing of its intention to cease to
supply Astra with the Product; or
13.2.3 by reason of Force Majeure be prevented from supplying the Product
to Astra for a period exceeding 180 days
Astra shall be entitled by service of notice in writing forthwith to
acquire a licence to manufacture the Product. Such licence shall commence
upon the effective date of such notices and shall be granted and continue
upon the terms and conditions contained in Schedule 2.
13.3 In the event that during any period in which Glycyx shall fail to supply
the Product to Astra by reason of:-
13.3.1 any breach by Glycyx in respect of which notice shall have been
served under Clause 13.2.1; or
13.3.2 any Force Majeure notified by Glycyx to Astra under Clause 13.2.3
Astra wishes to manufacture quantities of the Product to satisfy
requirements for the Product in the Territory Astra shall (by notice in
writing to Glycyx) forthwith be entitled to a temporary licence to
manufacture the Product during such period only and Provided That:-
-17-
13.3.3 such licence shall be upon the terms specified in Schedule 2; and
13.3.4 such licence shall permit manufacture by Astra of only such
quantities of the Product as may reasonably be required to fulfill
actual and reasonably anticipated orders on Astra for the Product
during such period and a reasonable period thereafter.
13.4 In order to satisfy itself of its ability to manufacture the Product Astra
shall be entitled at any time during the term of this Agreement to effect a
trial manufacture of bulk quantity of the Product Provided Always That:-
13.4.1 Glycyx shall provide such assistance and technical information as
Astra may reasonably require for such trial; and
13.4.2 Glycyx shall be entitled to attend and observe such trial; and
13.4.3 such trial shall be conducted at the sole cost and expense of
Astra but Glycyx shall if such trial quantity is used by Astra for
commercial purposes be entitled to charge Astra for the Product
produced as if it were Product sold by Glycyx to Astra under this
Agreement at a price calculated [*] obtained by Glycyx on the
supply of Product under the terms of this agreement [*] in the
Principal Markets or such higher figure as Glycyx may show by
documentary evidence [*].
13.4.4 Astra shall be solely responsible and liable for the quality of the
Product produced in the trial; and
13.4.5 Astra shall be licensed to use the Patents and any intellectual
property rights existing in the Product for such trial only; and
13.4.6 Astra shall not use all or any information received for the purpose
of the trial for any other purpose whatsoever and shall not use the
same after the trial unless and until a licence to manufacture shall
become effective under the terms of Clauses 13.2 or 13.3; and
13.4.7 Glycyx shall procure registration of Astra as a supplier under the
Drug Master File for the Product Provided Always That Astra shall
not exercise any right as such a registered supplier unless and
until a manufacturing licence shall become effective under Clauses
13.2 or 13.3.
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
-18-
14. TRADEMARK LICENCE
-----------------
14.1 Glycyx hereby grants to Astra a sole and exclusive licence to use the
Trademark on the Product and in connection with the marketing and
exploitation of the Product in the Territory only.
14.2 Glycyx undertakes to procure the grant of such rights and licence as may
reasonably be required to give effect to Clause 14.1 from the Trademark
owner, Biorex, and shall obtain Biorex's execution of such agreements as
are referred to in Clause 5.5.2.
14.3 Astra hereby confirms and acknowledges that it is licensed to use the
Trademark only as set out in this Agreement and Astra further
acknowledges:-
14.3.1 that all goodwill in the Trademark in any part of the Territory
(whether or not generated by the activities of Astra under this
Agreement) shall vest in Biorex; and
14.3.2 that any application for registration of the Trademark shall be
made in the name of Biorex only; and
14.3.3 undertakes to transfer and assign to Glycyx (or as it may direct)
any right, title or interest required by Glycyx or Biorex for
registration of the Trademark in any part of the Territory in the
name of Biorex and for all goodwill in the Territory to vest in
Biorex.
14.4 In consideration of the rights and licence granted to Astra by Glycyx in
respect of the Trademark Astra shall pay to Glycyx a licence fee at the
rate of [*] of all Product bearing the Trademark supplied by Astra (or any
Astra Associate) to any third party. Such licence fee shall commence on the
date of this Agreement and shall continue to be payable for such period of
time in which Astra shall continue to use the Trademark under the licence
hereby granted.
15. LICENCE PAYMENT
---------------
15.1 Astra shall keep true and accurate records of the sales of all Product
manufactured by it pursuant to any licence granted under Clauses 13.2 or
13.3 and of all Product sold by it at any time bearing the Trade ▇▇▇▇ and
Astra shall within ninety (90) days of the end of each period of six months
(such periods to end on 30 June and 31 December) send Glycyx a full
statement showing the calculation of all sums due and owing to Glycyx
15.1.1 in respect of the manufacturing licence under the provisions of
Clause 6 of Schedule 2; and
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
-19-
15.1.2 in respect of the Trade ▇▇▇▇ Licence under the provisions of Clause
14
and with such statement shall make payment in pounds sterling by express
payment through the banking system into such bank account as Glycyx shall
designate for such purpose, of such sum as is shown as due on the
statement. The provisions of Clause 10.1.2 shall apply in calculating the
applicable exchange rate.
15.2 Astra shall allow Glycyx or its auditors or representative reasonable
access during normal business hours to inspect the books of account of
Astra or any Astra Associate in order to verify the accuracy and
calculation of any statements delivered under Clause 15.1 Provided That
such verification shall be at the sole cost and expense of Glycyx.
15.3 In the event of any dispute between the parties concerning the calculation
and/or payment of any fee due under this Clause 15 an independent auditor
shall be appointed by the agreement of the parties or in the absence of
agreement at the request of either party by the President for the time
being of the Institute of Chartered Accountants in England and Wales who
acting as an expert and not as an arbitrator shall have full and free
access to all relevant information and data and shall be asked to determine
and settle any such dispute and in the absence of manifest error his
decision shall be final and binding on the parties. The independent
auditor's fees shall be paid by the parties in such proportions as he shall
direct.
15.4 Interest shall be payable to Glycyx by Astra at a rate of two per cent (2%)
above the base lending rate from time to time of Barclays Bank plc on all
outstanding fees due and payable by Astra to Glycyx under the provisions of
this Clause 15 both before and after judgment.
16. PRODUCT LIABILITY
-----------------
16.1 Glycyx hereby agrees to indemnify Astra against any action, claim, loss and
damage suffered by or awarded against Astra in connection with any claim
against Astra from a third party arising from any breach by Glycyx (or its
subcontractors or nominees) of the warranty and undertaking contained in
clause 9.6 Provided Always That such indemnity shall not extend to any
liability, cost, expense or damage suffered or incurred by reason of any
defect in any Product which was detected or should have been detected by
Astra by means of the Quality Test Procedures applied (or which should have
been applied) by Astra within 45 days of the date of delivery of the
Product under the provisions of Clause 9.7.
16.2 Astra undertakes to indemnify and hold Glycyx harmless against all and any
loss, damage, claim or liability suffered or incurred by Glycyx in any
circumstances
-20-
whatsoever save only where Glycyx is liable under Clause 16.1.
17. CONFIDENTIAL INFORMATION
------------------------
17.1 Astra hereby agrees and undertakes that during the application of this
Clause 17 and for a period of ten years thereafter (howsoever termination
may be caused or arise) it shall keep confidential and shall not without
the prior written consent of Glycyx disclose to any third party any
information of a confidential nature belonging to Glycyx or Biorex
(including trade secrets and information of commercial value) which may
become known to Astra from Glycyx in connection with this Agreement and/or
the Research Agreement Provided Always That such obligation of
confidentiality shall not extend to any part of such confidential
information which:
17.1.1 shall otherwise than by reason of any default by Astra become
freely available to the general public; or
17.1.2 Astra can show by documentary evidence was in its possession or
control prior to disclosure free of any obligation of
confidentiality; or
17.1.3 Astra can show by documentary evidence shall have come into the
possession or control of Astra from a third party free of any
obligation of confidentiality subsequent to disclosure hereunder; or
17.1.4 Astra is obliged by law or regulation to disclose to a third party
provided that such disclosure shall only be to the extent required
by such law or regulation.
and Provided Further that in the event that this Agreement is terminated by
Glycyx Astra shall forthwith cease any use of such information for any
purpose whatsoever
17.2 Astra shall ensure that any employee of, or consultant to, Astra who shall
obtain any confidential information in connection with the performance of
this Agreement shall be bound by obligations of confidentiality
substantially similar to the provisions of Clause 17.1.
17.3 Glycyx acknowledges the importance of keeping all material information
relating to the Product confidential and Glycyx will use all reasonable
endeavours to make sure that no such information is made public or
otherwise made available to third parties in any manner which would
jeopardize the exclusivity in the Territory granted to Astra hereunder.
18. INTELLECTUAL PROPERTY
---------------------
18.1 Astra acknowledges that save as expressly provided herein or as may be
required in connection with the performance by
-21-
Astra of any obligations under the Research Agreement Astra shall have no
right, title, interest or licence in or to the Patents or otherwise any
intellectual property rights of Biorex or Glycyx in Balsalazide or the
Product,
18.2 In the event that either party becomes aware of any infringement by any
third party within the Territory of any intellectual property rights of
Glycyx and/or Biorex in the Patents, Balsalazide, the Product or the
Trademark it shall forthwith notify the other party. Glycyx shall be
entitled to take such action (or procure such action by Biorex) as it may
in its sole discretion consider appropriate against any such third party
infringer Provided Always That:-
18.2.1 Astra shall give such assistance as Glycyx may reasonably require
in connection with any such action (subject to reimbursement by
Glycyx of all costs reasonably incurred by Astra); and
18.2.2 Glycyx shall keep Astra informed of the conduct and progress of
such action but shall be entitled to conduct, pursue and settle such
action in such manner as it shall reasonably consider appropriate
and to retain any damages awarded against any such infringer;
in the event that such infringement shall continue and Glycyx shall fail to
take or procure any action to prevent any continued infringement Astra may
(in its sole discretion) at its sole expense initiate and pursue such
action as it considers appropriate to prevent any continued infringement
Provided Further That:-
18.2.3 Glycyx shall give (and shall use reasonable endeavours to procure
from Biorex) such assistance as Astra may reasonably require in
connection with any such action (subject to reimbursement by Astra
of all costs reasonably incurred by Glycyx and/or Biorex); and
18.2.4 Astra shall keep Glycyx informed of the conduct and progress of
such action but shall be entitled to conduct, pursue and settle such
action in such manner as it shall reasonably consider appropriate
(having regard to the continuing value of any such intellectual
property rights to Glycyx and/or Biorex and the effect which any
such infringement shall have had or will have on the exploitation in
the Territory by Astra of the Product) and to retain any damages
awarded against any such infringer.
18.3 In the event that any claim is made against Astra by any third party
alleging infringement of any rights of any third party by the use and
exploitation of the Product by Astra shall be entitled at its sole cost and
expense to defend any such claim in such manner as it may in its sole
discretion consider appropriate Provided Always That
-22-
18.3.1 Glycyx shall give (and shall use reasonable endeavours to procure
from Biorex) such assistance as Astra may reasonably require in such
action (subject to reimbursement by Astra of all costs reasonably
incurred by Glycyx and/or Biorex); and
18.3.2 Astra shall keep Glycyx informed of the conduct and progress of
such action but shall be entitled to conduct, pursue and settle such
action in such manner as it shall reasonably consider appropriate
(having regard to the continuing value of any such intellectual
property rights to Glycyx and/or Biorex and the effect which any
such infringement shall have had or will have on the exploitation in
the Territory by Astra of the Product) and to retain any damages
awarded against any such infringer; and
18.3.3 (save only for any liability arising by reason of any breach by
Glycyx of the warranties contained in Clause 11.1 of the Research
Agreement) Glycyx shall not be liable in any manner whatsoever to
Astra for any loss or damages suffered incurred or awarded against
Astra in connection with any such claim.
19. SUB-DISTRIBUTORS AND SUB-LICENSEES
----------------------------------
19.1 Astra is hereby granted the right to appoint sub-distributors for the
Product in countries within the Territory Provided Always That
19.1.1 Astra shall remain solely liable for the performance of its
obligations hereunder in each part of the Territory; and
19.1.2 in any part of the Territory where there is resident an Astra
Associate any sub-distributor appointed shall only be such Astra
Associate.
20. TERMINATION
-----------
20.1 The rights and obligations of the parties contained in Clauses 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 17, 18, 19 and 22 shall cease forthwith upon
the date of expiry of a period of 15 years from the date of first Launch
Provided Always That
20.1.1 the Trademark Licence granted under Clause 14 shall continue
thereafter in accordance with its terms and Clause 15 will remain
valid with respect to Clause 14; and
20.1.2 any licence granted to Astra to manufacture under Clause 13.2 shall
continue indefinitely thereafter in accordance with Clause 6.4 of
Schedule 2; and
20.1.3 any licence or interest in all or any part of the Patents,
Balsalazide and/or the Product shall continue indefinitely
thereafter.
-23-
20.2 Either party to this Agreement shall be entitled to terminate this
Agreement forthwith by notice in writing to the other in the event that:-
20.2.1 the other party shall fail to pay any sum due hereunder on the due
date and shall fail to remedy such breach within (30) thirty days of
being required in writing by the other party so to do; or
20.2.2 the other party shall commit a material breach of any of the terms
and conditions of this Agreement and shall fail to remedy the same
(if capable of remedy) within ninety (90) days of being required in
writing by the other party so to do provided that such right of
termination shall not arise in the event of any breach by Glycyx of
its obligations under Clause 9 which circumstance is governed by the
provisions of Clause 13 only; or
20.2.3 the other party goes into liquidation (either voluntary or
compulsory) or shall be the subject of any petition for winding up;
or
20.2.4 the other party shall make any assignment or arrangement for the
benefit of its creditors or cease or threaten to cease to carry on
its business in the ordinary course; or
20.2.5 a receiver, administrative receiver, or receiver and manager, or
judicial manager or administrator is appointed over the whole or any
part of the assets of either party or if any court proceedings are
commenced for the appointment of an administrator or receiver to
either party; or
20.2.6 the other party shall become unable to pay its debts as they become
due in the ordinary course of business or shall otherwise become
subject or seek relief under any law relating to insolvency in any
jurisdiction relevant to such other party; or
20.2.7 the party serving such notice shall have served notice of
termination on such other party under the provisions of Clause 7.4
of the Research Agreement provided that in the event that Astra
assumes all obligations in connection with the conduct and
completion of the Project in accordance with Clause 6.6 of the
Research Agreement no event referred to in such Clause 6.6 shall
constitute grounds for breach under this Agreement or the Research
Agreement.
20.3 Any waiver by either party of a breach of any provision of this Agreement
shall not be considered as a waiver of any subsequent breach of the same or
any provisions of this Agreement.
20.4 Any termination of this Agreement shall be without prejudice
-24-
to the right of either party to recover any monies due to it under this
Agreement or the rights or remedies of either party in respect of any
breach prior to the effective date of termination of this Agreement.
20.5 Glycyx and Astra each undertake to the other that during the term of this
Agreement it shall not exercise any right which it may have (or may
acquire) to terminate the Biorex Agreement without prior consultation with
the other and without taking such action as may be appropriate to ensure
that the rights granted to such other hereunder are not prejudiced to any
material extent.
21. CONSEQUENCES OF TERMINATION
21.1 In the event of termination of this Agreement under Clause 20.2 by Glycyx
prior to the expiry of a period of 15 years from date of Launch Astra
shall:
21.1.1 forthwith, cease all marketing, sale and promotion of the Product;
and
21.1.2 immediately telegraphically transfer all monies due and payable to
Glycyx as at the date of termination into Glycyx's bank account
designated under Clause 11.1; and
21.1.3 immediately return to Glycyx all information and data of whatsoever
nature relating to the Product together with all copies thereof
(other than correspondence between Glycyx and Astra) which Astra may
have in its possession or under its control including but without
limitation all scientific, medical and safety data relating to the
Product; and
21.1.4 immediately cease use of all or any confidential information of
Glycyx delivered in connection with this Agreement and the
Trademark; and
21.1.5 take all such steps as may reasonably be required to transfer or
procure the transfer to Glycyx (or its nominee) of all such produce
licences and approvals as may have been obtained for the marketing
and sale of the Product in any part of the Territory; and
21.1.6 Glycyx shall purchase such stocks of the Product (inclusive of
packaging) as Astra shall still have in its possession once it has
fulfilled all orders outstanding as at the date of termination at a
price calculated as cost price to Astra Provided That Glycyx shall
not be obliged to purchase any of the stocks of the Product which do
not have at least two thirds of its approved shelf life unexpired or
are otherwise not of merchantable quality.
21.2 In the event of termination of this Agreement under Clause 20.2 by Astra
prior to the expiry of a period of fifteen years from the date of Launch
the rights and obligations of
-25-
Astra under this Agreement shall continue subject always to the terms of
the Biorex/Astra Agreement.
22. ASSIGNMENT
----------
22.1 The benefit of this Agreement is personal to Astra and to Glycyx and shall
not be capable of assignment by either of them without the prior consent in
writing of the other party (such consent not to be unreasonably withheld or
delayed).
23. FORCE MAJEURE
-------------
23.1 If the performance of any obligations under this Agreement by either party
is affected by Force Majeure it shall forthwith notify the other party of
the nature and extent thereof.
23.2 Neither party shall be deemed to be in breach of this Agreement or
otherwise be liable to the other by reason of any delay in performance or
non-performance of any of its obligations hereunder to the extent that such
delay or non-performance is due to any Force Majeure which has been
notified to the other party in writing.
24. COSTS
-----
24.1 Each party hereto shall bear its own costs in relation to the negotiation,
drafting, preparation, and execution of this Agreement.
25. CONFIDENTIALITY OF THIS AGREEMENT
---------------------------------
25.1 The contents of this Agreement shall remain confidential as between the
parties. Neither party shall, without the prior written consent of the
other (such consent not to be unreasonably withheld without justification),
disclose any of the financial terms of this Agreement to any other person,
firm or company save for
25.1.1 disclosure by Glycyx to Biorex and Salix Pharmaceuticals Inc. in
circumstances where such third party shall have accepted obligations
of confidentiality in respect of the information disclosed; and
25.1.2 such disclosure as may be required by any relevant law or
regulatory authority.
26. NATURE OF THE AGREEMENT
------------------------
26.1 Nothing in this Agreement shall create or be deemed to create any
partnership, joint venture or the relationship of principal and agent
between the parties.
26.2 Each party acknowledges that, in entering into this Agreement, it does not
do so on the basis of, and does not rely on, any representation, warranty
or other provision (except as expressly provided herein or in the Research
-26-
Agreement) and all conditions, warranties or other terms implied by Statute
or common law are hereby excluded to the fullest extent permitted by law.
26.3 This Agreement (including all the Schedules) together with the Research
Agreement and any agreements entered into pursuant to this Agreement
constitutes the entire understanding and agreement between the parties with
respect to the subject matter of this Agreement and supersedes all prior
agreements, negotiations and discussions between the parties relating to
this Agreement.
26.4 This Agreement may not be released, discharged, abandoned, charged or
modified, in any manner, except by an instrument in writing signed by a
duly authorised officer or representative from each of the parties hereto.
26.5 This Agreement shall be governed by and construed in all respects in
accordance with the laws of England and each party hereby submits to the
exclusive jurisdiction of the English courts. For the purpose of accepting
service of process in connection with any action commenced before the High
Court in England the parties hereto hereby absolutely, unconditionally and
irrevocably appoint the following agents to accept process on their behalf
it being unconditionally agreed that for this purpose such process will be
properly and effectively served if the same is left at the addresses set
out below:-
Astra: F.A.O. The Managing Director
Astra Pharmaceuticals Limited
Home ▇▇▇▇ ▇▇▇▇▇▇
▇▇▇▇▇ ▇▇▇▇▇▇▇
▇▇▇▇▇
▇▇▇ ▇▇▇
Glycyx: F.A.O., Glycyx Pharmaceuticals Limited
Camas Partners Limited
Camas House
▇▇ ▇▇▇▇ ▇▇▇▇
▇▇▇▇▇▇▇
▇▇▇▇▇▇▇▇▇▇▇▇
▇▇▇▇ ▇▇▇
27. NOTICES
-------
27.1 All notices to be served by the parties to this Agreement shall be served
only in the English language.
27.2 Notices shall be sufficiently served if dispatched by first class or
express post (meaning the fastest normal method of mail transmit in the
country of dispatch) to the address of the receiving party set out below
Glycyx ▇▇▇▇ ▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇
▇▇▇▇▇ ▇▇▇
▇▇▇▇ ▇▇▇▇
▇▇ ▇▇▇▇▇ ▇.▇.▇.
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F.A.O. ▇ ▇ ▇▇▇▇▇▇▇▇
Astra Kvarnbergagatan ▇▇
▇-▇▇▇ ▇▇ ▇▇▇▇▇▇▇▇▇▇
▇▇▇▇▇▇
F.A.O. Vice President Legal Affairs
Any modification to this address must in itself be notified in writing to
the other party in accordance with the terms of this sub-clause.
27.3 In the absence of proof to the contrary notices properly sent hereunder
shall be deemed to have been duly served 10 days after the date of
dispatch.
27.4 It shall be permitted for notices to be served hereunder by facsimile
transmission and for this purpose the following fax number below shall
apply:
27.4.1 in the case of Glycyx at ▇▇▇▇ ▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇ ▇▇▇▇▇ ▇▇▇ ▇▇▇▇ ▇▇▇▇
▇▇ ▇▇▇▇▇ ▇▇▇ facsimile transmission number ▇▇▇-▇▇▇-▇▇▇▇ and marked
for the attention of ▇ ▇ ▇▇▇▇▇▇▇▇
27.4.2 in the case of Astra at ▇▇▇▇▇▇▇▇▇▇▇▇▇▇▇ ▇▇, ▇-▇▇▇ ▇▇ ▇▇▇▇▇▇▇▇▇▇,
▇▇▇▇▇▇ facsimile transmission number ▇▇▇ ▇▇▇ ▇▇ ▇▇ ▇▇ and marked for
the attention of Vice President Legal Affairs
provided that such notice is confirmed by return facsimile and shall be
deemed served 24 hours after the time of receipt of such return facsimile.
AS WITNESS the hands of the duly authorised representatives of the parties
hereto the day and year first above written.
-28-
SCHEDULE 1
----------
THE PATENTS
-----------
Distribution Schedule 1 (Pages 1 to 28)
SCHEDULE I
PATENTS
PATENT NUMBER FILING DATE GRANT DATE DUE TO EXPIRE
UK 2,080,796 Complete 07/07/2001
Specification
7.07.1981
France 1,493,313 21.07.1981 21.07.2001
Italy 1,138,450 10.07.1981 10.07.2001
Japan 1,433,303 16.07.1981 07.04.2001
U.S.A. 4,412,992 08.07.1981 01.11.2000
F.R.G. 3,120,019 21.07.1981 15.02.90 21.07.2001
(Distribution Schedule 1 cont...)
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[SEAL] (12) UK Patent (19) GB (▇▇) ▇ ▇▇▇ ▇▇▇ B
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(54) Title of invention
2-hydroxy-5-phenylazobenzoic acid derivatives and pharmaceutical
compositions containing them
(51) INTCL/3/:C07C 107/06A61K 31/60 31/63 C07C l43/54 143/78
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(21) Application No (73) Proprietor
8120914 Biorex laboratories Limited.
Biorex House,
Canonbury Villas,
(22) Date of filing ▇▇▇▇▇▇ ▇▇ ▇▇▇.
7 Jul 1981
(30) Priority data
(31) 023826
(32) 21 Jul 1980
(33) Untied Kingdom (GB)
(72) Inventors
▇▇▇▇▇▇▇▇ Po ▇▇▇▇ ▇▇▇▇
(43) Application published
10 Feb 1982
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(45) Patent finished
12 Oct 1983
(52) Domestic classification
C2C 220 227 22Y ▇▇▇ ▇▇▇ ▇▇▇ ▇▇▇
29Y 30Y 321 323 325 32Y 332 342
34Y 360 361 365 366 367 368 36Y (74) Agent and or Address for
385 394 39Y 510 51X 534 583 60Y Service
▇▇▇ ▇▇▇ ▇▇▇ ▇▇▇ ▇▇▇ ▇▇▇ ▇▇▇ ▇▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇▇▇ and Co.,
▇▇▇ ▇▇▇ ▇▇▇ 661 662 668 699 802 ▇▇▇, ▇▇▇▇ ▇▇▇▇,
▇▇▇ ▇▇ KH KJ KN KR KT RC SG ▇▇▇▇▇▇ ▇▇▇▇ ▇▇▇.
U1S 1318 C2C
(56) Documents Cited
None
(58) Field of search
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▇▇▇▇▇▇ THE PATENT OFFICE
(Distribution Schedule 1 cont...)
-1-
"2-Hydroxy-5-phenylazobenzoic acid derivatives
and pharmaceutical compositions containing them".
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(Distribution Schedule 1 cont...)
-2-
The present invention is concerned with new pharmaceutical compositions
containing derivatives of 2-hydroxy-5-phenylazobenzoic acid, most of which are
new.
Ulcerative colitis is a disease of increasing prevalence for which at
present the only satisfactory treatment is the administration of salazopyrin,
which has the following structural formula:
[FORMULA OMITTED]
However, one serious disadvantage of salazopyrin is that it is broken down
in the intestinal tract to give sulphapyridine which gives rise to undesirable
side effects. Furthermore, salazopyrin is insoluble in water.
We have now found that when the pyridylsulphamoyl moiety of salazopyrin is
replaced by certain nonheterocyclic organic radicals, compounds are obtained
which are very useful for the treatment of ulcerative colitis and have the great
advantage that breakdown thereof in the intestinal tract does not give rise to
undesirable metabolic products. Furthermore, many of them are soluble in water,
which is advantageous for ease of administration, and have a very low acute
toxicity.
(Distribution Schedule 1 cont...)
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Thus, according to the present invention, there are provided
pharmaceutical compositions containing at least one compound of the general
formula:
[FORMULA OMITTED]
5 wherein X is an -SO\\2\\-or -CO- group and R is either a non-heterocyclic
aromatic ring system, preferably a benzene ring, optionally substituted by
a radical of the general formula -(CH\\2\\)\\n\\-Y or is a radical of the
general formula-(CH\\2\\)\\n\\-Y, in which Y is a hydroxyl group, an
10 unsubstituted or substituted amino group or a carboxylic or sulphonic acid
group and n is a whole number of from 1 to 6 and in which one or more
-
hydrogen atoms in the alkylene radical can be replaced by unsubstituted or
substituted amino groups or alkyl radicals: and/or containing at least one
15 ester thereof and/or at least one non-toxic, pharmaceutically acceptable
salt thereof, in admixture with a solid or liquid pharmaceutical diluent or
carrier.
16 Most of the compounds of general formula (I) are new. Consequently,
the present invention also provides new compounds of the general formula:-
[FORMULA OMITTED]
(Distribution Schedule 1 cont...)
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wherein X is an -SO\\2\\- or -CO- group and R is either a non-heterocyclic
aromatic ring system, preferably a benzene ring, optionally substituted by
a radical of the general formula -(CH\\2\\)\\n\\-Y or is a radical of the
5 general formula -(CH\\2\\)-\\n\\-Y, in which Y is a hydroxyl group or an
unsubstituted or substituted amino group or a carboxylic or sulphonic acid
group and n is a whole number of from 1 to 6 and in which one or more of
-
the hydrogen atoms in the alkylene radical can be replaced by unsubstituted
10 or substituted amino groups or alkyl radicals, with the proviso that
R-NH-X-is other than a -CO-NH-CH\\2\\-COOH radical: and the esters and the
non-toxic, pharmacologically acceptable salts thereof, for example the
salts with alkali metals and alkaline earth metals or with non-toxic
15 amines.
Substituted amino groups present in the compounds according to the
present invention are preferably mono or dialkylamino radicals, the alkyl
moieties of which contain up to 6 and preferably up to 3 carbon atoms,
20 methyl and ethyl being especially preferred.
The compounds of general formula (I) can be prepared by diazotising an
amine of the general formula:-
[FORMULA OMITTED]
(Distribution Schedule 1 cont...)
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in which R and X have the same meaning as above, followed by coupling with
salicylic acid, whereafter, if desired, the compound obtained is salified
with a non-toxic inorganic or organic base.
The following Examples are given for the purpose of illustrating the
present invention:-
Example 1.
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a) A mixture of 100 g. N-acetylsulphanilyl chloride, 80 g. aniline
sulphate and 80 g. sodium carbonate in 500 ml. acetone was heated under
reflux while stirring, for 5 hours, cooled and then added to a mixture of
dilute hydrochloric acid and ice. The precipitate obtained was filtered
off, washed with water and diethyl ether and dried in a vacuum at 50deg.C.
to give 110 g. of almost pure N-acetylsulphanilylanilide; m.p. 212 -
215deg.C.
b) 100 g. N-Acetylsulhanilylanilide was heated under reflux for 3 hours
in 150 ml. aqueous hydrochloric acid (1:1 v/v). After cooling, the reaction
mixture was diluted with water and further cooled to 0deg.C. The 90 g. of
sulphanilylanilide hydrochloride which deposited were filtered off, washed
with ice-cold water and recrystallised from ethanol: m.P. 191 - 193.5deg.C.
c) 10g. Sulphanilylanilide hydrochloride and 10 ml. concentrated
hydrochloric acid in 600 ml. ethanol were gently warmed to dissolve, then
cooled to 5deg.C. and treated dropwise with 30 ml. of a 10% aqueous
solution
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of sodium nitrite. The reaction mixture was left to stand for 1 hour at 0
to 5deg.C. and then filtered while maintaining the temperature at 0 to
50deg.C., the filtrate was added dropwise to a solution of 5 g. salicylic
acid in 100 ml. of an aqueous solution containing 4 g. sodium carbonate and
7 g. sodium hydroxide cooled to 0deg.C. The reaction mixture was left to
stand for 3 hours at 0deg.C. and at ambient temperature for 20 hours, while
maintaining a pH of (greater than) 8 whereafter it was concentrated on a
rotavapor apparatus and acidified. The gummy precipitate obtained was
separated off and boiled with water several times to remove excess
salicylic acid. The residue was dissolved in diethyl ether and the ethereal
solution was washed with water, dried over anhydrous sodium sulphate and
treated with charcoal. After filtering and removing the diethyl ether, the
crude product obtained was dissolved in the minimum amount of acetone and
ten times the volume of diethyl ether added thereto. Upon cooling, there
were obtained 3.5 g. 5-(4-phenylsulphamoylphenylazo)-salicylic acid; m.p:
232-234 deg.C.
d) 11 g. 5-(4-Phenylsulphamoylphenylazo)-salicylic acid in 100 ml.
ethanol were treated with an ethanolic solution of an equivalent amount of
sodium hydroxide. The resulting solution was concentrated to a small volume
at 30deg.C. and 20 mm. Hg, whereafter an equal volume of diethyl ether was
added to the concentrate. Upon
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cooling, sodium 5-(4-phenylsulphamoylphenylazo)-salicylate deposited, which
was filtered off, washed with diethyl ether and petroleum ether (b.p. 40 -
60deg.C.) and dried at 50deg.C. in a vacuum: m.p. 257 - 259deg.C. The yield
was 12 g.
Example 2
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a) A solution of 22 g. 4-aminohippuric acid in 20 ml. hydrochloric acid
and 200 ml. water was cooled to 0deg.C. and treated dropwise, while
stirring, with 80 ml. of a 10% aqueous solution of sodium nitrite. The
reaction mixture was then stirred for 1 hour, whereafter a solution of 14
g. salicylic acid in 150 ml. 2N aqueous sodium hydroxide solution
containing 15 g. sodium carbonate and cooled to 0deg.C. was added dropwise
thereto. The reaction mixture was left to stand overnight at ambient
temperature and then poured into a mixture of ice and dilute hydrochloric
acid. The fine precipitate obtained was extracted with boiling ethyl
acetate and the solution treated with charcoal. After filtering, the
filtrate was evaporated to remove the solvent and the residue was
crystallised from boiling ethanol to give 30 g. 5-(4-
carboxymethylcarbamoylphenylazo)salicylic acid; m.p. 260 - 262deg.C.
b) A solution of 11 g. 5-(4-carboxymethylcarbamoylphenylazo)-salicylic
acid in 500 ml. warm ethanol was treated with an ethanolic solution
containing two equivalents of sodium hydroxide and the deposit obtained
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was filtered off, washed with ethanol and diethyl ether and dried in a
vacuum at 50deg.C. There were obtained 12.5 g of the disodium salt 5-(4-
carboxymethylcarbamoylphenylazo)-salicylic acid; m.p. greater than
360deg.C.
Example 3.
----------
9.71 g. Aminohippuric acid were dissolved in a mixture of 40 ml. 2.5N
hydrochloric acid and 10 ml. 2.5N sulphuric acid and 50 g. ice added
thereto. A solution of 3.5 g. sodium nitrite in 15 ml. water were added
steadily at 0deg.C., the reaction mixture being well stirred during the
addition. After 75 minutes at 0deg.C., the reaction mixture was added to a
solution of 6.9 g. salicylic acid in 37 ml. of a mixture of 9 parts by
volume of 5N aqueous sodium hydroxide solution and 1 part by volume of 5N
aqueous sodium carbonate solution, the temperature being kept at 0deg.C. by
the addition of ice.
After 15 minutes, 23 ml. of a mixture of 4 parts by volume of 5N
hydrochloric acid and 1 part by volume of 5N acetic acid was slowly added,
while stirring. The precipitate obtained was filtered off, washed with
distilled water and dried in a vacuum at 80deg.C. to give 17.2 g. (100% of
theory) 5-(4-carboxymethylcarbamoylphenylazo)-salicylic acid, which can be
recrystallised from 80% acetic acid, aqueous acetone or aqueous
dimethylformamide to give a yellow, crystalline product of at least 99%
purity in a yield of 80 to 95%; m.p. 260 - 262deg.C.
(Distribution Schedule 1 cont...)
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Example 4.
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a) 125 g. Finely powdered 4-nitrobenzoyl chloride were added portionwise
while stirring, to a solution of 70 g, b-alanine in 500 ml, water
containing 65 g. sodium hydroxide and cooled to 50deg.C. The reaction
mixture was stirred for 3 hours and then added to a mixture of ice and
hydrochloric acid. The precipitate obtained was filtered off, washed with
water and dried by suction. After crystallisation of the dried product from
hot acetone, there were obtained 130 g. 4-nitro-benzoyl-B-alanine: m.p.
164 -166deg.C.
b) A suspension of 15 g. finely powdered 4-nitrobenzoyl-B-alanine in 200
ml.ethanol was stirred in an atmosphere of hydrogen in the presence of 1 g.
of palladium-charcoal (5%) while cooling gently. When the absorption of
hydrogen had ceased, the reaction mixture was filtered and the filtrate
concentrated to a small volume. Upon adding diethyl ether and cooling, 4-
aminobenzoyl-B-alanine was obtained. The yield was 11.5 g.; m.p. 156 - 158
deg.C.
c) 8.8g. 4-Aminobenzoyl-B-alanine were triturated with 12 ml.
hydrochloric acid and the paste obtained was dissolved in 100 ml. water.
The solution was cooled to -5deg.C. and a solution of 3 g. sodium nitrite
in 20 ml. water, cooled to 0deg.C., was added dropwise, while stirring. The
diazotised solution was left for 1 hour, at 0deg.C. and was then added
dropwise at -5deg.C. to a solution
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-10-
of 6 g. salicylic acid in 70 ml, water containing 3.6 g. sodium hydroxide
and 7 g. sodium carbonate. The final reaction mixture was adjusted to a pH
of about 8, stirred for 2 to 3 hours and added to a mixture of dilute
5 hydrochloric acid and ice. The precipitate obtained was filtered off,
washed with water and suction dried. Crystallisation from hot ethanol gave
11.9 g. 5-(4-carboxyethylcarbamoylphenylazo)-salicylic acid; m.p. 254 -
255deg.C.
10 10.7 g. of the free acid were dissolved in 300 ml. warm ethanol and
treated with a solution of 2.4 g. sodium hydroxide in 25 ml. ethanol. The
precipitate obtained was filtered off, washed with ethanol and diethyl
ether and dried in a vacuum at is 50deg.C. to give 11.5 g. of the disodium
15 salt of 5-(4-carboxyethylcarbamoylphenylazo)-salicylic acid; m.p. (greater
than) 350deg.C.
Example 5.
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20 a) 20 g. Finely powdered 4-nitrobenzoyl chloride were added portionwise
to 12.5 g. taurine in a solution of 8 g. sodium hydroxide in 50 ml. water.
The reaction mixture was stirred for 3 hours and then acidified.
Precipitated 4-nitrobenzoic acid was filtered off and the filtrate
25 distilled to dryness at a pressure of 15 mm, Hg. The residue was extracted
with boiling ethanol and the extract then cooled to give a yield of 23.6 g.
4-nitrobenzoyltaurine; m.p. 278 -280deg.C.
(Distribution Schedule 1 cont...)
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b) A solution of 17 g. 4-nitrobenzoyltaurine in 100 ml. water was stirred
in an atmosphere of hydrogen in the presence of 1 g. palladium-charcoal
(5%) until the absorption of hydrogen ceased. The reaction mixture was then
5 filtered, the filtrate was mixed with 20 ml. hydrochloric acid and the
suspension of the hydrochloride obtained cooled to -5deg.C. This was added
dropwise, while stirring, to a solution of 5 g. sodium nitrite in 30 ml.
water. The diazotised solution thus obtained was stirred for 30 minutes and
10 then added to 9.5 g, salicylic acid in a solution of 11 g. sodium hydroxide
in 100 ml. water, cooled to -2deg.C. The mixture was stirred for 3 hours,
poured into a mixture of ice and 15 ml. hydrochloric acid and stirred at
0deg.C. for 30 minutes. The precipitate obtained was filtered off and
15 washed with ice-cold water. Crystallisation from 20% aqueous ethanol gave
18.2 g. 5-(4-sulphoethylcarbamoylphenylazo)-salicylic acid; m.p. (greater
than) 350deg.C. (decomp.).
20 Example 6
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a) A solution of 10 ml. ethanolamine in 120 ml. 10% aqueous sodium
hydroxide solution was cooled to 5deg.C. and 30 g. finely powdered 4-
nitrobenzoyl chloride added thereto portionwise. The reaction mixture was
25 stirred for 24 hours and filtered, The solid obtained, which mainly
consisted of bis-(4-nitrobenzoyl)-ethanol-amine, was hydrolysed with 200
ml, of 4% aqueous
(Distribution Schedule 1 cont...)
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ethanolic sodium hydroxide at ambient temperature for 24 hours. The
reaction mixture was added to the above filtrate, acidified and the
precipitated 4-nitrobenzoic acid was filtered off. The filtrate was
5 concentrated and the 13 g. of precipitated N-(4-nitrobenzoyl)-ethanolamine
isolated. The mother liquor was distilled to dryness and the residue was
boiled with ethanol. Concentration of the ethanolic extract gave a further
5.3 g. of product: m.p. 134 - 135deg.C.
10 b) A solution of 21 g. of N-(4-nitrobenzoyl)-ethanolamine in 400 ml.
ethanol was stirred in an atmosphere of hydrogen in the presence of 1 g.
palladium-charcoal (5%) until the absorption of hydrogen had ceased. The
catalyst was filtered of and the ethanolic solution was evaporated to
15 dryness to give a thick oil which slowly solidified. Thin layer
chromatography showed that the N-(4-aminobenzoyl)-ethanolamine thus
obtained had a purity of more than 99%: it was used as such for the next
stage of the synthesis.
20 c) A solution of 16 g. N-(4- aminobenzoyl)-ethanol-amine in 20 ml.
hydrochloric acid and 150 ml. water was cooled to -5deg.C. and treated
dropwise, while stirring, with a solution of 7 g. sodium nitrite in 50 ml.
water. The reaction mixture was further stirred for 1 hour and then added
25 dropwise to 120 ml. of 10% aqueous sodium hydroxide solution containing 13
g. salicylic acid and cooled to -2deg.C. The reaction mixture was
(Distribution Schedule 1 cont...)
-13-
stirred for 3 hours and the precipitate obtained filtered off, washed with
ice-cold water, suction dried and crystallised from hot ethanol to give 11
g. sodium 5-(4-hydroxyethylcarbamoylphenylazo)-salicylate: m.p. 286 -
288deg.C. (decomp.).
The filtrate from which the sodium salt had been removed was
acidified. The precipitate obtained was filtered off, washed with water,
suction dried, charcoaled in ethyl acetate-methanol (2:1 v/v) and
concentrated to give 2.7 g. 5-(4-hydroxyethylcarbamoylphenylazo)-salicylic
acid which was identical in all respects to the free acid regenerated from
the sodium salt; m.p. 225 - 226deg.C. (decomp.).
Example 7.
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a) A solution of 7 g. alanine in 65 ml. of 10% aqueous sodium hydroxide
solution was treated portionwise, while stirring, with 12.5 g. finely
powdered 4-nitrobenzoyl chloride. The reaction mixture was stirred at
5deg.C. for 20 hours, acidified and the precipitate isolated, washed with
water and suction dried. Repeated fractional crystallisation from acetone-
diethyl ether (2:1 v/v) gave 4-nitrobenzoylalanine: m.p. 199 200deg.C.
b) 2 g. 4-Nitrobenzoylalanine in 50 ml. ethanol were hydrogenated in the
presence of 0.2 g. palladium-charcoal (5%). Removal of the catalyst and of
the solvent gave a solid which was crystallised from
(Distribution Schedule 1 cont...)
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ethanol-diethyl ether (1:2 v/v) to give 4-aminobenzoyl alanine; m.p, 198 -
199deg.C.
c) A solution of 0.8 g. 4-aminobenzoyl alanine in 15 ml. 1N hydrochloric
acid was cooled to -5deg.C. and diazotised with 5 ml. of 10% aqueous sodium
nitrite solution for 30 minutes. The reaction mixture was then added to a
solution of 0.7 g, salicylic acid in 15 ml. of water containing 0.8 g.
sodium hydroxide and 0.5 g. sodium carbonate. After 2 hours, the reaction
mixture was acidified and the precipitate obtained was isolated, dissolved
in ethyl acetate and the solution was washed, dried and charcoaled. The
solution was then concentrated and cooled to give 0.9 g. 5-[4-(a-
methylcarboxymethylcarbamoyl)-phenylazo]-salicylic acid: m.p. 252 -
254deg.C.
Example 8
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a) 20 g. Acetylsulphanilyl chloride were added portionwise at 5deg.C.,
with stirring, to a solution of 15 g. 4-aminophenylacetic acid in 10%
aqueous sodium hydroxide solution. The reaction mixture was further stirred
for 4 hours and then added to a mixture of dilute hydrochloric acid and
ice. The precipitate obtained was isolated, taken up in ethyl acetate,
washed with water, dried and evaporated to give 22 g. acetylsulphanilyl-4-
(carboxymethyl)-anilide.
b) 3.5 g. Acetylsulphanilyl-4-(carboxymethyl)anilide in 7 ml. 5N
hydrochloric acid were heated under
(Distribution Schedule 1 cont...)
-15-
reflux for 2 hours, cooled, diluted with 20 ml. ice and water and cooled
to -5deg.C. 8 ml. of 10% aqueous sodium nitrite solution were added
thereto and after 30 minutes the diazotised solution was added to 1.4 g.
salicylic acid in 20 ml. of an aqueous solution of 2 g. sodium hydroxide
and 2 g. sodium carbonate cooled to below 0deg.C. The reaction mixture
was stirred for 2 hours and then added to a mixture of hydrochloric acid
and ice. The precipitate obtained was isolated and dissolved in ethyl
acetate and the solution washed with water, dried and charcoaled. Upon
concentrating the filtered solution and adding an equal volume of diethyl
either to the filtrate, the desired product slowly crystallised out.
There were obtained is 3 g. 5-[4-(4-carboxymethylphenyl)-
sulphamoylphenylazo)salicylic acid; m.p. 252 - 254deg.C.
Example 9.
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a) A solution of 12 g. 6-aminohexanoic acid in 60 ml. of 10% aqueous
sodium hydroxide solution was treated portionwise with 9 g. finely powdered
4-nitrobenzoyl chloride. After 4 hours, the reaction mixture was added to a
mixture of dilute hydrochloric acid and ice. The precipitate obtained was
isolated, washed with water and crystallised from acetone to give 12.6 g.
6-(4-nitrobenzoylamino)-hexanoic acid; m.p. 148 - 150deg.C.
(Distribution Schedule 1 cont...)
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b) A solution of 6 g. 6-(4-nitrobenzoylamino)hexanoic acid in 150 ml.
ethanol was hydrogenated in the presence of 0.5 g. palladium-charcoal (5%)
until the reaction was complete. The catalyst and solvent were removed and
the residue was crystallised from ethanol-diethyl ether (1:1 v/v) to give
4.7 g. 6-(4-aminobenzoylamino)-hexanoic acid; m.p. 132 - 134deg.C.
c) A solution of 2.5 g. 6-(4-aminobenzoylamino). hexanoic acid in 15 ml.
2N hydrochloric acid was cooled to -5deg.C. and treated dropwise, while
stirring, with 8 ml. of a 10% aqueous solution of sodium nitrite. The
reaction mixture was stirred for 30 minutes and then added at -5deg.C. to
salicylic acid in 20 ml. of water containing 2 g. sodium hydroxide and 1 g.
sodium carbonate. After 3 hours, the reaction mixture was acidified and the
precipitate obtained was isolated by centrifuging, dissolved in ethyl
acetate, washed, dried and concentrated to a small volume. Upon cooling,
there were obtained 2.7 g. 5-(4-carboxypentylcarbamoylphenylazo)-salicylic
acid: m.p. 238 -239deg.C.
Example 10.
-----------
a) A solution of 13 g. copper sulphate in 60 ml. water and a solution of
2 g. sodium hydroxide in 30 ml. water were added simultaneously to a
solution of 7.5 g. lysine in 50 ml. water, followed by the addition of 50
ml. of 10% aqueous sodium bicarbonate solution.
(Distribution Schedule 1 cont...)
-17-
The precipitated salt was filtered off and the blue filtrate was added,
with vigorous stirring, to a solution of 7 g. 4-nitrobenzoyl chloride in 50
ml. acetone. The reaction mixture was stirred for 20 hours and the
precipitate obtained was filtered off, washed with water, methanol and
diethyl ether and dried in a vacuum at 50deg.C. to give the copper salt of
E-(4-nitrobenzoyl)-lysine.
b) A suspension of 7 g. of the copper salt of E-(4-nitrobenzoyl)-lysine
in 30 ml. water was stirred with 6 ml. hydrochloric acid until dissolution
was complete. Hydrogen sulphide was passed in for 1 hour and precipitated
copper sulphide then filtered off. The filtrate was evaporated to dryness
and the residue was taken up in 20 ml, methanolic hydrogen chloride and
heated under reflux for 3 hours. The cooled reaction mixture was diluted
with water, rendered alkaline with sodium carbonate and extracted with
ethyl acetate to give 4.8 g. E-(4-nitrobenzoyl)-lysine methyl ester in the
form of a yellow oil.
c) A solution of 1 g. E -(4-nitrobenzoyl)-lysine methyl ester in 2 ml.
methyl iodide and 0.2 ml. acetone was left to stand for 20 hours at ambient
temperature, whereafter the NMR showed the reaction to be complete. The
volatile materials were evaporated off to leave E:-(4-nitrobenzoyl)-a,a-
dimethyllysine methyl ester in the form of an oil.
(Distribution Schedule 1 cont...)
-18-
d) 1 g. E -(4-nitrobenzoyl)-a,a-dimethyllysine methyl ester in 20 ml.
ethanol was hydrogenated in the presence of 0.1 g. palladium-charcoal (5%)
until the absorption of hydrogen had ceased. The catalyst was filtered off
and the filtrate evaporated to dry-ness. The residue was taken up in 5 ml.
2N hydrochloric acid, cooled to -5deg.C. and treated with 2.5 ml. of 10%
aqueous sodium nitrite solution. After standing for 30 minutes, the clear
solution was added at -5deg.C. to a solution of 0.5 g. salicylic acid in 20
ml. of a 1N aqueous sodium hydroxide solution. After subsequently standing
for 3 hours at 20deg.C., the reaction mixture was acidified and extracted
with diethyl ether to remove unreacted salicylic acid. The aqueous phase
was adjusted to pH 7 by adding IN aqueous sodium hydroxide solution and the
resulting solution was evaporated to dryness. The residue was further dried
by adding toluene and subsequently evaporating it and the residue then
extracted with methanol. The methanolic solution was concentrated to a
small volume. After adding diethyl ether and cooling, the disodium salt of
5-[4-(a-dimethylaminocarboxypentylcarbamoyl)-phenylazo]-salicylic acid
separated out; m.p. (greater than) 210deg.C. (decomp.).
Example 11.
-----------
a) A solution of 30 ml. N,N-diethylethylenediamine in 100 ml. water was
treated portionwise. while
(Distribution Schedule 1 cont...)
-19-
stirring, with 15 g. finely powdered 4-nitrobenzoyl chloride. The reaction
mixture was stirred for 20 hours and the precipitate obtained was filtered
off, washed with water and aqueous sodium carbonate solution and
crystallised from petroleum ether-diethyl ether (1:1 v/v) to give 6 g. N,N-
diethyl-N'-(4-nitrobenzoyl)-ethylenediamine; m.p. 49 - 51deg.C.
b) A solution of 5 g. N,N-diethyl-N'-(4-nitrobenzoyl)-ethylenediamine in
40 ml. ethanol was hydrogenated in the presence of 0.3 g. palladium-
charcoal (5%) until the reaction was complete. The catalyst and solvent
were removed to give 5 g. N,N-diethyl-N-(4-aminobenzoyl)-ethylenediamine in
the form of an oil.
c) A solution of 2.35 g, N,N-diethyl-N'-(4-aminobenzoyl)-ethylenediamine
in 20 ml, 2N hydrochloric acid was cooled to -5deg.C. and treated with 8
ml. of a 10% aqueous solution of sodium nitrite. The reaction mixture was
stirred for 30 minutes and added to 1.4 g. salicylic acid in a solution of
1.6 g. sodium hydroxide and 2 g. sodium carbonate in 20 ml. water. After 3
hours at 0 to 20deg.C., sodium chloride was added to the reaction mixture
to salt out the desired diazo compound. This was filtered off, washed with
water and hot methanol and dried to give 2.3 g. 5-(4-
diethylaminoethylcarbamoylphenylazo)-salicylic acid; m.p. 252 - 254deg.C.
(decomp.).
The pharmaceutical compositions according to the present invention
contain at least one of the compounds
(Distribution Schedule 1 cont...)
-20-
(I) in admixture with a solid or liquid pharmaceutical carrier.
Solid compositions for oral administration include compressed tablets,
pills, dispersible powders and granules. In such solid compositions, one of
the compounds (I) is admixed with at least one inert diluent, such as
calcium carbonate, starch, alginic acid or lactose. The compositions may
also comprise, as is normal practice, additional substances other than
inert diluents, for example, lubricating agents, such as magnesium
stearate,
Liquid compositions for oral administration include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups and elixirs containing
inert diluents commonly used in the art, such as water and liquid paraffin.
Besides inert diluents, such compositions may also comprise adjuvants, such
as wetting and suspension agents, and sweetening and flavouring agents.
The compositions according to the present invention for oral
administration, include capsules of absorbable material, such as gelatine,
containing at least one of the compounds (I), with or without the addition
of diluents or excipients.
The percentage of active material in tire compositions of the present
invention may be varied, it being necessary that it should constitute a
proportion such that a suitable dosage for the desired therapeutic
(Distribution Schedule 1 cont...)
-21-
effect shall be obtained. In general, the preparations of the present
invention should be administered orally or parenterally to humans to give
500 to 5000 mg. and preferably 500 to 2000 mg. of active substance per day.
The following Examples illustrate pharmaceutical compositions
according to the present invention:
Example 12.
-----------
600 mg, tablets are prepared containing:
disodium salt of 5-(4-carboxyethyl-
carbamoylphenylazo)-salicylic acid 500 mg.
starch 50 mg.
lactose 45 mg.
magnesium stearate 5 mg.
Example 13.
-----------
450 mg. tablets are prepared containing:
disodium salt of 5-(4-carboxymethyl-
carbamoylphenylazo)-salicylic acid 250 mg.
starch 100 mg.
lactose 95 mg.
magnesium stearate 5 mg.
The tablets according to Examples 12 and 13 are intended for
administration to humans for the treatment of ulcerative Colitis.
An attempt was made to establish an acute oral toxicity profile for
the disodium salts of 5-(4-carboxymethylcarbamoylphenylazo)-salicylic acid
and of 5-(4-carboxyethylcarbamoylphenylazo)-salicylic
(Distribution Schedule 1 cont...)
-22-
acid, using rats and mice as experimental animals but this was not possible
due to their low toxicity. No deaths were observed with the carboxymethyi
compound when administered to mice at a dosage of 3 g./kg. and to rats at a
dosage of 2 g./kg. and no deaths were observed with the carboxy--ethyl
compound when administered to mice at a dosage of 4 g. /kg. and to rats at
a dosage of 2 g./kg.
Experiments have also been carried out on groups of 6 male Wistar rats
in order to ascertain whether the new compounds according to the present
invention split in the same manner as sulphasalazine to liberate 5-
aminosalicylic acid (5-ASA). The test compounds were administered in an
amount of 45 to 50 mg./kg. The results obtained are set out in the
following Table:-
test compound % of dose measured as 5-ASA
-------------------------------------------------------------
faeces urine total
-------------------------------------------------------------------------------------------------------
sulphasalazine 26 (plus/minus) 4 17 (plus/minus) 2 43 (plus/minus) 4
=======================================================================================================
Example 1 24 (plus/minus) 3 19 (plus/minus) 3 43 (plus/minus) 3
Example 2 17 (plus/minus) 3 17 (plus/minus) 6 34 (plus/minus) 5
Example 4 22 (plus/minus) 2 14 (plus/minus) 2 36 (plus/minus) 3
Example 5 26 (plus/minus) 3 15 (plus/minus) 2 41 (plus/minus) 5
Example 6 22 (plus/minus) 2 19 (plus/minus) 3 41 (plus/minus) 4
(Distribution Schedule 1 cont...)
-23-
The above results clearly demonstrate that the new compounds of the
present invention split in the same manner as sulphasalazine and can be
expected to exert at least as beneficial an effect as sulphasalazine but
without the disadvantage of giving rise to other compounds which exert
undesirable side effects, such as the sulphapyridine formed from
sulphasalazine.
(Distribution Schedule 1 cont...)
-24-
Patent Claims
-------------
1. 2-Hydroxy-5-phenylazobenzoic acid derivatives of the general formula:-
[FORMULA OMITTED]
5 wherein X is an -SO2- or -Co- group and R is either a non-heterocyclic
aromatic ring system optionally substituted by a radical of the general
formula -(CH\\2\\)\\n\\-Y or is a radical of the general formula -
(CH\\2\\)\\n\\-Y, in which Y is a hydroxyl group, an unsubstituted or
10 substituted amino group or a carboxylic or sulphonic acid group and n is a
-
whole number of from 1 to 6 and in which one or more of the hydrogen atoms
in the alkylene radical can be replaced by unsubstituted or substituted
15 amino groups or alkyl radicals, with the proviso that R-NH-X- is other than
a -CO-NH-CH\\2\\-COOH radical; and the esters and non-toxic,
pharmacologically acceptable salts thereof.
2. 5-(4-Phenylsulphamoylphenylazo)-salicylic acid and the sodium salt
thereof.
20 3. Disodium salt of 5-(4-carboxymethylcarbamoylphenylazo)-salicylic acid.
4. 5-(4-Carboxyethylcarbamoylphenylazo)-salicylic acid and the disodium
salt thereof.
(Distribution Schedule 1 cont...)
-25-
5. 5-(4-Sulphoethylcarbamoylphenylazo)-salicylic acid.
6. 5-(4-Hydroxyethylcarbamoylphenylazo)-salicylic acid and the sodium
salt thereof.
5 7. 5-[(a-Methylcarboxymethylcarbamoyl)-phenylazo]-alicylic acid.
8. 5-[ 4- (4-Carboxymethylphenyl)-sulphamoylphenylazo]-salicylic acid.
10 9. 5-(4-Carboxypentylcarbamoylphenylazo)-salicylic acid.
10. 5-[-(a-Dimethylaminocarboxypentylcarbamoyl)-phenylazo]-salicylic acid
and the disodium salt thereof.
l1. 5-(4-Diethylaminoethylcarbamoylphenylazo)-salicylic acid.
15 12. A pharmaceutical composition containing at least one compound of the
general formula:
[GRAPHICS APPEARS HERE]
wherein X is an -SO2- or -CO- group and R is either a non-heterocylic ring
system optionally substituted by a radical of the general formula -
20 (CH\\2\\)\\n\\-Y-in or is a radical of the general formula -(CH\\2\\)\\n\\-
Y, in which Y is a hydroxyl group, an unsubstituted or substituted amino
group or a carboxylic or sulphonic acid group and n is a whole number of
-
from 1 to 6 and
(Distribution Schedule 1 cont...)
-26-
in which one or more hydrogen atoms in the alkylene radical can be replaced
by unsubstituted or substituted amino groups or alkyl radicals, and/or
containing at least one ester thereof and/or at least one non-toxic,
5 pharmaceutically acceptable salt thereof, in admixture with a solid or
liquid pharmaceutical diluent or carrier.
13. Pharmaceutical compositions according to claim 12, substantially as
10 hereinbefore described and exemplified.
14. Process for the preparation of compounds of the general formula given
in claim 12, wherein an amine of the general formula:-
[FORMULA OMITTED]
15 in which R and X have the same meanings as above, is diazotised and coupled
with salicylic acid, whereafter, if desired, the compound obtained is
salified with a non-toxic inorganic or organic base.
15. Process for the preparation of compounds of the general formula given
20 in claim 12 and of the salts thereof, substantially as hereinbefore
described and exemplified.
16. Compounds of the general formula given in claim 12, whenever prepared
25 by the process according to claim 14 or 15.
-29-
SCHEDULE 2
----------
TERMS AND CONDITIONS APPLICABLE TO THE
--------------------------------------
MANUFACTURING LICENCE UNDER CLAUSE 13.2
---------------------------------------
1. With effect from the effective date of notice served by Astra under and in
accordance with Clause 13.2 of the Agreement (and Clause 6.6.3 of the
Research Agreement) Glycyx shall grant Astra a licence to manufacture the
Product in the Territory for sale in the Territory only under the terms of
the Agreement and this Schedule 2.
2. For the avoidance of doubt Glycyx shall not be prevented from manufacturing
or continuing to manufacture the Product or appointing sub-contractors to
manufacture the Product for sale by Glycyx or its customers both inside and
outside the Territory subject to the exclusivity granted to Astra in
respect of the Territory under the terms of the Agreement.
3. Glycyx shall supply Astra with such technical information and assistance as
Astra may reasonably require (and which has not previously been supplied to
Astra pursuant to Clause 13.4) to enable Astra to produce the Product in
commercial quantities Provided Always That Glycyx shall be reimbursed all
costs and expenses incurred by it in supplying such information and
assistance to Astra.
4. Astra undertakes to Glycyx that it will manufacture the Product fully in
accordance with the Bulk Product Specification and the Finished Product
Specification (annexed to the Agreement in the approved form) and with the
Drug Master File for the Product and in accordance with European Community
Good Manufacturing Practice.
5. Astra shall be entitled to market, distribute and sell the Product
manufactured by it only in accordance with the terms and provisions of the
Agreement.
6. In consideration of the licence to manufacture Astra shall pay to Glycyx a
fee calculated as a percentage of the Factory Sales Price of all Product
manufactured by or on behalf of Astra pursuant to this licence and sold by
Astra or any Astra Associate such percentage to be:
6.1 [*]
6.2 [*]
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
-30-
6.3 [*]
6.3.1 [*] Provided Always that
6.3.2 in the event that the [*]
6.3.3 the actual cost of manufacture of the Product incurred by Astra
shall be calculated upon the expiry of 12 months from the date of
service of notice under Clause 13.2 (and fees shall be payable
during such 12 month period on an estimate and shall be adjusted
retrospectively upon such calculation) by Astra which shall produce
to Glycyx full details of all actual direct costs of manufacture
(being materials labour and direct manufacturing overhead and
interest) and its calculation of the average actual cost per
kilogram of Product incurred in such 12 month period and upon
agreement by Glycyx of such actual cost, it shall remain fixed
thereafter for the period in which fees under this Clause 6 shall
remain payable.
6.4 [*]
6.5 [*]
7. Astra shall be solely liable for all losses, damages, costs and expenses
arising out of any claim by any third party in connection with any Product
manufactured by Astra and Astra hereby agrees fully and effectively to
indemnify Glycyx against any claims, damages, costs, expenses, or other
losses incurred by Glycyx arising out of or in connection with any Product
manufactured by ▇▇▇▇▇,
▇. The licence to manufacture granted hereunder shall continue
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
-31-
for such period in which Astra may wish to manufacture the Product provided
always that such licence shall terminate in the event of termination of the
Agreement by Glycyx under the provisions of Clause 20.2.
9. In the event that Astra decides to have the Product manufactured by a sub-
contractor Astra may appoint such sub-contractor provided that Astra shall
ensure that the sub-contractor shall perform in accordance with this
Agreement and Astra shall remain liable for the acts of its sub-contractor
so appointed.
-32-
SCHEDULE 3
----------
"Bulk Product Specifications"
and
"Finished Product Specifications"
BALSALAZIDE SODIUM
------------------
Specification - "IN-HOUSE"
--------------------------
[*]
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
-33-
BALSALAZIDE SODIUM
------------------
Specification - "PL Submission"
--------------------------------
[*]
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
-34-
COLAZIDETM CAPSULES
-------------------
1. GENERAL CHARACTERISTICS
-----------------------
Red/maroon, hard gelatin lock-fit capsule shells, size 00, containing a dry
orange/yellow powder.
2. FINISHED PRODUCT SPECIFICATION
------------------------------
[*]
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
-35-
SCHEDULE 4
-----------
MANUFACTURING AGREEMENT
-----------------------
TECHNICAL ARRANGEMENTS
between
ASTRA PHARMACEUTICAL PRODUCTION AB a Company incorporated under the laws of
Sweden whose principal place of business is at ▇-▇▇▇ ▇▇ ▇▇▇▇▇▇▇▇▇▇, ▇▇▇▇▇▇
hereinafter called ASTRA
and
GLYCYX PHARMACEUTICALS LTD a Company incorporated under the laws of Bermuda
whose registered office is at ▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇ ▇▇▇▇▇▇▇ hereinafter
called GLYCYX
WHEREBY it is agreed as follows:-
Supply of Product
-----------------
1. GLYCYX will supply the Product specified in the Schedule to this agreement
("the Product") to ASTRA upon the terms and conditions of this agreement
and otherwise as agreed between the parties.
2. GLYCYX will use its site(s) at [ ] for
manufacturing and control activities of the Product.
Quality of manufacturing materials used by GLYCYX
-------------------------------------------------
3. GLYCYX shall obtain the manufacturing materials specified in Schedule 2.
4. GLYCYX is solely responsible for ensuring that each batch of manufacturing
material used by GLYCYX has been examined and complies with the
specifications in Schedule 2.
GMP standard
------------
5. All manufacture and quality control operations of GLYCYX shall be carried
out according to the current Basic Standard of Good Manufacturing Practice
for Pharmaceutical Products - including supplementary recommendations -
adopted by the Pharmaceutical Inspection Convention (PIC) and issued by the
EFTA Secretariat, Geneva.
Changes in quality standards, formula, manufacturing and quality control
------------------------------------------------------------------------
procedures
----------
6. The procedures of manufacture and quality control shall be as agreed by the
parties and any change in such procedures shall be agreed upon by both
parties in writing.
-36-
7. GLYCYX may not sub-contract any manufacturing or quality control operations
to any Glycyx site other than that specified in Clause 2 or sub-contractor
without prior notice in writing to ASTRA and providing such period of
notice is reasonably required by ASTRA for ASTRA to meet Drug Regulatory
requirements.
Responsibility for release of product manufactured by GLYCYX
---------------------------------------------------------------
8. GLYCYX shall only release batches of Product for shipment to ASTRA which
have been examined and comply with the specifications in Schedule 5
Provided Always that ASTRA shall be solely responsible for the final
approval of batches of Product manufactured by GLYCYX.
Storage
-------
9. GLYCYX shall store all manufacturing materials and Products in accordance
with GMP recommendations and the storage conditions prescribed therein [and
agreed between the parties].
Documentation
-------------
10. GLYCYX shall keep:-
10.1 reference samples (solvents excluded) and quality control records for
each batch of manufacturing material used by GLYCYX; and
10.2 manufacturing and quality control records for each batch of the
Product manufactured for ASTRA by GLYCYX
for a period of six years from the date of manufacture or such longer
period as may be agreed upon in writing between ASTRA and GLYCYX.
11. Each shipment of the Products from GLYCYX to ASTRA shall be accompanied by
a certificate of analysis with the following information:-
11.1 the results of such tests as may by agreement of the parties be
carried out by GLYCYX; and
11.2 a statement by GLYCYX that the batch of Products has been released
for shipment to ASTRA in accordance with the following criteria:-
11.2.1 all manufacturing materials used in the manufacture of the
Products have complied with the specification in Schedule 2;
and
11.2.2 all manufacture and quality control operations by GLYCYX have
been carried out according to current GMP, manufacturing, in
process control and testing procedures, as
-37-
well as Standard Operating Procedures in the form agreed
between the parties.
11.3 the manufacturing date.
12. GLYCYX agrees to submit to ASTRA upon receipt of any request therefor from
Astra:-
12.1 copies of all manufacturing and quality control records of any batch
of the Products manufactured by GLYCYX; and
12.2 copies of the quality control records of any batch of manufacturing
materials used by GLYCYX.
Quality Audit
-------------
13. During normal working hours and upon reasonable notice ASTRA shall be
entitled to inspect the manufacturing and quality control areas at GLYCYX's
site.
14. During quality audits by ASTRA and upon request, GLYCYX shall inform ASTRA
of the outcome of inspections by the National Drug Inspectorate of GLYCYX's
site.
15. GLYCYX shall supply ASTRA with all relevant information reasonably required
for the investigation of any complaints concerning the quality of the
Products.
Post production product inspection
---------------------------------
16. ASTRA is solely responsible for all post production inspection of the
Product.
Contact persons
---------------
17. Contact persons in matters relating to manufacture and quality control
under the terms of this Agreement are:-
- on behalf of ASTRA
Folke Ljungner
Senior Manager, Quality Assurance Tablets
Astra Pharmaceutical Production AB
▇-▇▇▇ ▇▇ ▇▇▇▇▇▇▇▇▇▇, ▇▇▇▇▇▇
phone: +46-8-553 27072
fax: +46-8-553 28857
- on behalf of GLYCYX
Date: Date:
ASTRA PHARMACEUTICAL PRODUCTION AB GLYCYX
-----------------------------------------
-38-
APPENDIX 1
----------
Products to be Manufactured by GLYCYX and supplied to ASTRA
-----------------------------------------------------------
PRODUCT SPECIFICATION NO.
------- -----------------
Date: Date:
ASTRA PHARMACEUTICAL PRODUCTION AB GLYCYX
----------------------------------- -----------------------------------
-39-
APPENDIX 2
-----------
Manufacturing materials to be supplied by GLYCYX
------------------------------------------------
NAME SPECIFICATION NO.
---- -----------------
Date: Date:
ASTRA PHARMACEUTICAL PRODUCTION AB GLYCYX
----------------------------------- ----------------------------------
-40-
SIGNED by )
for and on behalf of GLYCYX ) /s/ ▇▇▇▇▇ ▇▇▇▇▇▇▇▇
PHARMACEUTICALS LTD in the presence)
of:-
/s/ ▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇
SIGNED by ) /s/ ▇▇▇▇▇ ▇▇▇▇▇▇
for and on behalf of AB ASTRA in )
the presence of:- )
/s/ ▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇
▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇▇ President and
Legal Counsel Group Chief Executive Officer
